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- #218040 - COSTELLO SYNDROME; CSTLO
- OMIM
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<span class="h4">#218040</span>
<br />
<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/218040"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#otherFeatures">Other Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#diagnosis">Diagnosis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#clinicalManagement">Clinical Management</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=COSTELLO SYNDROME" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=218040[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3071" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/fe33a2d6-0651-4ef2-a321-2923a423a7e7/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0050469" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/218040" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0050469" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 309776008<br />
<strong>ORPHA:</strong> 3071<br />
<strong>DO:</strong> 0050469<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
218040
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
COSTELLO SYNDROME; CSTLO
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
FACIOCUTANEOSKELETAL SYNDROME<br />
FCS SYNDROME
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES, INCLUDED; CMEMS, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/29?start=-3&limit=10&highlight=29">
11p15.5
</a>
</span>
</td>
<td>
<span class="mim-font">
Costello syndrome
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/218040"> 218040 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
HRAS
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/190020"> 190020 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/29?start=-3&limit=10&highlight=29">
11p15.5
</a>
</span>
</td>
<td>
<span class="mim-font">
Congenital myopathy with excess of muscle spindles
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/218040"> 218040 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
HRAS
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/190020"> 190020 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/218040" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/218040" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/218040" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Height </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Increased birth length <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748450&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748450</a>]</span><br /> -
Short stature <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422065006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422065006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237836003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237836003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237837007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237837007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E34.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E34.31</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R62.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R62.52</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.43" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.43</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349588&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349588</a>, <a href="https://bioportal.bioontology.org/search?q=C0013336&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013336</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003510</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Weight </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Increased birth weight <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748451&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748451</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Fetal overgrowth <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839271&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839271</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003517" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003517</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003517" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003517</a>]</span><br /> -
Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br /> -
Postnatal onset growth deficiency <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857534&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857534</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Head </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Macrocephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12138000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12138000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1145403003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1145403003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q75.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q75.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221355&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221355</a>, <a href="https://bioportal.bioontology.org/search?q=C2243051&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2243051</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000256</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001355" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001355</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000256</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=dd989bb153739761147ef05dc870b050" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Macrocephaly-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=dd989bb153739761147ef05dc870b050&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Large anterior fontanel <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866134</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000260</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000260</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Coarse facies <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845847&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845847</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000280</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000280</a>]</span><br /> -
Full cheeks <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866231&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866231</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000293" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000293</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000293" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000293</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=85459d10e5df48479ec4a2ec6cfc0455" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Cheeks,Full-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=85459d10e5df48479ec4a2ec6cfc0455&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Micrognathia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32958008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32958008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M26.04" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M26.04</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/524.04" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">524.04</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0025990&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025990</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000347</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000347</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=9149eccae19753e96defbd69602ab882" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Micrognathia-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=9149eccae19753e96defbd69602ab882&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Pointed chin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844505&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844505</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000307" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000307</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000307" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000307</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=7974ac288cfc8dbf20fe3f16a7844d32" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Chin,Pointed-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=7974ac288cfc8dbf20fe3f16a7844d32&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Low-set ears <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95515009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95515009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q17.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q17.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239234&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239234</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000369" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000369</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000369" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000369</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=9f0956aaa4fd45c34f94336afbbdc931" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Ear,Low-Set-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=9f0956aaa4fd45c34f94336afbbdc931&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Thickened lobes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857535&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857535</a>]</span><br /> -
Posteriorly rotated ears <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253251006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253251006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0431478&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0431478</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000358" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000358</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000358" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000358</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypertelorism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22006008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22006008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q75.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q75.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/376.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">376.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020534&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020534</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000316" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000316</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000316" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000316</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=593a4d488f00bb03351a0ddffaf4ac9a" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Eyes,Widely_Spaced-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=593a4d488f00bb03351a0ddffaf4ac9a&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Epicanthal folds <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74824007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74824007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0678230&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0678230</a>, <a href="https://bioportal.bioontology.org/search?q=C0229249&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0229249</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000286</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000286</a>]</span><br /> -
Downslanting palpebral fissures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246800008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246800008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423110&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423110</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000494" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000494</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000494" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000494</a>]</span><br /> -
Strabismus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22066006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22066006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.40</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038379&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038379</a>, <a href="https://bioportal.bioontology.org/search?q=C2020541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2020541</a>, <a href="https://bioportal.bioontology.org/search?q=C1423541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1423541</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000486" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000486</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000486" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000486</a>]</span><br /> -
Ptosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11934000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11934000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/29696001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">29696001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.409" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.409</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.40</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/374.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.3</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/374.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.30</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0005745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005745</a>, <a href="https://bioportal.bioontology.org/search?q=C0033377&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033377</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000508</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=76abf29563d4adc64d21da86221224b1" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Ptosis-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=76abf29563d4adc64d21da86221224b1&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Nose </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Depressed nasal bridge <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836542&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836542</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005280</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005280</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=7043769fd21a78a413fd758918cdda17" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Nasal_Bridge,Depressed-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=7043769fd21a78a413fd758918cdda17&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Anteverted nostrils <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/708670007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">708670007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1840077&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1840077</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000463" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000463</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000463" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000463</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Mouth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Thick lips <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836543&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836543</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012471" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012471</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012471" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012471</a>]</span><br /> -
Macroglossia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25273001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25273001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/270516002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">270516002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K14.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K14.8</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q38.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q38.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/750.15" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">750.15</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0024421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024421</a>, <a href="https://bioportal.bioontology.org/search?q=C0009677&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009677</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000158" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000158</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000158" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000158</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=ac5acf24e74116d49a4df85084887155" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Tongue,Large-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=ac5acf24e74116d49a4df85084887155&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
High-arched palate <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/27272007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">27272007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q38.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q38.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240635&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240635</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000218</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000218</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Teeth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Defective enamel formation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4011989&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4011989</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Neck </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Short neck <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95427009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95427009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0521525&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0521525</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000470" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000470</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000470" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000470</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=5edf45ce6835f32360d28d26249e2531" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Neck,Short-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=5edf45ce6835f32360d28d26249e2531&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Webbed neck <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11731003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11731003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q18.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q18.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/744.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">744.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221217&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221217</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000465" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000465</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000465" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000465</a>]</span><br /> -
Loose, redundant neck skin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857536&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857536</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypertrophic cardiomyopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/195020003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">195020003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/233873004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">233873004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45227007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45227007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I42.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I42.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I42.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I42.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/425.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">425.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/425.11" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">425.11</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551472&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551472</a>, <a href="https://bioportal.bioontology.org/search?q=C0340425&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0340425</a>, <a href="https://bioportal.bioontology.org/search?q=C0007194&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007194</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001639</a>]</span><br /> -
Pulmonic stenosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56786000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56786000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1956257&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1956257</a>, <a href="https://bioportal.bioontology.org/search?q=C0034089&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034089</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001642" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001642</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001642" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001642</a>]</span><br /> -
Mitral valve prolapse <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409712001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409712001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8074002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8074002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026267&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026267</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001634" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001634</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001634" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001634</a>]</span><br /> -
Ventricular septal defect <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30288003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30288003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253549006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253549006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/768552007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">768552007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q21.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q21.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/745.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">745.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018818&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018818</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001629" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001629</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001629" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001629</a>]</span><br /> -
Atrial septal defect <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253366007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253366007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405752007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405752007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/70142008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">70142008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q21.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q21.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q21.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q21.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018817&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018817</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001631" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001631</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001631" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001631</a>]</span><br /> -
Dysrhythmias <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/698247007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">698247007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I49.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I49.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/427.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/427" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003811&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003811</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011675" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011675</a>]</span><br /> -
Arrhythmias <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/698247007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">698247007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I49.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I49.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/427.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/427" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003811&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003811</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011675" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011675</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011675" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011675</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Obstructive sleep apnea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78275009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78275009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G47.33" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G47.33</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/327.23" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">327.23</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0520679&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0520679</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002870" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002870</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002870" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002870</a>]</span><br />
</span>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Airways </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Tracheomalacia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95434006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95434006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0948187&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0948187</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002779" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002779</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002779" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002779</a>]</span><br /> -
Bronchomalacia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54203008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54203008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/233788001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">233788001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0264353&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0264353</a>, <a href="https://bioportal.bioontology.org/search?q=C0340231&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0340231</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002780" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002780</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002786" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002786</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002780" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002780</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Lung </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pneumothorax, recurrent <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0747708&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0747708</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36118008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36118008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J93.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J93.9</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002107</a>]</span><br /> -
Lymphangiectasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48087001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48087001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I89.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I89.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0024214&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024214</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031842" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031842</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031842" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031842</a>]</span><br /> -
Alveolar/capillary dysplasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/708028001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">708028001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2677362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2677362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033208" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033208</a>]</span><br /> -
Small lungs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80825009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80825009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0265783&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265783</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002089" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002089</a>]</span><br /> -
Respiratory failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409622000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409622000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J96.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J96.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1145670&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1145670</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002878" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002878</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002878" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002878</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CHEST </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Features </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Barrel chest <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/24228002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">24228002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0264172&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0264172</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001552" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001552</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001552" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001552</a>]</span><br /> -
Pectus carinatum <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/205101001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">205101001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38774000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38774000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/754.82" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.82</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2939416&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2939416</a>, <a href="https://bioportal.bioontology.org/search?q=C0158731&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0158731</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000768" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000768</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000768" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000768</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Poor suck in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857549&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857549</a>]</span><br /> -
Pyloric stenosis, hypertrophic <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48644003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48644003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q40.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q40.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/750.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">750.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700639&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700639</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002021" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002021</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Dilated calyces (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2749702&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2749702</a>]</span><br /> -
Echogenic kidneys with thick-walled pelvises (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3150280&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3150280</a>]</span><br /> -
Renal failure (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42399005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42399005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N19</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/586" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">586</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0035078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035078</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Limbs </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Restricted elbow motion <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849955&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849955</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002996" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002996</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002996" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002996</a>]</span><br /> -
Tight Achilles tendon <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/203076007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">203076007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0410264&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0410264</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001771" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001771</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001771" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001771</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hands </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Deep palmar creases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857539&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857539</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006191" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006191</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006191" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006191</a>]</span><br /> -
Hyperextensible finger <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844577&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844577</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001187" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001187</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001187" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001187</a>]</span><br /> -
Wide distal phalanges <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857541</a>]</span><br /> -
Palmar nevi <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857542&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857542</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Feet </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Deep plantar creases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857953&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857953</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001869" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001869</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001869" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001869</a>]</span><br /> -
Clubfeet <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397932003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397932003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1156475005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1156475005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q66.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q66.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q66.89" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q66.89</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/754.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009081&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009081</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001762" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001762</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001762" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001762</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cutis laxa (especially hands and feet) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857543&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857543</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/58588007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">58588007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q82.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q82.8</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000973" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000973</a>]</span><br /> -
Loose, redundant skin <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/201093004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">201093004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0581342&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0581342</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001582" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001582</a>]</span><br /> -
Dark skin pigmentation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857544</a>]</span><br /> -
Papillomas (perioral, nasal, and anal regions) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857545&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857545</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/711329002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">711329002</a>]</span><br /> -
Acanthosis nigricans <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/402599005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">402599005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/72129000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">72129000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L83</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0000889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0000889</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000956" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000956</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000956" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000956</a>]</span><br /> -
Palmar nevi <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857542&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857542</a>]</span><br /> -
Deep palmar creases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857539&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857539</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006191" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006191</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006191" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006191</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Nails </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Thin, deep-set nails <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848516&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848516</a>]</span><br /> -
Koilonychia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/66270006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">66270006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221261&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221261</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001598" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001598</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001598" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001598</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=228be9f2e482f666464932400bf48c1b" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/NYexcgDAWT8VDQxKubFUEm52xxy4caTK-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=228be9f2e482f666464932400bf48c1b&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Brittle nails <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/69192004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">69192004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0546956&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0546956</a>, <a href="https://bioportal.bioontology.org/search?q=C5779504&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5779504</a>, <a href="https://bioportal.bioontology.org/search?q=C1856963&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1856963</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030804" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030804</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001808</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001808</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hair </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Curly hair <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/225570000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">225570000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0558165&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0558165</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002212" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002212</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002212" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002212</a>]</span><br /> -
Sparse hair <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1162675003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1162675003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5551005&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5551005</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008070" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008070</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008070" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008070</a>]</span><br /> -
Thin anterior head hair <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857547&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857547</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Delayed psychomotor development <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
Sleep disorder <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39898005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39898005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G47" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G47</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G47.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G47.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0851578&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0851578</a>]</span><br /> -
Mental retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a>, <a href="https://bioportal.bioontology.org/search?q=C0025362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
Cerebral atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/278849000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">278849000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235946&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235946</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span><br /> -
Ventriculomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413808003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413808003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1531647&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1531647</a>, <a href="https://bioportal.bioontology.org/search?q=C3278923&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278923</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002119" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002119</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002119" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002119</a>]</span><br /> -
Hydrocephalus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230745008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230745008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G91</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G91.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020255&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020255</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000238" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000238</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000238" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000238</a>]</span><br /> -
Posterior fossa crowding, progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278023&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278023</a>]</span><br /> -
Enlarged cerebellum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278024&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278024</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012081" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012081</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012081" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012081</a>]</span><br /> -
Cerebellar tonsillar herniation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278025&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278025</a>]</span><br /> -
Chiari I malformation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253185002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253185002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0750929&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0750929</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007099" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007099</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007099" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007099</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> VOICE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Hoarse voice <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/50219008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">50219008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R49.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R49.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019825&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019825</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001609" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001609</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001609" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001609</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEOPLASIA </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Epithelioma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1187225007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1187225007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1187425009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1187425009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/118285006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">118285006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/722688002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">722688002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/71298006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">71298006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0553707&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0553707</a>, <a href="https://bioportal.bioontology.org/search?q=C1368683&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1368683</a>, <a href="https://bioportal.bioontology.org/search?q=C0007097&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007097</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031492" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031492</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0030731" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030731</a>]</span><br /> -
Bladder carcinoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/255108000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">255108000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0699885&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0699885</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002862" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002862</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002862" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002862</a>]</span><br /> -
Rhabdomyosarcoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30924005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30924005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302847003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302847003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0035412&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035412</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002859" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002859</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002859" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002859</a>]</span><br /> -
Vestibular schwannoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/126949007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">126949007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027859&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027859</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009588" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009588</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009588" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009588</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> PRENATAL MANIFESTATIONS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Amniotic Fluid </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Polyhydramnios <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86203003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86203003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/O40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">O40</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/657.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">657.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/657" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">657</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020224&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020224</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001561" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001561</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001561" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001561</a>]</span><br />
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- Preterm delivery <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/282020008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">282020008</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/644.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">644.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151526&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151526</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001622" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001622</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001622" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001622</a>]</span><br />
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<strong> LABORATORY ABNORMALITIES </strong>
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- Hypoglycemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237630007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237630007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271327008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271327008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302866003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302866003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1179458001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1179458001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E16.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E16.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/251.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">251.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020615&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020615</a>, <a href="https://bioportal.bioontology.org/search?q=C5767385&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5767385</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001943</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001943</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- De novo mutation in most cases<br /> -
Characteristic facial features become more apparent with age<br /> -
Associated with advanced paternal age<br /> -
Sudden death <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26636000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26636000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011071&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011071</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001699" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001699</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001699" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001699</a>]</span><br /> -
Phenotypic overlap with Noonan syndrome 3 (<a href="/entry/609942">609942</a>) or cardiofaciocutaneous syndrome (<a href="/entry/115150">115150</a>)<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the V-Ha-RAS Harvey rat sarcoma viral oncogene homolog gene (HRAS, <a href="/entry/190020#0001">190020.0001</a>)<br />
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<p>A number sign (#) is used with this entry because of evidence that Costello syndrome (CSTLO) is caused by heterozygous mutation in the HRAS gene (<a href="/entry/190020">190020</a>) on chromosome 11p15. A variant of Costello syndrome, congenital myopathy with excess of muscle spindles, is also caused by mutation in HRAS.</p>
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<strong>Description</strong>
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<p>Costello syndrome is a rare multiple congenital anomaly syndrome associated in all cases with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and developmental disability. Facial warts, particularly nasolabial, are often present in childhood (<a href="#45" class="mim-tip-reference" title="Kerr, B., Delrue, M.-A., Sigaudy, S., Perveen, R., Marche, M., Burgelin, I., Stef, M., Tang, B., Eden, O. B., O&#x27;Sullivan, J., De Sandre-Giovannoli, A., Reardon, W., and 14 others. &lt;strong&gt;Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.&lt;/strong&gt; J. Med. Genet. 43: 401-405, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16443854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16443854&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2005.040352&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16443854">Kerr et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16443854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<div class="mim-changed mim-change"><p>Costello syndrome shows phenotypic overlap with cardiofaciocutaneous syndrome (CFC; <a href="/entry/115150">115150</a>) and Noonan syndrome (see <a href="/entry/163950">163950</a>).</p></div>
<p>In patients with a clinical diagnosis of Costello syndrome, <a href="#90" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. &lt;strong&gt;Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.&lt;/strong&gt; J. Med. Genet. 44: 131-135, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17056636/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17056636&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2006.046300&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17056636">Zenker et al. (2007)</a> identified mutations in the KRAS gene, but noted that these patients may later develop features of CFC syndrome. In either case, the findings underscore the central role of Ras in the pathogenesis of these phenotypically related disorders (<a href="#90" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. &lt;strong&gt;Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.&lt;/strong&gt; J. Med. Genet. 44: 131-135, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17056636/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17056636&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2006.046300&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17056636">Zenker et al., 2007</a>). However, <a href="#44" class="mim-tip-reference" title="Kerr, B., Allanson, J., Delrue, M. A., Gripp, K. W., Lacombe, D., Lin, A. E., Rauen, K. A. &lt;strong&gt;The diagnosis of Costello syndrome: nomenclature in Ras/MAPK pathway disorders. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 146A: 1218-1220, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18386799/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18386799&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32273&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18386799">Kerr et al. (2008)</a> commented that the diagnosis of Costello syndrome should only be used to refer to patients with mutations in the HRAS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18386799+17056636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Clinical Features</strong>
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<p><a href="#8" class="mim-tip-reference" title="Costello, J. M. &lt;strong&gt;A new syndrome: mental subnormality and nasal papillomata.&lt;/strong&gt; Aust. Paediat. J. 13: 114-118, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/907573/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;907573&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1440-1754.1977.tb01135.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="907573">Costello (1977)</a> described 2 unrelated children with a syndrome comprising short stature, redundant skin of the neck, palms, soles, and fingers, curly hair, papillomata around the mouth and nares, and mental retardation. <a href="#16" class="mim-tip-reference" title="Der Kaloustian, V. M., Moroz, B., McIntosh, N., Watters, A. K., Blaichman, S. &lt;strong&gt;Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 41: 69-73, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1951465/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1951465&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320410118&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1951465">Der Kaloustian et al. (1991)</a> reported a boy with the same syndrome. The parents were not consanguineous in any of the 3 cases. The patient of <a href="#16" class="mim-tip-reference" title="Der Kaloustian, V. M., Moroz, B., McIntosh, N., Watters, A. K., Blaichman, S. &lt;strong&gt;Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 41: 69-73, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1951465/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1951465&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320410118&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1951465">Der Kaloustian et al. (1991)</a> had an aged facial appearance with thin anterior hair of the head. Epicanthal folds, large, depressed nasal bridge, and large earlobes were noted. The verrucal lesions were present around the anus as well as around the mouth and nares. The loose skin over the hands and feet was also thickened and the palms and soles were hyperkeratotic. The skin color was generally dark. Some similarities to the cardiofaciocutaneous syndrome (CFC; <a href="/entry/115150">115150</a>) and Noonan syndrome (<a href="/entry/163950">163950</a>) were noted. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=907573+1951465" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Martin, R. A., Jones, K. L. &lt;strong&gt;Delineation of the Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 41: 346-349, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1789291/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1789291&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320410316&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1789291">Martin and Jones (1991)</a> reported a 15-year-old girl with mental retardation, short stature, coarse face, thick and loose skin of the hands and feet, deep plantar and palmar creases, and nasal papillomata. <a href="#3" class="mim-tip-reference" title="Berberich, M. S., Carey, J. C., Hall, B. D. &lt;strong&gt;Resolution of the perinatal and infantile failure to thrive in a new autosomal recessive syndrome with the phenotype of a storage disorder and furrowing of palmar creases. (Abstract)&lt;/strong&gt; Proc. Greenwood Genet. Center 10: 78 only, 1991."None>Berberich et al. (1991)</a> reported 3 patients, 2 of whom were sibs, with a presumably new syndrome of failure to thrive, cardiomyopathy, and furrowing of palmar creases. Later these cases were diagnosed as Costello syndrome (<a href="#17" class="mim-tip-reference" title="Der Kaloustian, V. M. &lt;strong&gt;Not a new MCA/MR syndrome but probably Costello syndrome? (Letter)&lt;/strong&gt; Am. J. Med. Genet. 47: 170-171, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213900/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213900&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470206&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213900">Der Kaloustian, 1993</a>; <a href="#88" class="mim-tip-reference" title="Zampino, G., Mastroiacovo, P., Ricci, R., Zollino, M., Segni, G., Martini-Neri, M. E., Neri, G. &lt;strong&gt;Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology.&lt;/strong&gt; Am. J. Med. Genet. 47: 176-183, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213903/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213903&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470210&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213903">Zampino et al., 1993</a>). Additional patients were reported by <a href="#68" class="mim-tip-reference" title="Say, B., Gucsavas, M., Morgan, H., York, C. &lt;strong&gt;The Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 47: 163-165, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213897/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213897&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470203&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213897">Say et al. (1993)</a>, <a href="#79" class="mim-tip-reference" title="Teebi, A. S., Shaabani, I. S. &lt;strong&gt;Further delineation of Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 47: 166-168, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213898/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213898&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470204&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213898">Teebi and Shaabani (1993)</a>, <a href="#64" class="mim-tip-reference" title="Philip, N., Mancini, J. &lt;strong&gt;Costello syndrome and facio-cutaneous-skeletal syndrome.&lt;/strong&gt; Am. J. Med. Genet. 47: 174-175, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213902/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213902&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470209&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213902">Philip and Mancini (1993)</a>, and <a href="#88" class="mim-tip-reference" title="Zampino, G., Mastroiacovo, P., Ricci, R., Zollino, M., Segni, G., Martini-Neri, M. E., Neri, G. &lt;strong&gt;Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology.&lt;/strong&gt; Am. J. Med. Genet. 47: 176-183, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213903/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213903&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470210&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213903">Zampino et al. (1993)</a>. <a href="#88" class="mim-tip-reference" title="Zampino, G., Mastroiacovo, P., Ricci, R., Zollino, M., Segni, G., Martini-Neri, M. E., Neri, G. &lt;strong&gt;Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology.&lt;/strong&gt; Am. J. Med. Genet. 47: 176-183, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213903/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213903&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470210&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213903">Zampino et al. (1993)</a> provided photographs of a 24-year-old patient. <a href="#18" class="mim-tip-reference" title="Di Rocco, M., Gatti, R., Gandullia, P., Barabino, A., Picco, P., Borrone, C. &lt;strong&gt;Report on two patients with Costello syndrome and sialuria.&lt;/strong&gt; Am. J. Med. Genet. 47: 1135-1140, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8291534/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8291534&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470737&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8291534">Di Rocco et al. (1993)</a> reported 2 unrelated patients, a 5-year-old girl and a 3-year-old boy, with Costello syndrome and sialuria. <a href="#18" class="mim-tip-reference" title="Di Rocco, M., Gatti, R., Gandullia, P., Barabino, A., Picco, P., Borrone, C. &lt;strong&gt;Report on two patients with Costello syndrome and sialuria.&lt;/strong&gt; Am. J. Med. Genet. 47: 1135-1140, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8291534/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8291534&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470737&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8291534">Di Rocco et al. (1993)</a> suggested that urine and fibroblast sialic acid should be tested in other Costello syndrome patients. In both of their patients, feeding problems and abnormal speech were related to an oral motor apraxia. The girl also had acanthosis nigricans and abnormal glucose metabolism (fasting hypoglycemia and postprandial hyperglycemia). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8213900+8213897+1789291+8213902+8213903+8213898+8291534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Borochowitz, Z., Pavone, L., Mazor, G., Rizzo, R., Dar, H. &lt;strong&gt;New multiple congenital anomalies: mental retardation syndrome (MCA/MR) with facio-cutaneous-skeletal involvement.&lt;/strong&gt; Am. J. Med. Genet. 43: 678-685, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1621757/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1621757&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320430405&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1621757">Borochowitz et al. (1992)</a> reported 5 unrelated patients, 1 male and 4 females, with a previously undefined multiple congenital anomalies/mental retardation (MCA/MR) syndrome which they designated the faciocutaneoskeletal (FCS) syndrome. The features included mental retardation with specific sociable, humorous behavior, characteristic facial appearance, generally excessive skin, postnatal growth failure, and skeletal abnormalities. Consanguinity was noted in 2 patients, suggesting autosomal recessive inheritance. Coarse facies, wide hirsute forehead, wide anteverted nostrils, and thick lips were pictured. <a href="#57" class="mim-tip-reference" title="Martin, R. A., Jones, K. L. &lt;strong&gt;Facio-cutaneous-skeletal syndrome is the Costello syndrome. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 47: 169 only, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213899/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213899&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470205&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213899">Martin and Jones (1993)</a>, <a href="#17" class="mim-tip-reference" title="Der Kaloustian, V. M. &lt;strong&gt;Not a new MCA/MR syndrome but probably Costello syndrome? (Letter)&lt;/strong&gt; Am. J. Med. Genet. 47: 170-171, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213900/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213900&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470206&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213900">Der Kaloustian (1993)</a>, <a href="#80" class="mim-tip-reference" title="Teebi, A. S. &lt;strong&gt;Costello or facio-cutaneous-skeletal syndrome? (Letter)&lt;/strong&gt; Am. J. Med. Genet. 47: 172, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213901/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213901&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470207&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213901">Teebi (1993)</a>, <a href="#64" class="mim-tip-reference" title="Philip, N., Mancini, J. &lt;strong&gt;Costello syndrome and facio-cutaneous-skeletal syndrome.&lt;/strong&gt; Am. J. Med. Genet. 47: 174-175, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213902/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213902&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470209&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213902">Philip and Mancini (1993)</a>, and <a href="#88" class="mim-tip-reference" title="Zampino, G., Mastroiacovo, P., Ricci, R., Zollino, M., Segni, G., Martini-Neri, M. E., Neri, G. &lt;strong&gt;Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology.&lt;/strong&gt; Am. J. Med. Genet. 47: 176-183, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213903/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213903&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470210&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213903">Zampino et al. (1993)</a> suggested that the FCS syndrome described by <a href="#6" class="mim-tip-reference" title="Borochowitz, Z., Pavone, L., Mazor, G., Rizzo, R., Dar, H. &lt;strong&gt;New multiple congenital anomalies: mental retardation syndrome (MCA/MR) with facio-cutaneous-skeletal involvement.&lt;/strong&gt; Am. J. Med. Genet. 43: 678-685, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1621757/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1621757&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320430405&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1621757">Borochowitz et al. (1992)</a> is the same as the Costello syndrome. <a href="#7" class="mim-tip-reference" title="Borochowitz, Z., Pavone, L., Mazor, G., Rizzo, R., Dar, H. &lt;strong&gt;Facio-cutaneous-skeletal syndrome: new nosological entity or Costello syndrome? (Letter)&lt;/strong&gt; Am. J. Med. Genet. 47: 173 only, 1993."None>Borochowitz et al. (1993)</a> concluded, on the other hand, that 'it is premature to reach a definite conclusion at this stage.' <a href="#62" class="mim-tip-reference" title="Patton, M. A., Baraitser, M. &lt;strong&gt;Cutis laxa and the Costello syndrome.&lt;/strong&gt; J. Med. Genet. 30: 622, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8411045/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8411045&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.30.7.622&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8411045">Patton and Baraitser (1993)</a> reviewed 5 cases from their previous paper on cutis laxa (see <a href="/entry/219200">219200</a>) (<a href="#63" class="mim-tip-reference" title="Patton, M. A., Tolmie, J., Ruthnum, P., Bamforth, S., Baraitser, M., Pembrey, M. &lt;strong&gt;Congenital cutis laxa with retardation of growth and development.&lt;/strong&gt; J. Med. Genet. 24: 556-561, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3669050/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3669050&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.24.9.556&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3669050">Patton et al., 1987</a>) and concluded that the appropriate diagnosis was in fact Costello syndrome. Independently, <a href="#12" class="mim-tip-reference" title="Davies, S. J., Hughes, H. E. &lt;strong&gt;Cutis laxa: a feature of Costello syndrome. (Letter)&lt;/strong&gt; J. Med. Genet. 31: 85, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7512146/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7512146&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.31.1.85&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7512146">Davies and Hughes (1994)</a> reviewed case 7 from the same paper and, based on both history and clinical examination, made 'an unequivocal diagnosis of Costello syndrome.' In a longer report, <a href="#11" class="mim-tip-reference" title="Davies, S. J., Hughes, H. E. &lt;strong&gt;Costello syndrome: natural history and differential diagnosis of cutis laxa.&lt;/strong&gt; J. Med. Genet. 31: 486-489, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7520945/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7520945&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.31.6.486&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7520945">Davies and Hughes (1994)</a> described the development of one of the patients of <a href="#63" class="mim-tip-reference" title="Patton, M. A., Tolmie, J., Ruthnum, P., Bamforth, S., Baraitser, M., Pembrey, M. &lt;strong&gt;Congenital cutis laxa with retardation of growth and development.&lt;/strong&gt; J. Med. Genet. 24: 556-561, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3669050/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3669050&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.24.9.556&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3669050">Patton et al. (1987)</a> for more than 10 years and again emphasized that Costello syndrome should be included in the differential diagnosis of cutis laxa in association with postnatal growth retardation and developmental delay. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3669050+8213900+8213901+8213902+1621757+8213903+7512146+8411045+8213899+7520945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Izumikawa, Y., Naritomi, K., Tohma, T., Shiroma, N., Hirayama, K. &lt;strong&gt;The Costello syndrome: a boy with thick mitral valves and arrhythmias.&lt;/strong&gt; Jpn. J. Hum. Genet. 38: 329-334, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7505126/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7505126&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01874143&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7505126">Izumikawa et al. (1993)</a> reported the case of a 3-year-old boy who had typical clinical features except for the absence of nasal papillomas and who also had cardiac anomalies with extrasystoles and thick mitral valves. <a href="#47" class="mim-tip-reference" title="Kondo, I., Tamanaha, K., Ashimine, K. &lt;strong&gt;The Costello syndrome: report of a case and review of the literature.&lt;/strong&gt; Jpn. J. Hum. Genet. 38: 433-436, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7514457/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7514457&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01907991&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7514457">Kondo et al. (1993)</a> emphasized nasal papillomata as particularly characteristic of Costello syndrome and pointed out that the age at development ranged from 2 to 15 years in reported cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7514457+7505126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Fryns, J. P., Vogels, A., Haegeman, J., Eggermont, E., Van Den Berghe, H. &lt;strong&gt;Costello syndrome: a postnatal growth retardation syndrome with distinct phenotype.&lt;/strong&gt; Genet. Counsel. 5: 337-343, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7888135/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7888135&lt;/a&gt;]" pmid="7888135">Fryns et al. (1994)</a> described 2 unrelated patients with Costello syndrome, a 12-year-old girl and a 3.5-year-old boy. Severe postnatal growth retardation was the first clinical sign. Characteristic facial changes, loose and hyperelastic skin, and papillomata became progressively more evident with age. The patients presented a pleasant, happy nature and were mildly to moderately mentally retarded. <a href="#61" class="mim-tip-reference" title="Okamoto, N., Chiyo, H., Imai, K., Otani, K., Futagi, Y. &lt;strong&gt;A Japanese patient with the Costello syndrome.&lt;/strong&gt; Hum. Genet. 93: 605-606, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8168845/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8168845&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00202834&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8168845">Okamoto et al. (1994)</a> reported the case of a Japanese patient. A fundoplication was performed at the age of 11 months to treat severe gastroesophageal reflux. The infant had congenital bilateral subluxation of the hips. At the age of 7 years, there was generalized pigmentation and acanthosis nigricans around the neck and axilla. Endocrinologic evaluation demonstrated partial deficiency of growth hormone. Stating that 16 cases had been reported, <a href="#81" class="mim-tip-reference" title="Torrelo, A., Lopez-Avila, A., Mediero, I. G., Zambrano, A. &lt;strong&gt;Costello syndrome.&lt;/strong&gt; J. Am. Acad. Derm. 32: 904-907, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7722055/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7722055&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0190-9622(95)91559-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7722055">Torrelo et al. (1995)</a> presented the case of a 15-year-old girl and emphasized the cutaneous manifestations of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7722055+8168845+7888135" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#83" class="mim-tip-reference" title="Umans, S., Decock, P., Fryns, J. P. &lt;strong&gt;Costello syndrome: the natural history of a true postnatal growth retardation syndrome.&lt;/strong&gt; Genet. Counsel. 6: 121-125, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7546454/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7546454&lt;/a&gt;]" pmid="7546454">Umans et al. (1995)</a> described the natural history of the Costello syndrome in a child followed from birth to the age of 12 years. Severe feeding difficulties and poor sucking with swallowing difficulties are features. The history of polyhydramnios in almost all pregnancies indicates that diminished swallowing starts very early in fetal life. Generalized lymphoedema was noted at birth and hypotonia is a feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7546454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#59" class="mim-tip-reference" title="Mori, M., Yamagata, T., Mori, Y., Nokubi, M., Saito, K., Fukushima, Y., Momoi, M. Y. &lt;strong&gt;Elastic fiber degeneration in Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 61: 304-309, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8834040/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8834040&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1096-8628(19960202)61:4&lt;304::AID-AJMG2&gt;3.0.CO;2-U&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8834040">Mori et al. (1996)</a> described a case of Costello syndrome. The main clinical findings were loose skin of the neck, hands, and feet, deep palmar and plantar creases, typical 'coarse' face with thick lips and macroglossia, relative macrocephaly, mental retardation, short stature, arrhythmia, large size for gestational age, and poor feeding. The infant died of rhabdomyolysis at the age of 6 months. The major pathologic findings were fine, disrupted, and loosely-constructed elastic fibers in the skin, tongue, pharynx, larynx, and upper esophagus, but not in the bronchi, alveoli, aorta, or coronary arteries. The degeneration of elastic fibers was confirmed in the skin of a second Costello syndrome patient, that described previously by <a href="#87" class="mim-tip-reference" title="Yoshida, R., Fukushima, Y., Ohashi, H., Asoh, M., Fukuyama, Y. &lt;strong&gt;The Costello syndrome: are nasal papillomata essential?&lt;/strong&gt; Jpn. J. Hum. Genet. 38: 437-444, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8186422/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8186422&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01907992&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8186422">Yoshida et al. (1993)</a>. Autopsy also showed degeneration of the atrial conduction system, calcification and ballooning of skeletal muscle fibers with infiltration of macrophages, and myoglobin deposits in the collecting ducts of the kidney, consistent with rhabdomyolysis. They analyzed the clinical findings in 14 cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8834040+8186422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Costello, J. M. &lt;strong&gt;Costello syndrome: update on the original cases and commentary. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 62: 199-201, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8882404/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8882404&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320620203&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8882404">Costello (1996)</a> provided an update on the original cases and commented on other reported examples of this syndrome. Case 1 was reviewed at the age of 32 years. In summary, he had been known to have hypertension since the age of 17 years. Surgical operation had been required for recurrent inguinal hernia, ruptured cornea associated with keratoconus in the left eye, and hemorrhoidectomy. Duodenal ulcer and gastroesophageal reflux were diagnosed at age 20 following an episode of hematemesis and melena. Case 2 was reviewed at the age of 27 years. In summary, she had been asthmatic since age 18 years. Mammography at age 21 suggested severe fibroadenosis; warty hyperkeratosis of the nipples and lichenified eczema of the neck were noted. A cardiologic assessment was made at age 22 for a systolic murmur. <a href="#9" class="mim-tip-reference" title="Costello, J. M. &lt;strong&gt;Costello syndrome: update on the original cases and commentary. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 62: 199-201, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8882404/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8882404&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320620203&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8882404">Costello (1996)</a> presented a table of manifestations frequently seen in Costello syndrome and also in Noonan syndrome and/or CFC syndrome, as well as a table of manifestations frequently seen in Costello syndrome but infrequent or absent in the other 2 syndromes. Out of 16 cases reviewed, 13 had low-set ears with large/thick lobes, 13 had thick lips, 12 had nasal papillomas and/or papillomas elsewhere, 16 had loose skin of the hands and feet, 14 had deep palmar creases, 12 had hyperkeratotic palms and soles, and 12 had hyperextensible fingers. <a href="#9" class="mim-tip-reference" title="Costello, J. M. &lt;strong&gt;Costello syndrome: update on the original cases and commentary. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 62: 199-201, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8882404/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8882404&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320620203&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8882404">Costello (1996)</a> concluded that it is possible to make the clinical diagnosis of Costello syndrome with confidence. In particular, it is possible to differentiate Costello syndrome clearly from Noonan and CFC syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8882404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#72" class="mim-tip-reference" title="Siwik, E. S., Zahka, K. G., Wiesner, G. L., Limwongse, C. &lt;strong&gt;Cardiac disease in Costello syndrome.&lt;/strong&gt; Pediatrics 101: 706-709, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9521961/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9521961&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1542/peds.101.4.706&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9521961">Siwik et al. (1998)</a> reviewed the cardiac manifestations of Costello syndrome in 30 patients, 18 of whom had at least 1 cardiac abnormality. Of these 18, 9 had structural heart disease, 6 had hypertrophic cardiomyopathy (mean age of onset 6.5 years, range 5 months to 20 years), and 5 had tachyarrhythmias. The authors recommended cardiac evaluation for any patient in whom the diagnosis of Costello syndrome has been established, and subsequent follow-up of affected individuals for the development of hypertrophic cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#50" class="mim-tip-reference" title="Lin, A. E., Grossfeld, P. D., Hamilton, R. M., Smoot, L., Gripp, K. W., Proud, V., Weksberg, R., Wheeler, P., Picker, J., Irons, M., Zackai, E., Marino, B., Scott, C. I., Jr., Nicholson, L. &lt;strong&gt;Further delineation of cardiac abnormalities in Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 111: 115-129, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12210337/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12210337&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10558&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12210337">Lin et al. (2002)</a> reviewed the cardiac abnormalities in 94 patients with Costello syndrome and found the following in 59 (63%) patients: cardiovascular malformation in 30% (most commonly pulmonic stenosis), cardiac hypertrophy in 34%, and rhythm disturbances in 33% (most commonly atrial tachycardia). Most (68%) of the patients with a rhythm abnormality had a cardiovascular malformation, cardiac hypertrophy, or both. The authors recommended baseline and additional cardiac evaluations in all patients with Costello syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#85" class="mim-tip-reference" title="van Eeghen, A. M., van Gelderen, I., Hennekam, R.C.M. &lt;strong&gt;Costello syndrome: report and review.&lt;/strong&gt; Am. J. Med. Genet. 82: 187-193, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9934987/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9934987&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19990115)82:2&lt;187::aid-ajmg17&gt;3.0.co;2-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9934987">Van Eeghen et al. (1999)</a> reported the case of a 34-year-old woman with the diagnosis of Costello syndrome. Features included mental retardation, short stature, macrocephaly, 'coarse' face, hoarse voice, and redundant skin with deep palmar and plantar creases. She had wart-like lesions of the skin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9934987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Feingold, M. &lt;strong&gt;Costello syndrome and rhabdomyosarcoma. (Letter)&lt;/strong&gt; J. Med. Genet. 36: 582-583, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10424828/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10424828&lt;/a&gt;]" pmid="10424828">Feingold (1999)</a> reported a child with Costello syndrome who developed an alveolar rhabdomyosarcoma of the right foot at the age of 6 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10424828" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="Kerr, B., Eden, O. B., Dandamudi, R., Shannon, N., Quarrell, O., Emmerson, A., Ladusans, E., Gerrard, M., Donnai, D. &lt;strong&gt;Costello syndrome: two cases with embryonal rhabdomyosarcoma.&lt;/strong&gt; J. Med. Genet. 35: 1036-1039, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9863604/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9863604&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.35.12.1036&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9863604">Kerr et al. (1998)</a> reported 2 children diagnosed with Costello syndrome in the first months of life who developed retroperitoneal embryonal rhabdomyosarcoma. They suggested that increased risk of malignancy may be part of Costello syndrome. <a href="#60" class="mim-tip-reference" title="Moroni, I., Bedeschi, F., Luksch, R., Casanova, M., D&#x27;Incerti, L., Uziel, G., Selicorni, A. &lt;strong&gt;Costello syndrome: a cancer predisposing syndrome?&lt;/strong&gt; Clin. Dysmorph. 9: 265-268, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11045582/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11045582&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00019605-200009040-00006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11045582">Moroni et al. (2000)</a> reported a patient with Costello syndrome who developed an intrathoracic ganglioneuroblastoma. They cited several other patients with tumors and suggested that neural crest neoplasia may be a significant risk factor for children with Costello syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11045582+9863604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Franceschini, P., Licata, D., Di Cara, G., Guala, A., Bianchi, M., Ingrosso, G., Franceschini, D. &lt;strong&gt;Bladder carcinoma in Costello syndrome: report on a patient born to consanguineous parents and review.&lt;/strong&gt; Am. J. Med. Genet. 86: 174-179, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10449656/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10449656&lt;/a&gt;]" pmid="10449656">Franceschini et al. (1999)</a> reported a 12-year-old boy with Costello syndrome who was born to consanguineous parents. At age 11 years, this patient developed bladder carcinoma, a rare event in childhood, supporting an increased risk of malignancy in this syndrome. <a href="#32" class="mim-tip-reference" title="Gripp, K. W., Scott, C. I., Jr., Nicholson, L., Figueroa, T. E. &lt;strong&gt;Second case of bladder carcinoma in a patient with Costello syndrome. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 90: 256-259, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10678668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10678668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(20000131)90:3&lt;256::aid-ajmg16&gt;3.0.co;2-d&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10678668">Gripp et al. (2000)</a> likewise reported a case of transitional cell carcinoma of the bladder in a patient with Costello syndrome. Birth weight and birth length had been greater than the 95th centile but at the 50th centile within weeks or months. Gastrostomy tube placement was required at 6 months because of feeding problems and failure to thrive. Redundancy of skin folds of palms, labia majora, and other body areas was noted at that time. Biventricular concentric hypertrophic cardiomyopathy with asymmetric septal hypertrophy and a large pressure gradient from the left ventricle to the aorta were seen. Treatment with the beta blocker propranolol over a period of several years led to relief of the left ventricular outflow tract obstruction. Papillomata (squamous acanthomas) of the cheeks were noted at age 4; perineal papillomata developed at age 14. Hair growth was extremely slow requiring trims once a year. Nails were thin and dysplastic. Body odor was a persistent problem. The bladder cancer was discovered at the age of 14 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10449656+10678668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Gripp, K. W., Scott, C. I., Jr., Nicholson, L., McDonald-McGinn, D. M., Ozeran, J. D., Jones, M. C., Lin, A. E., Zackai, E. H. &lt;strong&gt;Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for a tumor screening protocol.&lt;/strong&gt; Am. J. Med. Genet. 108: 80-87, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11857556/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11857556&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10241&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11857556">Gripp et al. (2002)</a> reported 5 new cases of rhabdomyosarcoma in Costello syndrome, bringing the number of reported cases of solid tumors to 17. They pointed out that the frequency is in the same order of magnitude as that of solid tumors in Beckwith-Wiedemann syndrome (BWS; <a href="/entry/130650">130650</a>) and may justify tumor screening. In 8 of the 10 cases of Costello syndrome with rhabdomyosarcoma, the tumor originated from the abdomen, pelvis, or urogenital areas. Prior diagnosis of Costello syndrome was a prerequisite for the implementation of any screening protocol. Conversely, the diagnosis of Costello syndrome should be considered in individuals with rhabdomyosarcoma and physical findings suggestive of Costello syndrome. <a href="#14" class="mim-tip-reference" title="DeBaun, M. R. &lt;strong&gt;Screening for cancer in children with Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 108: 88-90, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11857557/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11857557&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10242&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11857557">DeBaun (2002)</a> reviewed the usefulness of screening in Costello syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11857557+11857556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Ioan, D. M., Fryns, J. P. &lt;strong&gt;Costello syndrome in two siblings and minor manifestations in their mother: further evidence for autosomal dominant inheritance?&lt;/strong&gt; Genet. Counsel. 13: 353-356, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12416645/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12416645&lt;/a&gt;]" pmid="12416645">Ioan and Fryns (2002)</a> described Costello syndrome in a brother and sister, with minor manifestations in their mother. The sibs had severe mental and motor retardation, feeding difficulties, failure to thrive in the first months of life, coarse facial appearance, skin hyperlaxity, and skeletal deformities. The mother presented with mild to moderate mental retardation, short stature, facial fullness, and wart-like lesions on her face. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12416645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Hennekam, R. C. M. &lt;strong&gt;Costello syndrome: an overview.&lt;/strong&gt; Am. J. Med. Genet. 117C: 42-48, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12561057/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12561057&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.c.10019&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12561057">Hennekam (2003)</a> stated that 115 cases of Costello syndrome had been described. He summarized clinical data on 73 of the cases and illustrated the characteristic facial appearance and palm of the hand. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12561057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Kawame, H., Matsui, M., Kurosawa, K., Matsuo, M., Masuno, M., Ohashi, H., Fueki, N., Aoyama, K., Miyatsuka, Y., Suzuki, K., Akatsuka, A., Ochiai, Y., Fukushima, Y. &lt;strong&gt;Further delineation of the behavioral and neurologic features in Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 118A: 8-14, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12605434/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12605434&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10236&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12605434">Kawame et al. (2003)</a> retrospectively reviewed the clinical records and findings in 5 girls and 5 boys with Costello syndrome. All showed significant postnatal growth retardation and severe feeding difficulties leading to failure to thrive from early infancy. All required tube feeding and some needed high-calorie formulas for variable periods. Developmental quotients/IQs in 7 children were 50 or less, and 3 were in the mildly retarded range. Five had seizures. Although happy and sociable personality had previously been established as characteristic of the disorder, <a href="#43" class="mim-tip-reference" title="Kawame, H., Matsui, M., Kurosawa, K., Matsuo, M., Masuno, M., Ohashi, H., Fueki, N., Aoyama, K., Miyatsuka, Y., Suzuki, K., Akatsuka, A., Ochiai, Y., Fukushima, Y. &lt;strong&gt;Further delineation of the behavioral and neurologic features in Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 118A: 8-14, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12605434/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12605434&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10236&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12605434">Kawame et al. (2003)</a> noted that during infancy, all 10 children showed significant irritability, including hypersensitivity to sound and tactile stimuli, sleep disturbance, and excessive shyness with strangers. These symptoms usually disappeared around 2 to 4 years of age. Other clinical features were cardiac abnormalities in 8, musculoskeletal abnormalities in all 10, and ophthalmologic manifestations in 5. Only 3 girls had papillomata. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12605434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Axelrad, M. E., Glidden, R., Nicholson, L., Gripp, K. W. &lt;strong&gt;Adaptive skills, cognitive, and behavioral characteristics of Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 128A: 396-400, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15264285/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15264285&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30140&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15264285">Axelrad et al. (2004)</a> performed standardized testing on 18 individuals with Costello syndrome. The Leiter International Performance Scale-Revised, a standardized nonverbal measure of intellectual ability, revealed a mean brief-IQ score of 57 (SD 12.5), within the range of mild mental retardation. In total, 17% of the participants had IQ scores within the severe range of mental retardation, 28% had IQ scores within the moderate range, 39% within the mild range, and 17% within the borderline range of intellectual functioning. Receptive language skills as assessed by the Peabody picture vocabulary test, 3rd edition, ranged from average functioning to 4 SD below the mean. Delays found on the Vineland adaptive behavior scales in the daily living skills, communication, and motor skills domains were comparable to the results seen in the Leiter brief-IQ. However, in the adaptive area of socialization, less than 50% participants fell in the low range of delay, and 25% of participants showed no delay in this domain. <a href="#2" class="mim-tip-reference" title="Axelrad, M. E., Glidden, R., Nicholson, L., Gripp, K. W. &lt;strong&gt;Adaptive skills, cognitive, and behavioral characteristics of Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 128A: 396-400, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15264285/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15264285&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30140&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15264285">Axelrad et al. (2004)</a> concluded that their study provides evidence supporting anecdotal data that Costello patients are quite social despite their cognitive difficulties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15264285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#86" class="mim-tip-reference" title="White, S. M., Graham, J. M., Jr., Kerr, B., Gripp, K., Weksberg, R., Cytrynbaum, C., Reeder, J. L., Stewart, F. J., Edwards, M., Wilson, M., Bankier, A. &lt;strong&gt;The adult phenotype in Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 136A: 128-135, 2005. Note: Erratum: Am. J. Med. Genet. 139A: 55 only, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15940703/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15940703&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30747&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15940703">White et al. (2005)</a> reviewed the clinical findings of 17 adults with Costello syndrome and found the major health problems to be bladder carcinoma, benign tumors including benign breast disease, Chiari malformations, gastroesophageal reflux, pubertal delay, and osteoporosis. Intellectual disability was mild to moderate in 14 of the patients and severe in 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15940703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#65" class="mim-tip-reference" title="Piccione, M., Piro, E., Pomponi, M. G., Matina, F., Pietrobono, R., Candela, E., Gabriele, B., Neri, G., Corsello, G. &lt;strong&gt;A premature infant with Costello syndrome due to a rare G13C HRAS mutation.&lt;/strong&gt; Am. J. Med. Genet. 149A: 487-489, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19213030/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19213030&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32674&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19213030">Piccione et al. (2009)</a> reported a premature male infant born at 29 weeks' gestation due to fetal distress who was found to have Costello syndrome confirmed by genetic analysis (G13C; <a href="/entry/190020#0007">190020.0007</a>). At birth, he was asystolic, neurologically depressed, had no spontaneous respiration, and had bilateral pneumothoraces. Further studies showed periventricular hyperechogenicity, septum pellucidum cysts, small choroid plexus hemorrhage, abdominal ascites, and atrial septal defect. At 4 months of age, he was noted to have relative macrocephaly, coarse face with hypertelorism, downslanting palpebral fissures, epicanthal folds, prominent eyes, short nose, low-set ears, large mouth, short neck, loose skin of hands and feet, sparse hair, hyperpigmented skin, deep palmar creases, joint laxity, reduced subcutaneous adipose tissue, and bilateral cryptorchidism. These features led to the clinical diagnosis of Costello syndrome. At 11 months of age, he had delayed motor development with central hypotonia, but adequate mental and speech development. Papillomata were not present. <a href="#65" class="mim-tip-reference" title="Piccione, M., Piro, E., Pomponi, M. G., Matina, F., Pietrobono, R., Candela, E., Gabriele, B., Neri, G., Corsello, G. &lt;strong&gt;A premature infant with Costello syndrome due to a rare G13C HRAS mutation.&lt;/strong&gt; Am. J. Med. Genet. 149A: 487-489, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19213030/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19213030&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32674&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19213030">Piccione et al. (2009)</a> noted that the distinctive features of Costello syndrome may be absent during the first months of life, especially in preterm infants who often have failure to thrive and decreased subcutaneous adipose tissue. The striking facial features of the disorder become more evident after the critical neonatal period. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19213030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#73" class="mim-tip-reference" title="Smith, L. P., Podraza, J., Proud, V. K. &lt;strong&gt;Polyhydramnios, fetal overgrowth, and macrocephaly: prenatal ultrasound findings of Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 149A: 779-784, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19288554/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19288554&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32778&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19288554">Smith et al. (2009)</a> reported a female infant with Costello syndrome born at 27 weeks' gestation in a pregnancy complicated by mild polyhydramnios and preterm labor. She had fetal overgrowth, large anterior fontanel, low-set thickened and posteriorly rotated ears, and coarse facies. She developed an arrhythmia with multiple ectopic foci (chaotic atrial rhythm) at 4 weeks of age. Cardiac examination showed a hyperdynamic precordium with a systolic heart murmur, and echocardiogram showed concentric hypertrophic cardiomyopathy with pulmonary valve stenosis. Other features included hepatomegaly, hand posturing with ulnar deviation of the wrist, and hypoplastic labia. She died at 6 months of age from complications of cardiac arrhythmia and bronchopulmonary dysplasia. Genetic analysis identified a G12S mutation in the HRAS gene (<a href="/entry/190020#0003">190020.0003</a>). <a href="#73" class="mim-tip-reference" title="Smith, L. P., Podraza, J., Proud, V. K. &lt;strong&gt;Polyhydramnios, fetal overgrowth, and macrocephaly: prenatal ultrasound findings of Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 149A: 779-784, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19288554/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19288554&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32778&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19288554">Smith et al. (2009)</a> emphasized the neonatal cardiac morbidity and mortality associated with Costello syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19288554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#49" class="mim-tip-reference" title="Lin, A. E., Alexander, M. E., Colan, S. D., Kerr, B., Rauen, K. A., Noonan, J., Baffa, J., Hopkins, E., Sol-Church, K., Limongelli, G., Digilio, M. C., Marino, B., and 11 others. &lt;strong&gt;Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome.&lt;/strong&gt; Am. J. Med. Genet. 155A: 486-507, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21344638/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21344638&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33857&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21344638">Lin et al. (2011)</a> reviewed the cardiac features of 61 patients with Costello syndrome ranging in age from 1 month to 40 years, with 13 patients over age 18 years. Cardiovascular abnormalities were present in 85% of patients. The most common finding was hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, which was present in 37 (61%) of the 61 patients. Among these patients, HCM was chronic or progressive in 14 (38%), stabilized in 11 (37%), regressed in 4 (11%), and was unknown in 8 (22%). A congenital heart defect was present in 27 (44%) of the 61 patients, most commonly nonprogressive valvar pulmonary stenosis. Arrhythmia occurred in 34 (56%) patients, atrial tachycardia in 15 (25%), and aortic dilation in 4 (7%). The cardiac features of 85 patients with HRAS mutations from the literature were also assessed. Congenital heart disease was present in 22% of patients, HCM in 68%, arrhythmia in 40%, atrial tachycardia in 7%, and aortic dilation in 1 patient. Cardiac tissue showed myocardial fiber disarray in 7 (70%) of 10 specimens, consistent with sarcomeric dysfunction. Ten (43%) of 23 deaths among both cohorts occurred in infants less than 1 year of age, and most of these deaths were cardiac-related. The most common HRAS mutation was G12S (<a href="/entry/190020#0003">190020.0003</a>), occurring in 84% of patients from the study and 71% of patients from the literature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21344638" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Congenital Myopathy with Excess of Muscle Spindles</em></strong></p><p>
<a href="#13" class="mim-tip-reference" title="de Boode, W. P., Semmekrot, B. A., ter Laak, H. J., van der Burgt, C. J. A. M, Draaisma, J. M. T., Lommen, E. J. P, Sengers, R. C. A., van Wijk-Hoek, J. M. &lt;strong&gt;Myopathology in patients with a Noonan phenotype.&lt;/strong&gt; Acta Neuropath. 92: 597-602, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8960317/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8960317&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004010050566&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8960317">De Boode et al. (1996)</a> reported 2 unrelated patients with progressive hypertrophic obstructive cardiomyopathy, Noonan syndrome-like facial anomalies, and increased density of muscle spindles in skeletal muscle biopsies. Both showed polyhydramnios on prenatal ultrasound and 1 had fetal hydrops. Death occurred at ages 3 weeks and 10 months, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8960317" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Selcen, D., Kupsky, W. J., Benjamins, D., Nigro, M. A. &lt;strong&gt;Myopathy with muscle spindle excess: a new congenital neuromuscular syndrome?&lt;/strong&gt; Muscle Nerve 24: 138-143, 2001. Note: Erratum: Muscle Nerve 24: 445 only, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11150980/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11150980&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1097-4598(200101)24:1&lt;138::aid-mus22&gt;3.0.co;2-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11150980">Selcen et al. (2001)</a> reported an infant with congenital weakness, hypotonia, arthrogryposis, atrial tachycardia, hypertrophic cardiomyopathy, and marked excess of muscle spindles on biopsy. He died at age 14 months from cardiorespiratory failure. Postmortem examination showed organomegaly. He also had bifrontal hallowing with fat pads below, triangular mouth, high-arched palate, and congenital neuroblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11150980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#75" class="mim-tip-reference" title="Stassou, S., Nadroo, A., Schubert, R., Chin, S., Gudavalli, M. &lt;strong&gt;A new syndrome of myopathy with muscle spindle excess.&lt;/strong&gt; J. Perinat. Med. 33: 179-182, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15843272/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15843272&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1515/JPM.2005.034&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15843272">Stassou et al. (2005)</a> reported a preterm neonate with arthrogryposis, hydrops fetalis, hypertrophic cardiomyopathy, and flaccid quadriplegia. Skeletal muscle biopsy showed increased muscle spindles encapsulated by fibrous tissue within most of the muscle fascicles sampled. She died at age 7 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15843272" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#15" class="mim-tip-reference" title="Della Marca, G., Vasta, I., Scarano, E., Rigante, M., De Feo, E., Mariotti, P., Rubino, M., Vollono, C., Mennuni, G. F., Tonali, P., Zampino, G. &lt;strong&gt;Obstructive sleep apnea in Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 140A: 257-262, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16419102/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16419102&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31076&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16419102">Della Marca et al. (2006)</a> found that 7 of 10 patients with Costello syndrome had obstructive sleep apnea as demonstrated by polysomnography and abnormally high apnea-hypopnea index. None of the patients were obese. All patients had 1 or more sites of narrowing in the upper airways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16419102" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Gripp, K. W., Innes, A. M., Axelrad, M. E., Gillan, T. L., Parboosingh, J. S., Davies, C., Leonard, N. J., Lapointe, M., Doyle, D., Catalano, S., Nicholson, L., Stabley, D. L., Sol-Church, K. &lt;strong&gt;Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype?&lt;/strong&gt; Am. J. Med. Genet. 146A: 683-690, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18247425/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18247425&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32227&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18247425">Gripp et al. (2008)</a> reported a boy with Costello syndrome and hypertrophic pyloric stenosis. A review identified pyloric stenosis in 5 (8.6%) of 58 patients with Costello syndrome, which is an increased frequency when compared to the general population (2.5 per 1,000). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18247425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Gripp, K. W., Hopkins, E., Doyle, D., Dobyns, W. B. &lt;strong&gt;High incidence of progressive postnatal cerebellar enlargement in Costello syndrome: brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities.&lt;/strong&gt; Am. J. Med. Genet. 152A: 1161-1168, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20425820/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20425820&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20425820[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33391&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20425820">Gripp et al. (2010)</a> found abnormal brain imaging in 27 (96%) of 28 patients with Costello syndrome. All 28 had macrocephaly, and 14 (50%) of 28 had ventriculomegaly, necessitating surgical intervention in 7 (25%). Twenty-seven (96%) of 28 patients had an enlarged cerebellum causing posterior fossa crowding with cerebellar tonsillar herniation, which progressed in 10 (59%) of 17 patients who had serial studies. Cerebellar herniation was not seen in studies performed before age 6 months, but developed between 8 and 15 months of age. Herniation caused Chiari type I malformation in 9 (32%) and syrinx formation in 7 (25%) of 28 patients, and 9 (32%) needed decompression intervention. Tethered cord release was performed in 2 (7%). The symptoms associated with tonsillar herniation resembled the most common presentation of infants with Costello syndrome, including poor feeding, respiratory distress with mixed central and obstructive apnea, ocular palsy, and constant arching. Serial studies showed progression of relative macrocephaly, frontal bossing, and cerebellar tonsillar herniation, consistent with accelerated postnatal growth. <a href="#25" class="mim-tip-reference" title="Gripp, K. W., Hopkins, E., Doyle, D., Dobyns, W. B. &lt;strong&gt;High incidence of progressive postnatal cerebellar enlargement in Costello syndrome: brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities.&lt;/strong&gt; Am. J. Med. Genet. 152A: 1161-1168, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20425820/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20425820&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20425820[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33391&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20425820">Gripp et al. (2010)</a> concluded that the findings indicated that macrocephaly and posterior fossa crowding are part of an ongoing process that occurs postnatally and results from disproportionate brain growth, rather than a static congenital anomaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20425820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Goodwin, A. F., Tidyman, W. E., Jheon, A. H., Sharir, A., Zheng, X., Charles, C., Fagin, J. A., McMahon, M., Diekwisch, T. G. H., Ganss, B., Rauen, K. A., Klein, O. D. &lt;strong&gt;Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation.&lt;/strong&gt; Hum. Molec. Genet. 23: 682-692, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24057668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24057668&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24057668[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddt455&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24057668">Goodwin et al. (2014)</a> studied 41 patients with Costello syndrome. Of the 33 patients who were examined for an enamel defect (<a href="#24" class="mim-tip-reference" title="Goodwin, A. F. &lt;strong&gt;Personal Communication.&lt;/strong&gt; San Francisco, Calif. 8/28/2014."None>Goodwin, 2014</a>), 29 (88%) showed decreased enamel mineralization. Many patients had evidence of abnormal pathologic wear, suggesting that the enamel was less densely mineralized and more susceptible to abrasion than normal. Scanning electron microscopy of exfoliated teeth showed irregular or absent parallel hydroxyapatite prisms as well as absence of inter-rod crystals between enamel rods compared to controls. Similar findings were observed in a mouse model of Costello syndrome with an Hras G12V mutation (<a href="/entry/190020#0001">190020.0001</a>). Ameloblasts at the labial aspect of the incisor of mutant mice were disorganized and had lost polarity compared to wildtype, and ameloblast progenitor cells were hyperproliferative. Treatment of adult mutant mice with MEK (see <a href="/entry/176872">176872</a>) inhibitors rescued the enamel defect and restored normal progenitor cell proliferation and differentiation, whereas treatment with a PIK3 inhibitor only corrected the progenitor cell proliferation defect. The findings indicated that activated HRAS negatively regulates enamel formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24057668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#28" class="mim-tip-reference" title="Gripp, K. W., Kawame, H., Viskochil, D. H., Nicholson, L. &lt;strong&gt;Elevated catecholamine metabolites in patients with Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 128A: 48-51, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15211656/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15211656&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30100&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15211656">Gripp et al. (2004)</a> found elevated catecholamine metabolite levels (vanillylmandelic acid and/or homovanillic acid) in the urine of 8 patients with Costello syndrome. Imaging studies and clinical follow-up did not lead to the identification of neuroblastoma or another catecholamine-secreting tumor in any patient. <a href="#28" class="mim-tip-reference" title="Gripp, K. W., Kawame, H., Viskochil, D. H., Nicholson, L. &lt;strong&gt;Elevated catecholamine metabolites in patients with Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 128A: 48-51, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15211656/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15211656&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30100&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15211656">Gripp et al. (2004)</a> concluded that in this patient group an elevation above the normal limit for catecholamine metabolites is more likely to be a variant than a sign of a neuroblastoma, and recommended that this assay not be used as a screening test. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15211656" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Inheritance</strong>
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<p>The vast majority of patients with Costello syndrome have de novo heterozygous mutations in the HRAS gene (<a href="#1" class="mim-tip-reference" title="Aoki, Y., Niihori, T., Kawame, H., Kurosawa, K., Ohashi, H., Tanaka, Y., Filocamo, M., Kato, K., Suzuki, Y., Kure, S., Matsubara, Y. &lt;strong&gt;Germline mutations in HRAS proto-oncogene cause Costello syndrome.&lt;/strong&gt; Nature Genet. 37: 1038-1040, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16170316/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16170316&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1641&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16170316">Aoki et al., 2005</a>; <a href="#45" class="mim-tip-reference" title="Kerr, B., Delrue, M.-A., Sigaudy, S., Perveen, R., Marche, M., Burgelin, I., Stef, M., Tang, B., Eden, O. B., O&#x27;Sullivan, J., De Sandre-Giovannoli, A., Reardon, W., and 14 others. &lt;strong&gt;Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.&lt;/strong&gt; J. Med. Genet. 43: 401-405, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16443854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16443854&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2005.040352&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16443854">Kerr et al., 2006</a>; <a href="#30" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Stabley, D. L., Nicholson, L., Scott, C. I., Jr., Doyle, D., Aoki, Y., Matsubara, Y., Zackai, E. H., Lapunzina, P., Gonzalez-Meneses, A., Holbrook, J., Agresta, C. A., Gonzalez, I. L., Sol-Church, K. &lt;strong&gt;HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.&lt;/strong&gt; Am. J. Med. Genet. 140A: 1-7, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16329078/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16329078&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31047&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16329078">Gripp et al., 2006</a>). Studies by <a href="#54" class="mim-tip-reference" title="Lurie, I. W. &lt;strong&gt;Genetics of the Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 52: 358-359, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7528974/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7528974&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320520321&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7528974">Lurie (1994)</a> found a significant increase of mean paternal age (38.0 years), suggesting sporadic autosomal dominant mutations as the most likely cause. Rare reports of affected sibs born to healthy parents may be explained by gonadal mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16443854+16329078+7528974+16170316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The molecular evidence presented by <a href="#1" class="mim-tip-reference" title="Aoki, Y., Niihori, T., Kawame, H., Kurosawa, K., Ohashi, H., Tanaka, Y., Filocamo, M., Kato, K., Suzuki, Y., Kure, S., Matsubara, Y. &lt;strong&gt;Germline mutations in HRAS proto-oncogene cause Costello syndrome.&lt;/strong&gt; Nature Genet. 37: 1038-1040, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16170316/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16170316&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1641&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16170316">Aoki et al. (2005)</a>, viz., the finding of heterozygous mutations in the HRAS gene (<a href="/entry/190020">190020</a>) in patients with Costello syndrome, convincingly refuted the hypothesis of autosomal recessive inheritance and favored gonadal mosaicism as the explanation of instances of affected sibs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16170316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Exclusion of Autosomal Recessive Inheritance</em></strong></p><p>
The hypothesis of autosomal recessive inheritance of Costello syndrome was based on 2 families with affected sibs (<a href="#3" class="mim-tip-reference" title="Berberich, M. S., Carey, J. C., Hall, B. D. &lt;strong&gt;Resolution of the perinatal and infantile failure to thrive in a new autosomal recessive syndrome with the phenotype of a storage disorder and furrowing of palmar creases. (Abstract)&lt;/strong&gt; Proc. Greenwood Genet. Center 10: 78 only, 1991."None>Berberich et al., 1991</a>; <a href="#88" class="mim-tip-reference" title="Zampino, G., Mastroiacovo, P., Ricci, R., Zollino, M., Segni, G., Martini-Neri, M. E., Neri, G. &lt;strong&gt;Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology.&lt;/strong&gt; Am. J. Med. Genet. 47: 176-183, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8213903/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8213903&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320470210&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8213903">Zampino et al., 1993</a>) and 2 consanguineous matings (<a href="#6" class="mim-tip-reference" title="Borochowitz, Z., Pavone, L., Mazor, G., Rizzo, R., Dar, H. &lt;strong&gt;New multiple congenital anomalies: mental retardation syndrome (MCA/MR) with facio-cutaneous-skeletal involvement.&lt;/strong&gt; Am. J. Med. Genet. 43: 678-685, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1621757/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1621757&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320430405&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1621757">Borochowitz et al., 1992</a>). <a href="#54" class="mim-tip-reference" title="Lurie, I. W. &lt;strong&gt;Genetics of the Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 52: 358-359, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7528974/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7528974&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320520321&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7528974">Lurie (1994)</a> reviewed 20 reported families and found that the 37 sibs of probands were all normal. In 6 families for whom pedigrees were not available, 2 affected sib pairs were born. Even if there were no normal offspring in these latter families, the occurrence of the Costello syndrome in only 2 of 39 sibs virtually excludes an autosomal recessive inheritance pattern (P = 0.999). Moreover, a significant increase of mean paternal age (38.0 years) and paternal-maternal age difference (7.36 years) suggests sporadic autosomal dominant mutations as a likely cause. The 2 reported cases of affected sibs born to healthy parents may be explained by gonadal mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8213903+7528974+1621757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>However, <a href="#21" class="mim-tip-reference" title="Franceschini, P., Licata, D., Di Cara, G., Guala, A., Bianchi, M., Ingrosso, G., Franceschini, D. &lt;strong&gt;Bladder carcinoma in Costello syndrome: report on a patient born to consanguineous parents and review.&lt;/strong&gt; Am. J. Med. Genet. 86: 174-179, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10449656/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10449656&lt;/a&gt;]" pmid="10449656">Franceschini et al. (1999)</a> reported a 12-year-old boy with Costello syndrome who was born to consanguineous (first cousins once removed) parents, which could be considered consistent with autosomal recessive transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10449656" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Apparent Autosomal Dominant Inheritance and Somatic Mosaicism</em></strong></p><p>
<a href="#42" class="mim-tip-reference" title="Johnson, J. P., Golabi, M., Norton, M. E., Rosenblatt, R. M., Feldman, G. M., Yang, S. P., Hall, B. D., Fries, M. H., Carey, J. C. &lt;strong&gt;Costello syndrome: phenotype, natural history, differential diagnosis, and possible cause.&lt;/strong&gt; J. Pediat. 133: 441-448, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9738731/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9738731&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(98)70284-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9738731">Johnson et al. (1998)</a> described 8 patients with Costello syndrome, including an affected sib pair, and reviewed the literature on 29 previously reported patients. They emphasized an association with advanced parental age, which was considered consistent with autosomal dominant inheritance with germline mosaicism. In their study the average paternal age was 40.3 years, with a mean maternal age of 35.8 years. Features noted in the patients of <a href="#42" class="mim-tip-reference" title="Johnson, J. P., Golabi, M., Norton, M. E., Rosenblatt, R. M., Feldman, G. M., Yang, S. P., Hall, B. D., Fries, M. H., Carey, J. C. &lt;strong&gt;Costello syndrome: phenotype, natural history, differential diagnosis, and possible cause.&lt;/strong&gt; J. Pediat. 133: 441-448, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9738731/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9738731&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(98)70284-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9738731">Johnson et al. (1998)</a> included cataracts in 2 patients, heat intolerance and increased sweating in 3, graying of hair in 1 (aged 8 years), and generalized amino aciduria in 3. Of all the patients reviewed, hypertrophic cardiomyopathy with valve dysfunction was found in 65% and delayed bone age in 85%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9738731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>A review of previously reported patients suggested to <a href="#85" class="mim-tip-reference" title="van Eeghen, A. M., van Gelderen, I., Hennekam, R.C.M. &lt;strong&gt;Costello syndrome: report and review.&lt;/strong&gt; Am. J. Med. Genet. 82: 187-193, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9934987/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9934987&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19990115)82:2&lt;187::aid-ajmg17&gt;3.0.co;2-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9934987">Van Eeghen et al. (1999)</a> that the disorder is autosomal dominant, caused either by a mutation in a single gene or by microdeletion. <a href="#39" class="mim-tip-reference" title="Ioan, D. M., Fryns, J. P. &lt;strong&gt;Costello syndrome in two siblings and minor manifestations in their mother: further evidence for autosomal dominant inheritance?&lt;/strong&gt; Genet. Counsel. 13: 353-356, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12416645/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12416645&lt;/a&gt;]" pmid="12416645">Ioan and Fryns (2002)</a> described Costello syndrome in a brother and sister, with minor manifestations in their mother. They suggested that this was further evidence for autosomal dominant inheritance. In a review of Costello syndrome, <a href="#35" class="mim-tip-reference" title="Hennekam, R. C. M. &lt;strong&gt;Costello syndrome: an overview.&lt;/strong&gt; Am. J. Med. Genet. 117C: 42-48, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12561057/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12561057&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.c.10019&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12561057">Hennekam (2003)</a> favored autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9934987+12561057+12416645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Gripp, K. W., Stabley, D. L., Nicholson, L., Hoffman, J. D., Sol-Church, K. &lt;strong&gt;Somatic mosaicism for an HRAS mutation causes Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 140A: 2163-2169, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16969868/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16969868&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31456&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16969868">Gripp et al. (2006)</a> reported a 15-year-old girl with Costello syndrome resulting from somatic mosaicism for the common G12S HRAS mutation (<a href="/entry/190020#0003">190020.0003</a>). Clinical features included short stature, developmental delay, mild mitral valve prolapse without hypertrophic cardiomyopathy, Achilles tendon contractures, sparse, thin and brittle hair, epicanthal folds, and a wide mouth with thick lips. She also had nasal papillomata and thickened toenails. Her skin showed areas of streaky hyperpigmentation over trunk and extremities. Molecular analysis of white blood cells failed to detect a mutation, but DNA derived from buccal swabs showed the G12S mutation in 25 to 30% of cells. The wide distribution throughout the skin suggested an early somatic mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16969868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#74" class="mim-tip-reference" title="Sol-Church, K., Stabley, D. L., Demmer, L. A., Agbulos, A., Lin, A. E., Smoot, L., Nicholson, L., Gripp, K. W. &lt;strong&gt;Male-to-male transmission of Costello syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism.&lt;/strong&gt; Am. J. Med. Genet. 149A: 315-321, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19206176/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19206176&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19206176[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32639&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19206176">Sol-Church et al. (2009)</a> described what they said was the first documented transmission of an HRAS mutation from a parent with somatic mosaicism to a child, resulting in typical Costello syndrome in the child. The child carried a heterozygous G12S mutation on the paternal allele. The father was noted to have features suggestive of mosaic Costello syndrome, including severe failure to thrive in early childhood, developmental delay, hyperkeratosis on both hands and his left foot, papillomas on the right left perianal region and nose, hyperpigmentation, thick ear lobes, and patches of curly hair. He did not have structural cardiac defects. The father expressed awareness that he and his son had similar physical and developmental traits of the disorder. DNA testing of the father showed that he was somatic mosaic for the G12S mutation, carrying it in 7 to 8% of his alleles, whereas the mother did not have the mutation. The findings showed the importance of parental evaluation, which has implications for genetic counseling. This family had been reported in abstract form by <a href="#5" class="mim-tip-reference" title="Bodkin, N. M., Mortimer, E. S., Demmer, L. A. &lt;strong&gt;Male to male transmission of Costello syndrome consistent with autosomal dominant inheritance. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 65: A143, 1999."None>Bodkin et al. (1999)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206176" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="diagnosis" class="mim-anchor"></a>
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<strong>Diagnosis</strong>
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<p><a href="#73" class="mim-tip-reference" title="Smith, L. P., Podraza, J., Proud, V. K. &lt;strong&gt;Polyhydramnios, fetal overgrowth, and macrocephaly: prenatal ultrasound findings of Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 149A: 779-784, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19288554/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19288554&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32778&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19288554">Smith et al. (2009)</a> reviewed prenatal ultrasound findings of 17 patients with Costello syndrome. Seven (41%) were preterm with delivery prior to 37 weeks' gestation, and the remaining 10 (59%) were term deliveries. There were 3 main prenatal findings on ultrasound: polyhydramnios, fetal overgrowth, and relative macrocephaly. Polyhydramnios was the most commonly reported prenatal complication, affecting 100% of pregnancies. Most (65%) patients had birth weight above the 90th centile, and 41% patients had birth weights greater than the 97th centile. A fourth less common finding was cardiac arrhythmia. <a href="#73" class="mim-tip-reference" title="Smith, L. P., Podraza, J., Proud, V. K. &lt;strong&gt;Polyhydramnios, fetal overgrowth, and macrocephaly: prenatal ultrasound findings of Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 149A: 779-784, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19288554/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19288554&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32778&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19288554">Smith et al. (2009)</a> noted that the combination of polyhydramnios and fetal overgrowth often prompts evaluation for maternal diabetes mellitus, but that recognition of Costello syndrome in utero is important because of the neonatal risk of cardiac mortality and morbidity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19288554" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="Kuniba, H., Pooh, R. K., Sasaki, K., Shimokawa, O., Harada, N., Kondoh, T., Egashira, M., Moriuchi, H., Yoshiura, K., Niikawa, N. &lt;strong&gt;Prenatal diagnosis of Costello syndrome using 3D ultrasonography amniocentesis confirmation of the rare HRAS mutation G12D. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 149A: 785-787, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18642361/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18642361&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32335&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18642361">Kuniba et al. (2009)</a> provided a case report of a Japanese fetus with severe Costello syndrome diagnosed using prenatal 3-dimensional ultrasonography at 23 weeks' gestation. Findings at that time included polyhydramnios, severe overgrowth (+5.3 SD using a Japanese fetal growth curve), and dysmorphic craniofacial features, such as large head, pointed chin, broad nasal bridge, and low-set ears. In addition, the wrists showed lateral deviation and flexion. Molecular analysis via amniocentesis identified an uncommon G12D mutation in the HRAS gene (<a href="/entry/190020#0013">190020.0013</a>). After birth, he developed respiratory failure, severe hypoglycemia, cardiac hypertrophy, and renal failure, and died soon after birth. The phenotype was similar to that reported by <a href="#52" class="mim-tip-reference" title="Lo, I. F. M., Brewer, C., Shannon, N., Shorto, J., Tang, B., Black, G., Soo, M. T., Ng, D. K. K., Lam, S. T. S., Kerr, B. &lt;strong&gt;Severe neonatal manifestations of Costello syndrome. (Letter)&lt;/strong&gt; J. Med. Genet. 45: 167-171, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18039947/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18039947&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2007.054411&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18039947">Lo et al. (2008)</a> in 2 infants with the G12D mutation, suggesting that this mutation is associated with a severe clinical outcome and death in early infancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18039947+18642361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="clinicalManagement" class="mim-anchor"></a>
<h4 href="#mimClinicalManagementFold" id="mimClinicalManagementToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Clinical Management</strong>
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<p><a href="#31" class="mim-tip-reference" title="Gripp, K. W., Morse, L. A., Axelrad, M., Chatfield, K. C., Chidekel, A., Dobyns, W., Doyle, D., Kerr, B., Lin, A. E., Schwartz, D. D., Sibbles, B. J., Siegel, D., Shankar, S. P., Stevenson, D. A., Thacker, M. M., Weaver, K. N., White, S. M., Rauen, K. A. &lt;strong&gt;Costello syndrome: clinical phenotype, genotype, and managment guidelines.&lt;/strong&gt; Am. J. Med. Genet. 179A: 1725-1744, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31222966/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31222966&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31222966[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.61270&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31222966">Gripp et al. (2019)</a> reported management guidelines based on expert opinion for the multisystem involvement seen in Costello syndrome. They recommended that at diagnosis, patients should have a complete cardiac evaluation, including echocardiogram, electrocardiogram, and Holter monitoring. Because hypertrophic cardiomyopathy (HCM) and non-reentrant atrial tachycardias are most often present in infancy, there should be frequent surveillance in the first 2 years of life. Abnormalities should be treated by a cardiologist or an electrophysiologist as needed. Due to risk of acquired and progressive cardiovascular abnormalities, screening for HCM, early coronary disease, lipid abnormalities and hypertension is warranted throughout life. At diagnosis, referral to neurology and an MRI of the brain (with a repeat 1 year later) and of the lower spine (for tethered cord) is recommended, with serial clinical examinations. Patients should be referred for early childhood services, and receive appropriate supportive educational, physical, and communication services. Because patients are at risk for failure to thrive, short stature, growth hormone deficiency, hypoglycemia, and delayed or precocious puberty, they should be referred at diagnosis to an endocrinologist, with screening for hypoglycemia and appropriate hormone testing with medical management of abnormalities. Because failure to thrive and poor feeding, along with other gastrointestinal complications, are seen in almost all young children with Costello syndrome, referral should be made to a gastroenterologist and dietitian. Patients should also be assessed at diagnosis and treated appropriately for airway issues, genitourinary abnormalities, and musculoskeletal abnormalities. Ongoing care should also include assessment and management for dental and ophthalmologic concerns. Patients with Costello syndrome are at risk for benign tumors, embryonal rhabdomyosarcoma, bladder carcinoma, and neuroblastoma. If a diagnosis is made before 10 years of age, patients should have an abdominal and pelvic ultrasound at diagnosis and then every 3 months until 8-10 years of age. Annual urinalysis starting at 10 years of age is recommended, with referral for evaluation for bladder carcinoma in the case of persistent hematuria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31222966" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="cytogenetics" class="mim-anchor"></a>
<h4 href="#mimCytogeneticsFold" id="mimCytogeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Cytogenetics</strong>
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<p><a href="#10" class="mim-tip-reference" title="Czeizel, A. E., Timar, L. &lt;strong&gt;Hungarian case with Costello syndrome and translocation t(1,22). (Letter)&lt;/strong&gt; Am. J. Med. Genet. 57: 501-503, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7677162/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7677162&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320570331&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7677162">Czeizel and Timar (1995)</a> described the case of a Hungarian girl with Costello syndrome in association with an apparently balanced translocation: 46,XX t(1;22)(q25;q11). The patient showed excessive generalized skin, more pronounced in the palms, 'wash woman's hands,' and soles, with elastolysis confirmed by histologic examination. The long tubular bones were osteoporotic. Spina bifida occulta was demonstrated in L5 and S1. Mental retardation was mild. She had a particularly sociable and humorous personality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7677162" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#77" class="mim-tip-reference" title="Sutajova, M., Neukirchen, U., Meinecke, P., Czeizel, A. E., Timar, L., Solyom, E., Gal, A., Kutsche, K. &lt;strong&gt;Disruption of the PDGFB gene in a 1;22 translocation patient does not cause Costello syndrome.&lt;/strong&gt; Genomics 83: 883-892, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15081117/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15081117&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ygeno.2003.10.012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15081117">Sutajova et al. (2004)</a> studied further the female patient originally reported by <a href="#10" class="mim-tip-reference" title="Czeizel, A. E., Timar, L. &lt;strong&gt;Hungarian case with Costello syndrome and translocation t(1,22). (Letter)&lt;/strong&gt; Am. J. Med. Genet. 57: 501-503, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7677162/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7677162&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320570331&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7677162">Czeizel and Timar (1995)</a> who was diagnosed with Costello syndrome and who carried an apparently balanced translocation, t(1;22). They showed that there were 2 derivative chromosomes 1 in her peripheral blood lymphocytes, in one of which the coding region of the PDGFB gene (<a href="/entry/190040">190040</a>), which maps to 22q13.1, was disrupted. In 18 patients with Costello syndrome, no pathogenic mutations were found in any of the genes belonging to the PDGF or PDGFR (see <a href="/entry/173490">173490</a>) gene families. Reevaluation of the clinical features of the translocation patient challenged the diagnosis of Costello syndrome. <a href="#77" class="mim-tip-reference" title="Sutajova, M., Neukirchen, U., Meinecke, P., Czeizel, A. E., Timar, L., Solyom, E., Gal, A., Kutsche, K. &lt;strong&gt;Disruption of the PDGFB gene in a 1;22 translocation patient does not cause Costello syndrome.&lt;/strong&gt; Genomics 83: 883-892, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15081117/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15081117&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ygeno.2003.10.012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15081117">Sutajova et al. (2004)</a> speculated, however, that the biologic consequences of the mutant PDGFB allele contributed to the unique disease phenotype of the patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15081117+7677162" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Maroti, Z., Kutsche, K., Sutajova, M., Gal, A., Nothwang, H. G., Czeizel, A. E., Timar, L., Solyom, E. &lt;strong&gt;Refinement and delineation of the breakpoint regions of a chromosome 1;22 translocation in a patient with Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 109: 234-237, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11977185/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11977185&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10314&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11977185">Maroti et al. (2002)</a> defined the location of the breakpoint regions of the 1;22 translocation. FISH analysis refined the cytogenetic breakpoint from 22q11 to 22q13.1. <a href="#76" class="mim-tip-reference" title="Suri, M., Garrett, C. &lt;strong&gt;Costello syndrome with acoustic neuroma and cataract. Is the Costello locus linked to neurofibromatosis type 2 on 22q?&lt;/strong&gt; Clin. Dysmorph. 7: 149-151, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9571289/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9571289&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00019605-199804000-00014&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9571289">Suri and Garrett (1998)</a> described a patient with Costello syndrome with acoustic neurinoma and cataract, both of which are features of neurofibromatosis type 2 (NF2; <a href="/entry/101000">101000</a>). Although they did not find a deletion or point mutation of the NF2 gene, located in 22q12.2, it was suggested that the gene for Costello syndrome might be close to NF2. If the Costello gene is located on 22q13.1, an inversion might have happened in the Costello/NF2 patient that escaped detection by conventional cytogenetic analysis. <a href="#55" class="mim-tip-reference" title="Maroti, Z., Kutsche, K., Sutajova, M., Gal, A., Nothwang, H. G., Czeizel, A. E., Timar, L., Solyom, E. &lt;strong&gt;Refinement and delineation of the breakpoint regions of a chromosome 1;22 translocation in a patient with Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 109: 234-237, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11977185/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11977185&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10314&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11977185">Maroti et al. (2002)</a> confirmed the 1q25 location of the other breakpoint. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9571289+11977185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="pathogenesis" class="mim-anchor"></a>
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<strong>Pathogenesis</strong>
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<p>Disruption of elastic fiber production, such as is observed in Costello syndrome, may arise either from low production of tropoelastin (see <a href="/entry/130160">130160</a>) and microfibrillar proteins, or from their inadequate secretion and extracellular assembly. <a href="#37" class="mim-tip-reference" title="Hinek, A., Smith, A. C., Cutiongco, E. M., Callahan, J. W., Gripp, K. W., Weksberg, R. &lt;strong&gt;Decreased elastin deposition and high proliferation of fibroblasts from Costello syndrome are related to functional deficiency in the 67-kD elastin-binding protein.&lt;/strong&gt; Am. J. Hum. Genet. 66: 859-872, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10712202/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10712202&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10712202[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302829&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10712202">Hinek et al. (2000)</a> undertook a study to assess the major steps of elastogenesis in fibroblasts derived from 6 children with Costello syndrome and from 3 age-matched normal children. Their data indicated that fibroblasts from patients with Costello syndrome produce normal levels of soluble tropoelastin and properly deposit an extracellular microfibrillar scaffold but are unable to assemble elastic fibers, because of a secondary deficiency in the 67-kD elastin-binding protein, which the authors called EBP. EBP is an enzymatically inactive spliced variant of beta-galactosidase (see <a href="/entry/230500">230500</a>) (<a href="#36" class="mim-tip-reference" title="Hinek, A., Rabinovitch, M., Keeley, F., Okamura-Oho, Y., Callahan, J. &lt;strong&gt;The 67-kD elastin/laminin-binding protein is related to an enzymatically inactive, alternatively spliced form of beta-galactosidase.&lt;/strong&gt; J. Clin. Invest. 91: 1198-1205, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8383699/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8383699&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI116280&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8383699">Hinek et al., 1993</a>; <a href="#66" class="mim-tip-reference" title="Privitera, S., Prody, C. A., Callahan, J. W., Hinek, A. &lt;strong&gt;The 67-kDa enzymatically inactive alternatively spliced variant of beta-galactosidase is identical to the elastin/laminin-binding protein.&lt;/strong&gt; J. Biol. Chem. 273: 6319-6326, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9497360/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9497360&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.273.11.6319&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9497360">Privitera et al., 1998</a>) that binds to the repeating hydrophobic domains on elastin. Because the normal association between tropoelastin and EBP can be disrupted by contact with galactosugar-bearing moieties, and because the fibroblasts from patients with Costello syndrome showed an unusual accumulation of chondroitin sulfate-bearing proteoglycans (CD44 (<a href="/entry/107269">107269</a>) and biglycan (<a href="/entry/301870">301870</a>)), <a href="#37" class="mim-tip-reference" title="Hinek, A., Smith, A. C., Cutiongco, E. M., Callahan, J. W., Gripp, K. W., Weksberg, R. &lt;strong&gt;Decreased elastin deposition and high proliferation of fibroblasts from Costello syndrome are related to functional deficiency in the 67-kD elastin-binding protein.&lt;/strong&gt; Am. J. Hum. Genet. 66: 859-872, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10712202/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10712202&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10712202[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302829&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10712202">Hinek et al. (2000)</a> postulated that a chondroitin sulfate may induce shedding of EBP from Costello cells and prevent normal recycling of this reusable tropoelastin chaperone. This conclusion was further supported by the fact that exposure to chondroitinase ABC, an enzyme capable of chondroitin sulfate degradation, restored normal production of elastic fibers by fibroblasts from patients with Costello syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10712202+8383699+9497360" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In histologic and immunohistochemical analyses of postmortem heart tissue from 3 children with Costello syndrome, <a href="#38" class="mim-tip-reference" title="Hinek, A., Teitell, M. A., Schoyer, L., Allen, W., Gripp, K. W., Hamilton, R., Weksberg, R., Kluppel, M., Lin, A. E. &lt;strong&gt;Myocardial storage of chondroitin sulfate-containing moieties in Costello syndrome patients with severe hypertrophic cardiomyopathy.&lt;/strong&gt; Am. J. Med. Genet. 133A: 1-12, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15637729/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15637729&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30495&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15637729">Hinek et al. (2005)</a> observed that cardiomyocytes from all 3 were characterized by pericellular and intracellular accumulation of chondroitin 6-sulfate-bearing glycosaminoglycans, with lower than normal deposition of chondroitin 4-sulfate. Their endocardia showed the presence of multiple foci of collagen-rich fibrotic tissue with a marked reduction of elastic fibers, and there were thin, short, and fragmented elastic fibers in the myocardial stroma, pericardium, and cardiac valves, coinciding with lowered expression of EBP. <a href="#38" class="mim-tip-reference" title="Hinek, A., Teitell, M. A., Schoyer, L., Allen, W., Gripp, K. W., Hamilton, R., Weksberg, R., Kluppel, M., Lin, A. E. &lt;strong&gt;Myocardial storage of chondroitin sulfate-containing moieties in Costello syndrome patients with severe hypertrophic cardiomyopathy.&lt;/strong&gt; Am. J. Med. Genet. 133A: 1-12, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15637729/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15637729&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30495&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15637729">Hinek et al. (2005)</a> proposed that an imbalance in sulfation of chondroitin sulfate molecules and subsequent accumulation of chondroitin 6-sulfate in cardiomyocytes contribute to the development of the hypertrophic cardiomyopathy of Costello syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15637729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
<a id="molecularGenetics" class="mim-anchor"></a>
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Molecular Genetics</strong>
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<p>Because of phenotypic overlap between Costello syndrome and Noonan syndrome (<a href="/entry/163950">163950</a>), and because mutations in the SHP2/PTPN11 gene (<a href="/entry/176876">176876</a>) had been demonstrated in the latter, <a href="#78" class="mim-tip-reference" title="Tartaglia, M., Cotter, P. D., Zampino, G., Gelb, B. D., Rauen, K. A. &lt;strong&gt;Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous and Costello syndromes.&lt;/strong&gt; Clin. Genet. 63: 423-426, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12752577/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12752577&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1034/j.1399-0004.2003.00076.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12752577">Tartaglia et al. (2003)</a> screened a cohort of 27 patients with clinically diagnosed Costello syndrome for PTPN11 mutations; they found none. The previous exclusion of PTPN11 mutations in cardiofaciocutaneous syndrome by <a href="#40" class="mim-tip-reference" title="Ion, A., Tartaglia, M., Song, X., Kalidas, K., van der Burgt, I., Shaw, A. C., Ming, J. E., Zampino, G., Zackai, E. H., Dean, J. C. S., Somer, M., Parenti, G., Crosby, A. H., Patton, M. A., Gelb, B. D., Jeffery, S. &lt;strong&gt;Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome.&lt;/strong&gt; Hum. Genet. 111: 421-427, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12384786/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12384786&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-002-0803-6&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12384786">Ion et al. (2002)</a> indicates that these 3 syndromes are distinct. <a href="#82" class="mim-tip-reference" title="Troger, B., Kutsche, K., Bolz, H., Luttgen, S., Gal, A., Almassy, Z., Caliebe, A., Freisinger, P., Hobbiebrunken, E., Morlot, M., Stefanova, M., Streubel, B., Wieczorek, D., Meinecke, P. &lt;strong&gt;No mutation in the gene for Noonan syndrome, PTPN11, in 18 patients with Costello syndrome. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 121A: 82-84, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12900909/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12900909&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20122&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12900909">Troger et al. (2003)</a> likewise found no mutation in the PTPN11 gene in 18 patients with Costello syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12384786+12752577+12900909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Gain-of-function mutant SHP2 proteins identified in Noonan syndrome have enhanced phosphatase activity, which results in activation of a RAS-MAPK cascade in a cell-specific manner. <a href="#1" class="mim-tip-reference" title="Aoki, Y., Niihori, T., Kawame, H., Kurosawa, K., Ohashi, H., Tanaka, Y., Filocamo, M., Kato, K., Suzuki, Y., Kure, S., Matsubara, Y. &lt;strong&gt;Germline mutations in HRAS proto-oncogene cause Costello syndrome.&lt;/strong&gt; Nature Genet. 37: 1038-1040, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16170316/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16170316&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1641&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16170316">Aoki et al. (2005)</a> hypothesized that genes mutated in Costello syndrome and in PTPN11-negative Noonan syndrome encode molecules that function upstream or downstream of SHP2 in signal pathways. Among these molecules, they sequenced the entire coding region of 4 RAS genes in genomic DNA from 13 individuals with Costello syndrome and 28 individuals with PTPN11-negative Noonan syndrome. In 12 of the 13 individuals with Costello syndrome, they found a heterozygous mutation in the HRAS gene (<a href="/entry/190020#0001">190020.0001</a>, <a href="/entry/190020#0003">190020.0003</a>-<a href="/entry/190020#0005">190020.0005</a>). All 4 of the mutations had previously been identified somatically in various tumors. Examination of genomic DNA from unaffected parents in 4 families identified no mutations, suggesting that mutations in the affected individuals arose de novo, although the possibility of germline mosaicism in a parent could not be excluded. No mutations in KRAS (<a href="/entry/190070">190070</a>), NRAS (<a href="/entry/164790">164790</a>), HRAS, or ERAS (<a href="/entry/300437">300437</a>) were observed in the 28 individuals with Noonan syndrome or in 1 individual with Costello syndrome. The observations suggested that germline mutations in HRAS perturb human development and increase susceptibility to tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16170316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Stabley, D. L., Nicholson, L., Scott, C. I., Jr., Doyle, D., Aoki, Y., Matsubara, Y., Zackai, E. H., Lapunzina, P., Gonzalez-Meneses, A., Holbrook, J., Agresta, C. A., Gonzalez, I. L., Sol-Church, K. &lt;strong&gt;HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.&lt;/strong&gt; Am. J. Med. Genet. 140A: 1-7, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16329078/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16329078&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31047&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16329078">Gripp et al. (2006)</a> and <a href="#19" class="mim-tip-reference" title="Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D., Rauen, K. A. &lt;strong&gt;HRAS mutation in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.&lt;/strong&gt; Am. J. Med. Genet. 140A: 8-16, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16372351/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16372351&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31078&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16372351">Estep et al. (2006)</a> simultaneously analyzed the HRAS gene in samples collected at International Costello Syndrome meetings over several years and identified heterozygous mutations in 33 of 40 and 33 of 36 patients diagnosed with Costello syndrome, respectively (20 patients participated in both studies, for a total of 56 different patients). All mutations were in codons 12 and 13; the majority in both studies (91% and 91%, respectively) were a G12S substitution (<a href="/entry/190020#0003">190020.0003</a>). <a href="#30" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Stabley, D. L., Nicholson, L., Scott, C. I., Jr., Doyle, D., Aoki, Y., Matsubara, Y., Zackai, E. H., Lapunzina, P., Gonzalez-Meneses, A., Holbrook, J., Agresta, C. A., Gonzalez, I. L., Sol-Church, K. &lt;strong&gt;HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.&lt;/strong&gt; Am. J. Med. Genet. 140A: 1-7, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16329078/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16329078&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31047&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16329078">Gripp et al. (2006)</a> analyzed 19 sets of parents, none of whom carried the mutation, confirming the de novo nature of mutations in Costello syndrome patients. <a href="#19" class="mim-tip-reference" title="Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D., Rauen, K. A. &lt;strong&gt;HRAS mutation in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.&lt;/strong&gt; Am. J. Med. Genet. 140A: 8-16, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16372351/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16372351&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31078&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16372351">Estep et al. (2006)</a> also analyzed 8 well-characterized patients diagnosed with cardiofaciocutaneous syndrome (CFC; <a href="/entry/115150">115150</a>) and found no mutations in the HRAS coding region, supporting a distinct etiology between the Costello and CFC syndromes. In a detailed review of these reports, <a href="#51" class="mim-tip-reference" title="Lin, A. E., Rauen, K. A., Gripp, K. W., Carey, J. C. &lt;strong&gt;Clarification of previously reported Costello syndrome patients. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 146A: 940-943, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18302240/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18302240&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32164&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18302240">Lin et al. (2008)</a> noted that <a href="#30" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Stabley, D. L., Nicholson, L., Scott, C. I., Jr., Doyle, D., Aoki, Y., Matsubara, Y., Zackai, E. H., Lapunzina, P., Gonzalez-Meneses, A., Holbrook, J., Agresta, C. A., Gonzalez, I. L., Sol-Church, K. &lt;strong&gt;HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.&lt;/strong&gt; Am. J. Med. Genet. 140A: 1-7, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16329078/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16329078&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31047&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16329078">Gripp et al. (2006)</a> and <a href="#19" class="mim-tip-reference" title="Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D., Rauen, K. A. &lt;strong&gt;HRAS mutation in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.&lt;/strong&gt; Am. J. Med. Genet. 140A: 8-16, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16372351/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16372351&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31078&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16372351">Estep et al. (2006)</a> had described a total of 49 patients, not 56 as originally stated. <a href="#51" class="mim-tip-reference" title="Lin, A. E., Rauen, K. A., Gripp, K. W., Carey, J. C. &lt;strong&gt;Clarification of previously reported Costello syndrome patients. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 146A: 940-943, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18302240/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18302240&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32164&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18302240">Lin et al. (2008)</a> also provided a detailed list of the clinical features of these patients and emphasized the need for a central registry in order to keep track of biologic material. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16329078+16372351+18302240" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients originally diagnosed with Costello syndrome but with features overlapping those of CFC, in whom no HRAS mutations were found (<a href="#19" class="mim-tip-reference" title="Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D., Rauen, K. A. &lt;strong&gt;HRAS mutation in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.&lt;/strong&gt; Am. J. Med. Genet. 140A: 8-16, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16372351/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16372351&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31078&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16372351">Estep et al., 2006</a>), <a href="#67" class="mim-tip-reference" title="Rauen, K. A. &lt;strong&gt;Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 140A: 1681-1683, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16804887/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16804887&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31315&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16804887">Rauen (2006)</a> identified missense mutations in the BRAF gene (<a href="/entry/164757#0020">164757.0020</a> and <a href="/entry/164757#0021">164757.0021</a>, respectively). <a href="#67" class="mim-tip-reference" title="Rauen, K. A. &lt;strong&gt;Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 140A: 1681-1683, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16804887/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16804887&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31315&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16804887">Rauen (2006)</a> stated that Costello syndrome and CFC can be distinguished by mutation analysis of genes in the RAS/MAPK pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16804887+16372351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Kerr, B., Delrue, M.-A., Sigaudy, S., Perveen, R., Marche, M., Burgelin, I., Stef, M., Tang, B., Eden, O. B., O&#x27;Sullivan, J., De Sandre-Giovannoli, A., Reardon, W., and 14 others. &lt;strong&gt;Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.&lt;/strong&gt; J. Med. Genet. 43: 401-405, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16443854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16443854&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2005.040352&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16443854">Kerr et al. (2006)</a> analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%). The mutations were de novo in all cases in which DNA samples were available from the parents. The most common mutation was G12S, which was found in 30 of 37 mutation-positive patients. All of the mutation-positive cases had failure to thrive as well as the facial appearance and hands characteristic of Costello syndrome; macrocephaly was found in 32 mutation-positive cases. In a patient with autistic features and microretrognathism, <a href="#45" class="mim-tip-reference" title="Kerr, B., Delrue, M.-A., Sigaudy, S., Perveen, R., Marche, M., Burgelin, I., Stef, M., Tang, B., Eden, O. B., O&#x27;Sullivan, J., De Sandre-Giovannoli, A., Reardon, W., and 14 others. &lt;strong&gt;Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.&lt;/strong&gt; J. Med. Genet. 43: 401-405, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16443854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16443854&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2005.040352&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16443854">Kerr et al. (2006)</a> identified a substitution in a novel region of HRAS (K117R; <a href="/entry/190020#0006">190020.0006</a>). <a href="#45" class="mim-tip-reference" title="Kerr, B., Delrue, M.-A., Sigaudy, S., Perveen, R., Marche, M., Burgelin, I., Stef, M., Tang, B., Eden, O. B., O&#x27;Sullivan, J., De Sandre-Giovannoli, A., Reardon, W., and 14 others. &lt;strong&gt;Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.&lt;/strong&gt; J. Med. Genet. 43: 401-405, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16443854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16443854&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2005.040352&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16443854">Kerr et al. (2006)</a> stated that, together with previously published series (<a href="#1" class="mim-tip-reference" title="Aoki, Y., Niihori, T., Kawame, H., Kurosawa, K., Ohashi, H., Tanaka, Y., Filocamo, M., Kato, K., Suzuki, Y., Kure, S., Matsubara, Y. &lt;strong&gt;Germline mutations in HRAS proto-oncogene cause Costello syndrome.&lt;/strong&gt; Nature Genet. 37: 1038-1040, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16170316/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16170316&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1641&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16170316">Aoki et al., 2005</a> and <a href="#30" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Stabley, D. L., Nicholson, L., Scott, C. I., Jr., Doyle, D., Aoki, Y., Matsubara, Y., Zackai, E. H., Lapunzina, P., Gonzalez-Meneses, A., Holbrook, J., Agresta, C. A., Gonzalez, I. L., Sol-Church, K. &lt;strong&gt;HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.&lt;/strong&gt; Am. J. Med. Genet. 140A: 1-7, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16329078/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16329078&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31047&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16329078">Gripp et al., 2006</a>), mutations in HRAS had been found in 82 (85%) of 96 patients with a clinical diagnosis of Costello syndrome and that overall, the frequency of malignancy in the published mutation-positive cases was 11%. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16443854+16329078+16170316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#89" class="mim-tip-reference" title="Zampino, G., Pantaleoni, F., Carta, C., Cobellis, G., Vasta, I., Neri, C., Pogna, E. A., De Feo, E., Delogu, A., Sarkozy, A., Atzeri, F., Selicorni, A., Rauen, K. A., Cytrynbaum, C. S., Weksberg, R., Dallapiccola, B., Ballabio, A., Gelb, B. D., Neri, G., Tartaglia, M. &lt;strong&gt;Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.&lt;/strong&gt; Hum. Mutat. 28: 265-272, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17054105/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17054105&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20431&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17054105">Zampino et al. (2007)</a> identified the common G12S mutation in 8 of 9 unrelated patients with Costello syndrome; the ninth child had a different mutation (<a href="/entry/190020#0008">190020.0008</a>). All mutations were de novo, paternally inherited and associated with advanced paternal age. None of 36 patients with Noonan syndrome or 4 with CFC syndrome had a mutation in the HRAS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#90" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. &lt;strong&gt;Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.&lt;/strong&gt; J. Med. Genet. 44: 131-135, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17056636/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17056636&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2006.046300&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17056636">Zenker et al. (2007)</a> identified 2 different heterozygous mutations in the KRAS gene (<a href="/entry/190070#0017">190070.0017</a>-<a href="/entry/190070#0018">190070.0018</a>) in 2 unrelated infants with Costello syndrome. Both patients had coarse facies, loose and redundant skin with deep palmar creases, heart defects, failure to thrive, and moderate mental retardation. <a href="#90" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. &lt;strong&gt;Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.&lt;/strong&gt; J. Med. Genet. 44: 131-135, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17056636/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17056636&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2006.046300&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17056636">Zenker et al. (2007)</a> noted that the patients may later develop features of CFC, which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17056636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 20-year-old woman with clinical features typical of Costello syndrome and additional findings seen in Noonan syndrome, who was negative for mutations in the PTPN11 and HRAS genes, <a href="#4" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., Brasil, A. S., Albano, L. M. J., Kim, C. A., Krieger, J. E. &lt;strong&gt;Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene.&lt;/strong&gt; J. Hum. Genet. 52: 521-526, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17468812/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17468812&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10038-007-0146-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17468812">Bertola et al. (2007)</a> identified a mutation in the KRAS gene (K5E; <a href="/entry/190070#0019">190070.0019</a>) that was not found in her unaffected mother or brother or in 100 controls. The patient was diagnosed with hypertrophic cardiomyopathy soon after birth, and evolved with severe developmental delay; lymphedema began in her lower extremities at age 15 years, and at age 18 years she developed nasal papillomata. The initial diagnosis was Noonan syndrome, but the presence of relative macrocephaly, coarse facial features, loose skin in the hands and feet with deep creases, dark skin, and particularly the development of nasal papillomata led to the diagnosis of Costello syndrome. <a href="#4" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., Brasil, A. S., Albano, L. M. J., Kim, C. A., Krieger, J. E. &lt;strong&gt;Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene.&lt;/strong&gt; J. Hum. Genet. 52: 521-526, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17468812/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17468812&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10038-007-0146-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17468812">Bertola et al. (2007)</a> noted that this mutation was in the same codon as that of 1 of the patients reported by <a href="#90" class="mim-tip-reference" title="Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K. &lt;strong&gt;Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.&lt;/strong&gt; J. Med. Genet. 44: 131-135, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17056636/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17056636&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2006.046300&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17056636">Zenker et al. (2007)</a> (K5N; <a href="/entry/190070#0017">190070.0017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17468812+17056636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#84" class="mim-tip-reference" title="van der Burgt, I., Kupsky, W., Stassou, S., Nadroo, A., Barroso, C., Diem, A., Kratz, C. P., Dvorsky, R., Ahmadian, M. R., Zenker, M. &lt;strong&gt;Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive Hras activation. (Letter)&lt;/strong&gt; J. Med. Genet. 44: 459-462, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17412879/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17412879&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2007.049270&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17412879">Van der Burgt et al. (2007)</a> identified mutations in the HRAS gene (see, e.g., <a href="/entry/190020#0001">190020.0001</a>; <a href="/entry/190020#0003">190020.0003</a>; <a href="/entry/190020#0009">190020.0009</a>; <a href="/entry/190020#0010">190020.0010</a>) in patients with congenital myopathy with excess muscle spindles, a variant of Costello syndrome. Three of the patients had been reported by <a href="#13" class="mim-tip-reference" title="de Boode, W. P., Semmekrot, B. A., ter Laak, H. J., van der Burgt, C. J. A. M, Draaisma, J. M. T., Lommen, E. J. P, Sengers, R. C. A., van Wijk-Hoek, J. M. &lt;strong&gt;Myopathology in patients with a Noonan phenotype.&lt;/strong&gt; Acta Neuropath. 92: 597-602, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8960317/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8960317&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004010050566&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8960317">de Boode et al. (1996)</a>, <a href="#71" class="mim-tip-reference" title="Selcen, D., Kupsky, W. J., Benjamins, D., Nigro, M. A. &lt;strong&gt;Myopathy with muscle spindle excess: a new congenital neuromuscular syndrome?&lt;/strong&gt; Muscle Nerve 24: 138-143, 2001. Note: Erratum: Muscle Nerve 24: 445 only, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11150980/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11150980&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1097-4598(200101)24:1&lt;138::aid-mus22&gt;3.0.co;2-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11150980">Selcen et al. (2001)</a>, and <a href="#75" class="mim-tip-reference" title="Stassou, S., Nadroo, A., Schubert, R., Chin, S., Gudavalli, M. &lt;strong&gt;A new syndrome of myopathy with muscle spindle excess.&lt;/strong&gt; J. Perinat. Med. 33: 179-182, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15843272/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15843272&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1515/JPM.2005.034&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15843272">Stassou et al. (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8960317+17412879+11150980+15843272" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#70" class="mim-tip-reference" title="Schulz, A. L., Albrecht, B., Arici, C., van der Burgt, I., Buske, A., Gillessen-Kaesbach, G., Heller, R., Horn, D., Hubner, C. A., Korenke, G. C., Konig, R., Kress, W., and 15 others. &lt;strong&gt;Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome&lt;/strong&gt; Clin. Genet. 73: 62-70, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18042262/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18042262&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2007.00931.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18042262">Schulz et al. (2008)</a> identified mutations in the HRAS gene in 28 (90.3%) of 31 patients with Costello syndrome. All mutations occurred in codons 12 or 13, and the HRAS mutations in 14 informative families could all be traced to the paternal allele. G12S was the most common mutation, occurring in 82.1% of patients. The phenotype was relatively homogeneous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18042262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated patients with Costello syndrome, <a href="#27" class="mim-tip-reference" title="Gripp, K. W., Innes, A. M., Axelrad, M. E., Gillan, T. L., Parboosingh, J. S., Davies, C., Leonard, N. J., Lapointe, M., Doyle, D., Catalano, S., Nicholson, L., Stabley, D. L., Sol-Church, K. &lt;strong&gt;Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype?&lt;/strong&gt; Am. J. Med. Genet. 146A: 683-690, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18247425/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18247425&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32227&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18247425">Gripp et al. (2008)</a> identified 2 different novel mutations in the HRAS gene (<a href="/entry/190020#0011">190020.0011</a>; <a href="/entry/190020#0012">190020.0012</a>). The facial features of both patients were less coarse than typically seen in Costello syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18247425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Lo, I. F. M., Brewer, C., Shannon, N., Shorto, J., Tang, B., Black, G., Soo, M. T., Ng, D. K. K., Lam, S. T. S., Kerr, B. &lt;strong&gt;Severe neonatal manifestations of Costello syndrome. (Letter)&lt;/strong&gt; J. Med. Genet. 45: 167-171, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18039947/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18039947&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2007.054411&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18039947">Lo et al. (2008)</a> described 4 infants with an unusually severe Costello syndrome, in whom they identified 3 mutations in the HRAS gene (<a href="/entry/190020#0003">190020.0003</a>, <a href="/entry/190020#0013">190020.0013</a>, and <a href="/entry/190020#0014">190020.0014</a>, respectively). The authors stated that hypoglycemia, renal abnormalities, severe early cardiomyopathy, congenital lung and airway abnormalities, pleural and pericardial effusion, chylous ascites, and pulmonary lymphangectasia are part of the clinical spectrum seen in Costello syndrome, and noted that lung pathology resembling alveolar capillary dysplasia was reported in 1 case. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18039947" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#29" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Nicholson, L., Allen, W., Cramer, A., Jones, K. L., Kutz, W., Peck, D., Rebolledo, M. A., Wheeler, P. G., Wilson, W., Al-Rahawan, M. M., Stabley, D. L., Sol-Church, K. &lt;strong&gt;Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 143A: 1472-1480, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17551924/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17551924&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31815&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17551924">Gripp et al. (2007)</a> reported 13 unrelated patients ages 0 to 8 years with a clinical diagnosis of Costello syndrome, Costello-like syndrome, or thought to have either CFC syndrome or Costello syndrome who were negative for mutations in the HRAS gene. De novo heterozygous BRAF or MEK1 mutations were identified in 8 and 5 patients, respectively. In a comparison to a group of previously published patients with HRAS mutations, <a href="#29" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Nicholson, L., Allen, W., Cramer, A., Jones, K. L., Kutz, W., Peck, D., Rebolledo, M. A., Wheeler, P. G., Wilson, W., Al-Rahawan, M. M., Stabley, D. L., Sol-Church, K. &lt;strong&gt;Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 143A: 1472-1480, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17551924/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17551924&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31815&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17551924">Gripp et al. (2007)</a> found several significant clinical differences between the 2 groups. Patients with an HRAS mutation and Costello syndrome tended to have polyhydramnios, ulnar deviation, growth hormone deficiency, and tachycardia more frequently than patients with BRAF or MEK1 mutations. Those with BRAF or MEK1 mutations had more cardiovascular malformations. Although the presence of more than 1 papilloma strongly suggested Costello syndrome over CFC, the authors noted that these lesions typically develop over time and thus may not be very helpful in the differential diagnosis of younger children. <a href="#29" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Nicholson, L., Allen, W., Cramer, A., Jones, K. L., Kutz, W., Peck, D., Rebolledo, M. A., Wheeler, P. G., Wilson, W., Al-Rahawan, M. M., Stabley, D. L., Sol-Church, K. &lt;strong&gt;Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.&lt;/strong&gt; Am. J. Med. Genet. 143A: 1472-1480, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17551924/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17551924&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31815&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17551924">Gripp et al. (2007)</a> concluded that the 13 patients in their study had CFC syndrome and not Costello syndrome, based on the clinical and molecular findings. The authors noted the phenotypic overlap between the 2 disorders, but suggested that Costello syndrome be reserved for patients with HRAS mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17551924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Gripp, K. W., Hopkins, E., Sol-Church, K., Stabley, D. L., Axelrad, M. E., Doyle, D., Dobyns, W. B., Hudson, C., Johnson, J., Tenconi, R., Graham, G. E., Sousa, A. B., Heller, R., Piccione, M., Corsello, G., Herman, G. E., Tartaglia, M., Lin, A. E. &lt;strong&gt;Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C.&lt;/strong&gt; Am. J. Med. Genet. 155A: 706-716, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21438134/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21438134&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21438134[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33884&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21438134">Gripp et al. (2011)</a> examined 12 individuals with Costello syndrome due to the HRAS G13C (<a href="/entry/190020#0007">190020.0007</a>) mutation and compared the phenotype to those with the HRAS G12S (<a href="/entry/190020#0003">190020.0003</a>) mutation. Individuals with G13C had many typical findings including polyhydramnios, failure to thrive, hypertrophic cardiomyopathy, macrocephaly, posterior fossa crowding, and developmental delay. Their facial features were less coarse and short stature was less severe. Statistically significant differences included the absence of several common features, including multifocal atrial tachycardia, ulnar deviation of the wrist, and papillomata; a noteworthy absence of malignant tumors did not reach statistical significance. There were some novel ectodermal findings associated with the G13C mutation, including loose anagen hair and long eyelashes requiring trimming (termed 'dolichocilia'). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21438134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#58" class="mim-tip-reference" title="McCormick, E. M., Hopkins, E., Conway, L., Catalano, S., Hossain, J., Sol-Church, K., Stabley, D. L., Gripp, K. W. &lt;strong&gt;Assessing genotype-phenotype correlation in Costello syndrome using a severity score.&lt;/strong&gt; Genet. Med. 15: 554-557, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23429430/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23429430&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2013.6&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23429430">McCormick et al. (2013)</a> developed a severity score for Costello syndrome based on various criteria, including feeding difficulties, cardiac abnormalities, orthopedic abnormalities, neurologic abnormalities, malignancies, bone density, and stature as well as mortality, and assessed 78 individuals blind to genotype. They then compared this to genotypes of the individuals and found that individuals with the G12A (<a href="/entry/190020#0004">190020.0004</a>) and the G12C (<a href="/entry/190020#0014">190020.0014</a>) HRAS mutations were more severely affected than those with other HRAS mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23429430" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#53" class="mim-tip-reference" title="Lorenz, S., Lissewski, C., Simsek-Kiper, P. O., Alanay, Y., Boduroglu, K., Zenker, M., Rosenberger, G. &lt;strong&gt;Functional analysis of a duplication (p.E63_D69dup) in the switch II region of HRAS: new aspects of the molecular pathogenesis underlying Costello syndrome.&lt;/strong&gt; Hum. Molec. Genet. 22: 1643-1653, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23335589/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23335589&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddt014&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23335589">Lorenz et al. (2013)</a> reported an 18-year-old girl, born of consanguineous Turkish parents, with a relatively mild form of Costello syndrome. The patient had mildly delayed psychomotor development as a child, as well as hypertrophic cardiomyopathy, osteoporosis, coarse facial features, short stature, hyperkeratotic skin lesions, pigmentary anomalies, and mild intellectual disability. Genetic analysis identified a de novo heterozygous 21-bp duplication in the HRAS gene, resulting in the duplication of amino acids 63 to 69 (E63_D69dup; <a href="/entry/190020#0018">190020.0018</a>). Five of these residues are an integral part of the HRAS switch II domain that mediates binding of HRAS with various regulator and effector proteins. In vitro cellular functional expression studies showed that the E63_D69dup mutation increased HRAS coprecipitation with certain effector proteins, but not with PIK3CA (<a href="/entry/171834">171834</a>). Overexpression of the mutant protein increased steady-state phosphorylation of downstream effectors MEK1/2 and ERK1/2, but not AKT. The mutant protein had some residual response to epidermal growth factor (EGF) stimulus compared to constitutively active HRAS mutations. The findings indicated that this duplication mutant has a gain-of-function effect for some effectors, but this is counteracted by a normal effect on PIK3CA signaling. <a href="#53" class="mim-tip-reference" title="Lorenz, S., Lissewski, C., Simsek-Kiper, P. O., Alanay, Y., Boduroglu, K., Zenker, M., Rosenberger, G. &lt;strong&gt;Functional analysis of a duplication (p.E63_D69dup) in the switch II region of HRAS: new aspects of the molecular pathogenesis underlying Costello syndrome.&lt;/strong&gt; Hum. Molec. Genet. 22: 1643-1653, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23335589/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23335589&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddt014&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23335589">Lorenz et al. (2013)</a> concluded that the attenuated phenotype in this patient was due to impaired regulator and effector binding of the E63_D69dup mutant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23335589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#69" class="mim-tip-reference" title="Schuhmacher, A. J., Guerra, C., Sauzeau, V., Canamero, M., Bustelo, X. R., Barbacid, M. &lt;strong&gt;A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition.&lt;/strong&gt; J. Clin. Invest. 118: 2169-2179, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18483625/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18483625&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18483625[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI34385&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18483625">Schuhmacher et al. (2008)</a> generated a mouse model of Costello syndrome by introduction of an oncogenic gly12-to-val mutation (<a href="/entry/190020#0001">190020.0001</a>) in the mouse Hras gene. Mutant mice developed hyperplasia of the mammary gland, but tumor development was rare. The mice showed some phenotypic features similar to those of Costello syndrome, including facial dysmorphism and cardiomyopathy. Mutant mice also developed systemic hypertension, extensive vascular remodeling, and fibrosis in both the heart and the kidneys resulting from abnormal upregulation of the renin-angiotensin II system, which responded to treatment with captopril. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18483625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="Aoki2005" class="mim-anchor"></a>
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Aoki, Y., Niihori, T., Kawame, H., Kurosawa, K., Ohashi, H., Tanaka, Y., Filocamo, M., Kato, K., Suzuki, Y., Kure, S., Matsubara, Y.
<strong>Germline mutations in HRAS proto-oncogene cause Costello syndrome.</strong>
Nature Genet. 37: 1038-1040, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16170316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16170316</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16170316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng1641" target="_blank">Full Text</a>]
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<a id="Axelrad2004" class="mim-anchor"></a>
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Axelrad, M. E., Glidden, R., Nicholson, L., Gripp, K. W.
<strong>Adaptive skills, cognitive, and behavioral characteristics of Costello syndrome.</strong>
Am. J. Med. Genet. 128A: 396-400, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15264285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15264285</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15264285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.30140" target="_blank">Full Text</a>]
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<a id="Berberich1991" class="mim-anchor"></a>
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Berberich, M. S., Carey, J. C., Hall, B. D.
<strong>Resolution of the perinatal and infantile failure to thrive in a new autosomal recessive syndrome with the phenotype of a storage disorder and furrowing of palmar creases. (Abstract)</strong>
Proc. Greenwood Genet. Center 10: 78 only, 1991.
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<a id="Bertola2007" class="mim-anchor"></a>
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Bertola, D. R., Pereira, A. C., Brasil, A. S., Albano, L. M. J., Kim, C. A., Krieger, J. E.
<strong>Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene.</strong>
J. Hum. Genet. 52: 521-526, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17468812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17468812</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17468812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s10038-007-0146-1" target="_blank">Full Text</a>]
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<a id="Bodkin1999" class="mim-anchor"></a>
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Bodkin, N. M., Mortimer, E. S., Demmer, L. A.
<strong>Male to male transmission of Costello syndrome consistent with autosomal dominant inheritance. (Abstract)</strong>
Am. J. Hum. Genet. 65: A143, 1999.
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<a id="Borochowitz1992" class="mim-anchor"></a>
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Borochowitz, Z., Pavone, L., Mazor, G., Rizzo, R., Dar, H.
<strong>New multiple congenital anomalies: mental retardation syndrome (MCA/MR) with facio-cutaneous-skeletal involvement.</strong>
Am. J. Med. Genet. 43: 678-685, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1621757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1621757</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1621757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320430405" target="_blank">Full Text</a>]
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<a id="Borochowitz1993" class="mim-anchor"></a>
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Borochowitz, Z., Pavone, L., Mazor, G., Rizzo, R., Dar, H.
<strong>Facio-cutaneous-skeletal syndrome: new nosological entity or Costello syndrome? (Letter)</strong>
Am. J. Med. Genet. 47: 173 only, 1993.
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<a id="Costello1977" class="mim-anchor"></a>
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Costello, J. M.
<strong>A new syndrome: mental subnormality and nasal papillomata.</strong>
Aust. Paediat. J. 13: 114-118, 1977.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/907573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">907573</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=907573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1440-1754.1977.tb01135.x" target="_blank">Full Text</a>]
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<a id="Costello1996" class="mim-anchor"></a>
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Costello, J. M.
<strong>Costello syndrome: update on the original cases and commentary. (Letter)</strong>
Am. J. Med. Genet. 62: 199-201, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8882404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8882404</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8882404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320620203" target="_blank">Full Text</a>]
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<a id="Czeizel1995" class="mim-anchor"></a>
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Czeizel, A. E., Timar, L.
<strong>Hungarian case with Costello syndrome and translocation t(1,22). (Letter)</strong>
Am. J. Med. Genet. 57: 501-503, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7677162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7677162</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7677162" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320570331" target="_blank">Full Text</a>]
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<a id="Davies1994" class="mim-anchor"></a>
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Davies, S. J., Hughes, H. E.
<strong>Costello syndrome: natural history and differential diagnosis of cutis laxa.</strong>
J. Med. Genet. 31: 486-489, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7520945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7520945</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7520945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.31.6.486" target="_blank">Full Text</a>]
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<a id="Davies1994" class="mim-anchor"></a>
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Davies, S. J., Hughes, H. E.
<strong>Cutis laxa: a feature of Costello syndrome. (Letter)</strong>
J. Med. Genet. 31: 85, 1994.
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[<a href="https://doi.org/10.1136/jmg.31.1.85" target="_blank">Full Text</a>]
</p>
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<a id="13" class="mim-anchor"></a>
<a id="de Boode1996" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
de Boode, W. P., Semmekrot, B. A., ter Laak, H. J., van der Burgt, C. J. A. M, Draaisma, J. M. T., Lommen, E. J. P, Sengers, R. C. A., van Wijk-Hoek, J. M.
<strong>Myopathology in patients with a Noonan phenotype.</strong>
Acta Neuropath. 92: 597-602, 1996.
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[<a href="https://doi.org/10.1007/s004010050566" target="_blank">Full Text</a>]
</p>
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<a id="14" class="mim-anchor"></a>
<a id="DeBaun2002" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
DeBaun, M. R.
<strong>Screening for cancer in children with Costello syndrome.</strong>
Am. J. Med. Genet. 108: 88-90, 2002.
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[<a href="https://doi.org/10.1002/ajmg.10242" target="_blank">Full Text</a>]
</p>
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<a id="15" class="mim-anchor"></a>
<a id="Della Marca2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Della Marca, G., Vasta, I., Scarano, E., Rigante, M., De Feo, E., Mariotti, P., Rubino, M., Vollono, C., Mennuni, G. F., Tonali, P., Zampino, G.
<strong>Obstructive sleep apnea in Costello syndrome.</strong>
Am. J. Med. Genet. 140A: 257-262, 2006.
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[<a href="https://doi.org/10.1002/ajmg.a.31076" target="_blank">Full Text</a>]
</p>
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<a id="16" class="mim-anchor"></a>
<a id="Der Kaloustian1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Der Kaloustian, V. M., Moroz, B., McIntosh, N., Watters, A. K., Blaichman, S.
<strong>Costello syndrome.</strong>
Am. J. Med. Genet. 41: 69-73, 1991.
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[<a href="https://doi.org/10.1002/ajmg.1320410118" target="_blank">Full Text</a>]
</p>
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<a id="17" class="mim-anchor"></a>
<a id="Der Kaloustian1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Der Kaloustian, V. M.
<strong>Not a new MCA/MR syndrome but probably Costello syndrome? (Letter)</strong>
Am. J. Med. Genet. 47: 170-171, 1993.
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[<a href="https://doi.org/10.1002/ajmg.1320470206" target="_blank">Full Text</a>]
</p>
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<a id="18" class="mim-anchor"></a>
<a id="Di Rocco1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Di Rocco, M., Gatti, R., Gandullia, P., Barabino, A., Picco, P., Borrone, C.
<strong>Report on two patients with Costello syndrome and sialuria.</strong>
Am. J. Med. Genet. 47: 1135-1140, 1993.
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[<a href="https://doi.org/10.1002/ajmg.1320470737" target="_blank">Full Text</a>]
</p>
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<a id="19" class="mim-anchor"></a>
<a id="Estep2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D., Rauen, K. A.
<strong>HRAS mutation in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.</strong>
Am. J. Med. Genet. 140A: 8-16, 2006.
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[<a href="https://doi.org/10.1002/ajmg.a.31078" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
<a id="Feingold1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Feingold, M.
<strong>Costello syndrome and rhabdomyosarcoma. (Letter)</strong>
J. Med. Genet. 36: 582-583, 1999.
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<a id="21" class="mim-anchor"></a>
<a id="Franceschini1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Franceschini, P., Licata, D., Di Cara, G., Guala, A., Bianchi, M., Ingrosso, G., Franceschini, D.
<strong>Bladder carcinoma in Costello syndrome: report on a patient born to consanguineous parents and review.</strong>
Am. J. Med. Genet. 86: 174-179, 1999.
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<a id="22" class="mim-anchor"></a>
<a id="Fryns1994" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Fryns, J. P., Vogels, A., Haegeman, J., Eggermont, E., Van Den Berghe, H.
<strong>Costello syndrome: a postnatal growth retardation syndrome with distinct phenotype.</strong>
Genet. Counsel. 5: 337-343, 1994.
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<a id="23" class="mim-anchor"></a>
<a id="Goodwin2014" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Goodwin, A. F., Tidyman, W. E., Jheon, A. H., Sharir, A., Zheng, X., Charles, C., Fagin, J. A., McMahon, M., Diekwisch, T. G. H., Ganss, B., Rauen, K. A., Klein, O. D.
<strong>Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation.</strong>
Hum. Molec. Genet. 23: 682-692, 2014.
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[<a href="https://doi.org/10.1093/hmg/ddt455" target="_blank">Full Text</a>]
</p>
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<a id="24" class="mim-anchor"></a>
<a id="Goodwin2014" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Goodwin, A. F.
<strong>Personal Communication.</strong>
San Francisco, Calif. 8/28/2014.
</p>
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<a id="25" class="mim-anchor"></a>
<a id="Gripp2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gripp, K. W., Hopkins, E., Doyle, D., Dobyns, W. B.
<strong>High incidence of progressive postnatal cerebellar enlargement in Costello syndrome: brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities.</strong>
Am. J. Med. Genet. 152A: 1161-1168, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20425820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20425820</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20425820[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20425820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.33391" target="_blank">Full Text</a>]
</p>
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<a id="26" class="mim-anchor"></a>
<a id="Gripp2011" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gripp, K. W., Hopkins, E., Sol-Church, K., Stabley, D. L., Axelrad, M. E., Doyle, D., Dobyns, W. B., Hudson, C., Johnson, J., Tenconi, R., Graham, G. E., Sousa, A. B., Heller, R., Piccione, M., Corsello, G., Herman, G. E., Tartaglia, M., Lin, A. E.
<strong>Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C.</strong>
Am. J. Med. Genet. 155A: 706-716, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21438134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21438134</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21438134[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21438134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.33884" target="_blank">Full Text</a>]
</p>
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<a id="27" class="mim-anchor"></a>
<a id="Gripp2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gripp, K. W., Innes, A. M., Axelrad, M. E., Gillan, T. L., Parboosingh, J. S., Davies, C., Leonard, N. J., Lapointe, M., Doyle, D., Catalano, S., Nicholson, L., Stabley, D. L., Sol-Church, K.
<strong>Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype?</strong>
Am. J. Med. Genet. 146A: 683-690, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18247425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18247425</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18247425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.32227" target="_blank">Full Text</a>]
</p>
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<a id="28" class="mim-anchor"></a>
<a id="Gripp2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gripp, K. W., Kawame, H., Viskochil, D. H., Nicholson, L.
<strong>Elevated catecholamine metabolites in patients with Costello syndrome.</strong>
Am. J. Med. Genet. 128A: 48-51, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15211656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15211656</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15211656" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.30100" target="_blank">Full Text</a>]
</p>
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<a id="29" class="mim-anchor"></a>
<a id="Gripp2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gripp, K. W., Lin, A. E., Nicholson, L., Allen, W., Cramer, A., Jones, K. L., Kutz, W., Peck, D., Rebolledo, M. A., Wheeler, P. G., Wilson, W., Al-Rahawan, M. M., Stabley, D. L., Sol-Church, K.
<strong>Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.</strong>
Am. J. Med. Genet. 143A: 1472-1480, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17551924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17551924</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17551924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.31815" target="_blank">Full Text</a>]
</p>
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<a id="30" class="mim-anchor"></a>
<a id="Gripp2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gripp, K. W., Lin, A. E., Stabley, D. L., Nicholson, L., Scott, C. I., Jr., Doyle, D., Aoki, Y., Matsubara, Y., Zackai, E. H., Lapunzina, P., Gonzalez-Meneses, A., Holbrook, J., Agresta, C. A., Gonzalez, I. L., Sol-Church, K.
<strong>HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.</strong>
Am. J. Med. Genet. 140A: 1-7, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16329078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16329078</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16329078" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.31047" target="_blank">Full Text</a>]
</p>
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<a id="31" class="mim-anchor"></a>
<a id="Gripp2019" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gripp, K. W., Morse, L. A., Axelrad, M., Chatfield, K. C., Chidekel, A., Dobyns, W., Doyle, D., Kerr, B., Lin, A. E., Schwartz, D. D., Sibbles, B. J., Siegel, D., Shankar, S. P., Stevenson, D. A., Thacker, M. M., Weaver, K. N., White, S. M., Rauen, K. A.
<strong>Costello syndrome: clinical phenotype, genotype, and managment guidelines.</strong>
Am. J. Med. Genet. 179A: 1725-1744, 2019.
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[<a href="https://doi.org/10.1002/ajmg.a.61270" target="_blank">Full Text</a>]
</p>
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<a id="32" class="mim-anchor"></a>
<a id="Gripp2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gripp, K. W., Scott, C. I., Jr., Nicholson, L., Figueroa, T. E.
<strong>Second case of bladder carcinoma in a patient with Costello syndrome. (Letter)</strong>
Am. J. Med. Genet. 90: 256-259, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10678668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10678668</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10678668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/(sici)1096-8628(20000131)90:3&lt;256::aid-ajmg16&gt;3.0.co;2-d" target="_blank">Full Text</a>]
</p>
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<a id="33" class="mim-anchor"></a>
<a id="Gripp2002" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gripp, K. W., Scott, C. I., Jr., Nicholson, L., McDonald-McGinn, D. M., Ozeran, J. D., Jones, M. C., Lin, A. E., Zackai, E. H.
<strong>Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for a tumor screening protocol.</strong>
Am. J. Med. Genet. 108: 80-87, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11857556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11857556</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11857556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.10241" target="_blank">Full Text</a>]
</p>
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<a id="34" class="mim-anchor"></a>
<a id="Gripp2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Gripp, K. W., Stabley, D. L., Nicholson, L., Hoffman, J. D., Sol-Church, K.
<strong>Somatic mosaicism for an HRAS mutation causes Costello syndrome.</strong>
Am. J. Med. Genet. 140A: 2163-2169, 2006.
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[<a href="https://doi.org/10.1002/ajmg.a.31456" target="_blank">Full Text</a>]
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<strong>Costello syndrome: an overview.</strong>
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[<a href="https://doi.org/10.1002/ajmg.c.10019" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI116280" target="_blank">Full Text</a>]
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<strong>Decreased elastin deposition and high proliferation of fibroblasts from Costello syndrome are related to functional deficiency in the 67-kD elastin-binding protein.</strong>
Am. J. Hum. Genet. 66: 859-872, 2000.
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[<a href="https://doi.org/10.1086/302829" target="_blank">Full Text</a>]
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<strong>Myocardial storage of chondroitin sulfate-containing moieties in Costello syndrome patients with severe hypertrophic cardiomyopathy.</strong>
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[<a href="https://doi.org/10.1002/ajmg.a.30495" target="_blank">Full Text</a>]
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<strong>Costello syndrome in two siblings and minor manifestations in their mother: further evidence for autosomal dominant inheritance?</strong>
Genet. Counsel. 13: 353-356, 2002.
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Ion, A., Tartaglia, M., Song, X., Kalidas, K., van der Burgt, I., Shaw, A. C., Ming, J. E., Zampino, G., Zackai, E. H., Dean, J. C. S., Somer, M., Parenti, G., Crosby, A. H., Patton, M. A., Gelb, B. D., Jeffery, S.
<strong>Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome.</strong>
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[<a href="https://doi.org/10.1007/s00439-002-0803-6" target="_blank">Full Text</a>]
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<strong>The Costello syndrome: a boy with thick mitral valves and arrhythmias.</strong>
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[<a href="https://doi.org/10.1007/BF01874143" target="_blank">Full Text</a>]
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<strong>Costello syndrome: phenotype, natural history, differential diagnosis, and possible cause.</strong>
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[<a href="https://doi.org/10.1016/s0022-3476(98)70284-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.10236" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32273" target="_blank">Full Text</a>]
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Kerr, B., Delrue, M.-A., Sigaudy, S., Perveen, R., Marche, M., Burgelin, I., Stef, M., Tang, B., Eden, O. B., O'Sullivan, J., De Sandre-Giovannoli, A., Reardon, W., and 14 others.
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[<a href="https://doi.org/10.1136/jmg.2005.040352" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.35.12.1036" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01907991" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32335" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.33857" target="_blank">Full Text</a>]
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<a id="Lin2002" class="mim-anchor"></a>
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Lin, A. E., Grossfeld, P. D., Hamilton, R. M., Smoot, L., Gripp, K. W., Proud, V., Weksberg, R., Wheeler, P., Picker, J., Irons, M., Zackai, E., Marino, B., Scott, C. I., Jr., Nicholson, L.
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[<a href="https://doi.org/10.1002/ajmg.10558" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32164" target="_blank">Full Text</a>]
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Lo, I. F. M., Brewer, C., Shannon, N., Shorto, J., Tang, B., Black, G., Soo, M. T., Ng, D. K. K., Lam, S. T. S., Kerr, B.
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[<a href="https://doi.org/10.1136/jmg.2007.054411" target="_blank">Full Text</a>]
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<strong>Functional analysis of a duplication (p.E63_D69dup) in the switch II region of HRAS: new aspects of the molecular pathogenesis underlying Costello syndrome.</strong>
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[<a href="https://doi.org/10.1093/hmg/ddt014" target="_blank">Full Text</a>]
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<strong>Genetics of the Costello syndrome.</strong>
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[<a href="https://doi.org/10.1002/ajmg.1320520321" target="_blank">Full Text</a>]
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<strong>Refinement and delineation of the breakpoint regions of a chromosome 1;22 translocation in a patient with Costello syndrome.</strong>
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[<a href="https://doi.org/10.1002/ajmg.10314" target="_blank">Full Text</a>]
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<strong>Delineation of the Costello syndrome.</strong>
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[<a href="https://doi.org/10.1002/ajmg.1320410316" target="_blank">Full Text</a>]
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<strong>Facio-cutaneous-skeletal syndrome is the Costello syndrome. (Letter)</strong>
Am. J. Med. Genet. 47: 169 only, 1993.
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[<a href="https://doi.org/10.1002/ajmg.1320470205" target="_blank">Full Text</a>]
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<strong>Assessing genotype-phenotype correlation in Costello syndrome using a severity score.</strong>
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[<a href="https://doi.org/10.1038/gim.2013.6" target="_blank">Full Text</a>]
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<strong>Elastic fiber degeneration in Costello syndrome.</strong>
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[<a href="https://doi.org/10.1002/(SICI)1096-8628(19960202)61:4&lt;304::AID-AJMG2&gt;3.0.CO;2-U" target="_blank">Full Text</a>]
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<strong>Costello syndrome: a cancer predisposing syndrome?</strong>
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[<a href="https://doi.org/10.1097/00019605-200009040-00006" target="_blank">Full Text</a>]
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<strong>A Japanese patient with the Costello syndrome.</strong>
Hum. Genet. 93: 605-606, 1994.
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[<a href="https://doi.org/10.1007/BF00202834" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.30.7.622" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.24.9.556" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320470209" target="_blank">Full Text</a>]
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<strong>A premature infant with Costello syndrome due to a rare G13C HRAS mutation.</strong>
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[<a href="https://doi.org/10.1002/ajmg.a.32674" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.273.11.6319" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31315" target="_blank">Full Text</a>]
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<strong>The Costello syndrome.</strong>
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[<a href="https://doi.org/10.1002/ajmg.1320470203" target="_blank">Full Text</a>]
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<strong>A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition.</strong>
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[<a href="https://doi.org/10.1172/JCI34385" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2007.00931.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/1097-4598(200101)24:1&lt;138::aid-mus22&gt;3.0.co;2-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1542/peds.101.4.706" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32778" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32639" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1515/JPM.2005.034" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00019605-199804000-00014" target="_blank">Full Text</a>]
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<strong>Disruption of the PDGFB gene in a 1;22 translocation patient does not cause Costello syndrome.</strong>
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[<a href="https://doi.org/10.1016/j.ygeno.2003.10.012" target="_blank">Full Text</a>]
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<strong>Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous and Costello syndromes.</strong>
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<li>
<a id="79" class="mim-anchor"></a>
<a id="Teebi1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Teebi, A. S., Shaabani, I. S.
<strong>Further delineation of Costello syndrome.</strong>
Am. J. Med. Genet. 47: 166-168, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8213898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8213898</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8213898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320470204" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="80" class="mim-anchor"></a>
<a id="Teebi1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Teebi, A. S.
<strong>Costello or facio-cutaneous-skeletal syndrome? (Letter)</strong>
Am. J. Med. Genet. 47: 172, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8213901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8213901</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8213901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320470207" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="81" class="mim-anchor"></a>
<a id="Torrelo1995" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Torrelo, A., Lopez-Avila, A., Mediero, I. G., Zambrano, A.
<strong>Costello syndrome.</strong>
J. Am. Acad. Derm. 32: 904-907, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7722055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7722055</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7722055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0190-9622(95)91559-1" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="82" class="mim-anchor"></a>
<a id="Troger2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Troger, B., Kutsche, K., Bolz, H., Luttgen, S., Gal, A., Almassy, Z., Caliebe, A., Freisinger, P., Hobbiebrunken, E., Morlot, M., Stefanova, M., Streubel, B., Wieczorek, D., Meinecke, P.
<strong>No mutation in the gene for Noonan syndrome, PTPN11, in 18 patients with Costello syndrome. (Letter)</strong>
Am. J. Med. Genet. 121A: 82-84, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12900909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12900909</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12900909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.20122" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="83" class="mim-anchor"></a>
<a id="Umans1995" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Umans, S., Decock, P., Fryns, J. P.
<strong>Costello syndrome: the natural history of a true postnatal growth retardation syndrome.</strong>
Genet. Counsel. 6: 121-125, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7546454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7546454</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7546454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="84" class="mim-anchor"></a>
<a id="van der Burgt2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
van der Burgt, I., Kupsky, W., Stassou, S., Nadroo, A., Barroso, C., Diem, A., Kratz, C. P., Dvorsky, R., Ahmadian, M. R., Zenker, M.
<strong>Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive Hras activation. (Letter)</strong>
J. Med. Genet. 44: 459-462, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17412879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17412879</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17412879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.2007.049270" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="85" class="mim-anchor"></a>
<a id="van Eeghen1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
van Eeghen, A. M., van Gelderen, I., Hennekam, R.C.M.
<strong>Costello syndrome: report and review.</strong>
Am. J. Med. Genet. 82: 187-193, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9934987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9934987</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9934987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/(sici)1096-8628(19990115)82:2&lt;187::aid-ajmg17&gt;3.0.co;2-2" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="86" class="mim-anchor"></a>
<a id="White2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
White, S. M., Graham, J. M., Jr., Kerr, B., Gripp, K., Weksberg, R., Cytrynbaum, C., Reeder, J. L., Stewart, F. J., Edwards, M., Wilson, M., Bankier, A.
<strong>The adult phenotype in Costello syndrome.</strong>
Am. J. Med. Genet. 136A: 128-135, 2005. Note: Erratum: Am. J. Med. Genet. 139A: 55 only, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15940703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15940703</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15940703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.30747" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="87" class="mim-anchor"></a>
<a id="Yoshida1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yoshida, R., Fukushima, Y., Ohashi, H., Asoh, M., Fukuyama, Y.
<strong>The Costello syndrome: are nasal papillomata essential?</strong>
Jpn. J. Hum. Genet. 38: 437-444, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8186422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8186422</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8186422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF01907992" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="88" class="mim-anchor"></a>
<a id="Zampino1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zampino, G., Mastroiacovo, P., Ricci, R., Zollino, M., Segni, G., Martini-Neri, M. E., Neri, G.
<strong>Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology.</strong>
Am. J. Med. Genet. 47: 176-183, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8213903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8213903</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8213903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320470210" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="89" class="mim-anchor"></a>
<a id="Zampino2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zampino, G., Pantaleoni, F., Carta, C., Cobellis, G., Vasta, I., Neri, C., Pogna, E. A., De Feo, E., Delogu, A., Sarkozy, A., Atzeri, F., Selicorni, A., Rauen, K. A., Cytrynbaum, C. S., Weksberg, R., Dallapiccola, B., Ballabio, A., Gelb, B. D., Neri, G., Tartaglia, M.
<strong>Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.</strong>
Hum. Mutat. 28: 265-272, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054105</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/humu.20431" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="90" class="mim-anchor"></a>
<a id="Zenker2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K.
<strong>Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.</strong>
J. Med. Genet. 44: 131-135, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17056636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17056636</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17056636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.2006.046300" target="_blank">Full Text</a>]
</p>
</div>
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<div>
<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Hilary J. Vernon - updated : 11/13/2020
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<div class="row collapse" id="mimCollapseContributors">
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Cassandra L. Kniffin - updated : 8/27/2014<br>Cassandra L. Kniffin - updated : 3/19/2014<br>Ada Hamosh - updated : 11/12/2013<br>Cassandra L. Kniffin - updated : 3/13/2013<br>Cassandra L. Kniffin - updated : 9/11/2012<br>Cassandra L. Kniffin - updated : 6/28/2011<br>Cassandra L. Kniffin - updated : 4/16/2010<br>Cassandra L. Kniffin - updated : 2/16/2010<br>Marla J. F. O'Neill - updated : 6/1/2009<br>Cassandra L. Kniffin - updated : 3/3/2009<br>Marla J. F. O'Neill - updated : 11/12/2008<br>Cassandra L. Kniffin - updated : 6/25/2008<br>Cassandra L. Kniffin - updated : 4/14/2008<br>Cassandra L. Kniffin - updated : 3/24/2008<br>Cassandra L. Kniffin - updated : 8/28/2007<br>Cassandra L. Kniffin - updated : 5/16/2007<br>Cassandra L. Kniffin - updated : 3/2/2007<br>Marla J. F. O'Neill - updated : 9/26/2006<br>Marla J. F. O'Neill - updated : 6/20/2006<br>Cassandra L. Kniffin - updated : 2/8/2006<br>Marla J. F. O'Neill - updated : 1/25/2006<br>Marla J. F. O'Neill - updated : 12/28/2005<br>Kelly A. Przylepa - updated : 11/8/2005<br>Marla J. F. O'Neill - updated : 10/19/2005<br>Victor A. McKusick - updated : 9/21/2005<br>Marla J. F. O'Neill - updated : 7/20/2004<br>Victor A. McKusick - updated : 5/6/2004<br>Victor A. McKusick - updated : 8/25/2003<br>Victor A. McKusick - updated : 6/4/2003<br>Victor A. McKusick - updated : 4/16/2003<br>Victor A. McKusick - updated : 3/7/2003<br>Victor A. McKusick - updated : 12/31/2002<br>Deborah L. Stone - updated : 10/25/2002<br>Victor A. McKusick - updated : 5/21/2002<br>Victor A. McKusick - updated : 2/8/2002<br>Ada Hamosh - updated : 2/6/2001<br>Victor A. McKusick - updated : 3/22/2000<br>Victor A. McKusick - updated : 2/24/2000<br>Sonja A. Rasmussen - updated : 10/5/1999<br>Michael J. Wright - updated : 8/13/1999<br>Victor A. McKusick - updated : 2/14/1999<br>Michael J. Wright - updated : 2/12/1999<br>Victor A. McKusick - updated : 1/25/1999<br>Ada Hamosh - updated : 6/15/1998<br>Victor A. McKusick - updated : 2/19/1998<br>Iosif W. Lurie - updated : 10/2/1996
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<div>
<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
<span class="text-nowrap mim-text-font">
Creation Date:
</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Victor A. McKusick : 11/20/1991
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<span class="mim-text-font">
carol : 01/14/2025
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<div class="row collapse" id="mimCollapseEditHistory">
<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
carol : 11/16/2020<br>carol : 11/13/2020<br>carol : 08/06/2020<br>carol : 01/05/2016<br>alopez : 8/4/2015<br>carol : 8/29/2014<br>mcolton : 8/28/2014<br>ckniffin : 8/27/2014<br>carol : 3/25/2014<br>mcolton : 3/25/2014<br>ckniffin : 3/19/2014<br>alopez : 11/12/2013<br>alopez : 7/10/2013<br>carol : 3/14/2013<br>ckniffin : 3/13/2013<br>carol : 2/27/2013<br>ckniffin : 9/11/2012<br>alopez : 1/20/2012<br>wwang : 7/13/2011<br>ckniffin : 6/28/2011<br>joanna : 5/17/2011<br>wwang : 4/30/2010<br>ckniffin : 4/16/2010<br>ckniffin : 4/16/2010<br>wwang : 2/18/2010<br>ckniffin : 2/16/2010<br>ckniffin : 2/4/2010<br>joanna : 9/16/2009<br>wwang : 6/3/2009<br>terry : 6/1/2009<br>wwang : 3/5/2009<br>ckniffin : 3/3/2009<br>wwang : 11/14/2008<br>terry : 11/12/2008<br>wwang : 9/12/2008<br>ckniffin : 9/8/2008<br>carol : 8/22/2008<br>ckniffin : 6/25/2008<br>carol : 5/5/2008<br>ckniffin : 4/14/2008<br>wwang : 4/3/2008<br>ckniffin : 3/24/2008<br>wwang : 3/18/2008<br>ckniffin : 3/17/2008<br>ckniffin : 9/12/2007<br>carol : 9/10/2007<br>ckniffin : 9/10/2007<br>carol : 9/6/2007<br>carol : 9/6/2007<br>ckniffin : 8/28/2007<br>wwang : 5/22/2007<br>ckniffin : 5/16/2007<br>carol : 3/8/2007<br>ckniffin : 3/2/2007<br>wwang : 9/27/2006<br>terry : 9/26/2006<br>carol : 8/28/2006<br>wwang : 6/20/2006<br>terry : 6/20/2006<br>wwang : 2/13/2006<br>ckniffin : 2/8/2006<br>wwang : 2/2/2006<br>terry : 1/25/2006<br>wwang : 12/29/2005<br>terry : 12/28/2005<br>alopez : 11/8/2005<br>wwang : 10/24/2005<br>terry : 10/19/2005<br>alopez : 10/14/2005<br>alopez : 9/26/2005<br>alopez : 9/23/2005<br>alopez : 9/23/2005<br>terry : 9/21/2005<br>terry : 4/18/2005<br>carol : 7/20/2004<br>tkritzer : 5/11/2004<br>terry : 5/6/2004<br>mgross : 3/17/2004<br>tkritzer : 8/27/2003<br>terry : 8/25/2003<br>tkritzer : 6/11/2003<br>terry : 6/4/2003<br>tkritzer : 4/28/2003<br>terry : 4/16/2003<br>carol : 3/18/2003<br>tkritzer : 3/18/2003<br>terry : 3/7/2003<br>cwells : 2/11/2003<br>terry : 12/31/2002<br>carol : 10/25/2002<br>carol : 10/25/2002<br>cwells : 6/4/2002<br>cwells : 6/4/2002<br>terry : 5/21/2002<br>alopez : 2/19/2002<br>terry : 2/8/2002<br>mcapotos : 2/12/2001<br>terry : 2/6/2001<br>carol : 11/13/2000<br>mgross : 4/3/2000<br>terry : 3/22/2000<br>alopez : 2/28/2000<br>terry : 2/24/2000<br>carol : 10/5/1999<br>terry : 8/13/1999<br>terry : 6/11/1999<br>mgross : 3/16/1999<br>mgross : 2/17/1999<br>mgross : 2/16/1999<br>carol : 2/14/1999<br>terry : 2/12/1999<br>carol : 2/5/1999<br>mgross : 2/5/1999<br>terry : 1/25/1999<br>alopez : 6/15/1998<br>terry : 2/19/1998<br>terry : 7/9/1997<br>carol : 6/3/1997<br>carol : 10/2/1996<br>mark : 9/19/1996<br>mark : 4/25/1996<br>terry : 4/18/1996<br>mark : 2/22/1996<br>terry : 2/19/1996<br>mark : 7/16/1995<br>carol : 2/3/1995<br>jason : 7/27/1994<br>mimadm : 2/19/1994<br>carol : 11/29/1993<br>carol : 11/22/1993
</span>
</div>
</div>
</div>
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<div class="row">
<div class="col-md-8 col-md-offset-1">
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<h3>
<span class="mim-font">
<strong>#</strong> 218040
</span>
</h3>
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<div>
<h3>
<span class="mim-font">
COSTELLO SYNDROME; CSTLO
</span>
</h3>
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<div>
<br />
</div>
<div>
<div >
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
FACIOCUTANEOSKELETAL SYNDROME<br />
FCS SYNDROME
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES, INCLUDED; CMEMS, INCLUDED
</span>
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<br />
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<p>
<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 309776008; &nbsp;
<strong>ORPHA:</strong> 3071; &nbsp;
<strong>DO:</strong> 0050469; &nbsp;
</span>
</p>
</div>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
11p15.5
</span>
</td>
<td>
<span class="mim-font">
Costello syndrome
</span>
</td>
<td>
<span class="mim-font">
218040
</span>
</td>
<td>
<span class="mim-font">
Autosomal dominant
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
HRAS
</span>
</td>
<td>
<span class="mim-font">
190020
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
11p15.5
</span>
</td>
<td>
<span class="mim-font">
Congenital myopathy with excess of muscle spindles
</span>
</td>
<td>
<span class="mim-font">
218040
</span>
</td>
<td>
<span class="mim-font">
Autosomal dominant
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
HRAS
</span>
</td>
<td>
<span class="mim-font">
190020
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because of evidence that Costello syndrome (CSTLO) is caused by heterozygous mutation in the HRAS gene (190020) on chromosome 11p15. A variant of Costello syndrome, congenital myopathy with excess of muscle spindles, is also caused by mutation in HRAS.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Costello syndrome is a rare multiple congenital anomaly syndrome associated in all cases with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and developmental disability. Facial warts, particularly nasolabial, are often present in childhood (Kerr et al., 2006). </p><p>Costello syndrome shows phenotypic overlap with cardiofaciocutaneous syndrome (CFC; 115150) and Noonan syndrome (see 163950).</p><p>In patients with a clinical diagnosis of Costello syndrome, Zenker et al. (2007) identified mutations in the KRAS gene, but noted that these patients may later develop features of CFC syndrome. In either case, the findings underscore the central role of Ras in the pathogenesis of these phenotypically related disorders (Zenker et al., 2007). However, Kerr et al. (2008) commented that the diagnosis of Costello syndrome should only be used to refer to patients with mutations in the HRAS gene. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Costello (1977) described 2 unrelated children with a syndrome comprising short stature, redundant skin of the neck, palms, soles, and fingers, curly hair, papillomata around the mouth and nares, and mental retardation. Der Kaloustian et al. (1991) reported a boy with the same syndrome. The parents were not consanguineous in any of the 3 cases. The patient of Der Kaloustian et al. (1991) had an aged facial appearance with thin anterior hair of the head. Epicanthal folds, large, depressed nasal bridge, and large earlobes were noted. The verrucal lesions were present around the anus as well as around the mouth and nares. The loose skin over the hands and feet was also thickened and the palms and soles were hyperkeratotic. The skin color was generally dark. Some similarities to the cardiofaciocutaneous syndrome (CFC; 115150) and Noonan syndrome (163950) were noted. </p><p>Martin and Jones (1991) reported a 15-year-old girl with mental retardation, short stature, coarse face, thick and loose skin of the hands and feet, deep plantar and palmar creases, and nasal papillomata. Berberich et al. (1991) reported 3 patients, 2 of whom were sibs, with a presumably new syndrome of failure to thrive, cardiomyopathy, and furrowing of palmar creases. Later these cases were diagnosed as Costello syndrome (Der Kaloustian, 1993; Zampino et al., 1993). Additional patients were reported by Say et al. (1993), Teebi and Shaabani (1993), Philip and Mancini (1993), and Zampino et al. (1993). Zampino et al. (1993) provided photographs of a 24-year-old patient. Di Rocco et al. (1993) reported 2 unrelated patients, a 5-year-old girl and a 3-year-old boy, with Costello syndrome and sialuria. Di Rocco et al. (1993) suggested that urine and fibroblast sialic acid should be tested in other Costello syndrome patients. In both of their patients, feeding problems and abnormal speech were related to an oral motor apraxia. The girl also had acanthosis nigricans and abnormal glucose metabolism (fasting hypoglycemia and postprandial hyperglycemia). </p><p>Borochowitz et al. (1992) reported 5 unrelated patients, 1 male and 4 females, with a previously undefined multiple congenital anomalies/mental retardation (MCA/MR) syndrome which they designated the faciocutaneoskeletal (FCS) syndrome. The features included mental retardation with specific sociable, humorous behavior, characteristic facial appearance, generally excessive skin, postnatal growth failure, and skeletal abnormalities. Consanguinity was noted in 2 patients, suggesting autosomal recessive inheritance. Coarse facies, wide hirsute forehead, wide anteverted nostrils, and thick lips were pictured. Martin and Jones (1993), Der Kaloustian (1993), Teebi (1993), Philip and Mancini (1993), and Zampino et al. (1993) suggested that the FCS syndrome described by Borochowitz et al. (1992) is the same as the Costello syndrome. Borochowitz et al. (1993) concluded, on the other hand, that 'it is premature to reach a definite conclusion at this stage.' Patton and Baraitser (1993) reviewed 5 cases from their previous paper on cutis laxa (see 219200) (Patton et al., 1987) and concluded that the appropriate diagnosis was in fact Costello syndrome. Independently, Davies and Hughes (1994) reviewed case 7 from the same paper and, based on both history and clinical examination, made 'an unequivocal diagnosis of Costello syndrome.' In a longer report, Davies and Hughes (1994) described the development of one of the patients of Patton et al. (1987) for more than 10 years and again emphasized that Costello syndrome should be included in the differential diagnosis of cutis laxa in association with postnatal growth retardation and developmental delay. </p><p>Izumikawa et al. (1993) reported the case of a 3-year-old boy who had typical clinical features except for the absence of nasal papillomas and who also had cardiac anomalies with extrasystoles and thick mitral valves. Kondo et al. (1993) emphasized nasal papillomata as particularly characteristic of Costello syndrome and pointed out that the age at development ranged from 2 to 15 years in reported cases. </p><p>Fryns et al. (1994) described 2 unrelated patients with Costello syndrome, a 12-year-old girl and a 3.5-year-old boy. Severe postnatal growth retardation was the first clinical sign. Characteristic facial changes, loose and hyperelastic skin, and papillomata became progressively more evident with age. The patients presented a pleasant, happy nature and were mildly to moderately mentally retarded. Okamoto et al. (1994) reported the case of a Japanese patient. A fundoplication was performed at the age of 11 months to treat severe gastroesophageal reflux. The infant had congenital bilateral subluxation of the hips. At the age of 7 years, there was generalized pigmentation and acanthosis nigricans around the neck and axilla. Endocrinologic evaluation demonstrated partial deficiency of growth hormone. Stating that 16 cases had been reported, Torrelo et al. (1995) presented the case of a 15-year-old girl and emphasized the cutaneous manifestations of the disorder. </p><p>Umans et al. (1995) described the natural history of the Costello syndrome in a child followed from birth to the age of 12 years. Severe feeding difficulties and poor sucking with swallowing difficulties are features. The history of polyhydramnios in almost all pregnancies indicates that diminished swallowing starts very early in fetal life. Generalized lymphoedema was noted at birth and hypotonia is a feature. </p><p>Mori et al. (1996) described a case of Costello syndrome. The main clinical findings were loose skin of the neck, hands, and feet, deep palmar and plantar creases, typical 'coarse' face with thick lips and macroglossia, relative macrocephaly, mental retardation, short stature, arrhythmia, large size for gestational age, and poor feeding. The infant died of rhabdomyolysis at the age of 6 months. The major pathologic findings were fine, disrupted, and loosely-constructed elastic fibers in the skin, tongue, pharynx, larynx, and upper esophagus, but not in the bronchi, alveoli, aorta, or coronary arteries. The degeneration of elastic fibers was confirmed in the skin of a second Costello syndrome patient, that described previously by Yoshida et al. (1993). Autopsy also showed degeneration of the atrial conduction system, calcification and ballooning of skeletal muscle fibers with infiltration of macrophages, and myoglobin deposits in the collecting ducts of the kidney, consistent with rhabdomyolysis. They analyzed the clinical findings in 14 cases. </p><p>Costello (1996) provided an update on the original cases and commented on other reported examples of this syndrome. Case 1 was reviewed at the age of 32 years. In summary, he had been known to have hypertension since the age of 17 years. Surgical operation had been required for recurrent inguinal hernia, ruptured cornea associated with keratoconus in the left eye, and hemorrhoidectomy. Duodenal ulcer and gastroesophageal reflux were diagnosed at age 20 following an episode of hematemesis and melena. Case 2 was reviewed at the age of 27 years. In summary, she had been asthmatic since age 18 years. Mammography at age 21 suggested severe fibroadenosis; warty hyperkeratosis of the nipples and lichenified eczema of the neck were noted. A cardiologic assessment was made at age 22 for a systolic murmur. Costello (1996) presented a table of manifestations frequently seen in Costello syndrome and also in Noonan syndrome and/or CFC syndrome, as well as a table of manifestations frequently seen in Costello syndrome but infrequent or absent in the other 2 syndromes. Out of 16 cases reviewed, 13 had low-set ears with large/thick lobes, 13 had thick lips, 12 had nasal papillomas and/or papillomas elsewhere, 16 had loose skin of the hands and feet, 14 had deep palmar creases, 12 had hyperkeratotic palms and soles, and 12 had hyperextensible fingers. Costello (1996) concluded that it is possible to make the clinical diagnosis of Costello syndrome with confidence. In particular, it is possible to differentiate Costello syndrome clearly from Noonan and CFC syndromes. </p><p>Siwik et al. (1998) reviewed the cardiac manifestations of Costello syndrome in 30 patients, 18 of whom had at least 1 cardiac abnormality. Of these 18, 9 had structural heart disease, 6 had hypertrophic cardiomyopathy (mean age of onset 6.5 years, range 5 months to 20 years), and 5 had tachyarrhythmias. The authors recommended cardiac evaluation for any patient in whom the diagnosis of Costello syndrome has been established, and subsequent follow-up of affected individuals for the development of hypertrophic cardiomyopathy. </p><p>Lin et al. (2002) reviewed the cardiac abnormalities in 94 patients with Costello syndrome and found the following in 59 (63%) patients: cardiovascular malformation in 30% (most commonly pulmonic stenosis), cardiac hypertrophy in 34%, and rhythm disturbances in 33% (most commonly atrial tachycardia). Most (68%) of the patients with a rhythm abnormality had a cardiovascular malformation, cardiac hypertrophy, or both. The authors recommended baseline and additional cardiac evaluations in all patients with Costello syndrome. </p><p>Van Eeghen et al. (1999) reported the case of a 34-year-old woman with the diagnosis of Costello syndrome. Features included mental retardation, short stature, macrocephaly, 'coarse' face, hoarse voice, and redundant skin with deep palmar and plantar creases. She had wart-like lesions of the skin. </p><p>Feingold (1999) reported a child with Costello syndrome who developed an alveolar rhabdomyosarcoma of the right foot at the age of 6 months. </p><p>Kerr et al. (1998) reported 2 children diagnosed with Costello syndrome in the first months of life who developed retroperitoneal embryonal rhabdomyosarcoma. They suggested that increased risk of malignancy may be part of Costello syndrome. Moroni et al. (2000) reported a patient with Costello syndrome who developed an intrathoracic ganglioneuroblastoma. They cited several other patients with tumors and suggested that neural crest neoplasia may be a significant risk factor for children with Costello syndrome. </p><p>Franceschini et al. (1999) reported a 12-year-old boy with Costello syndrome who was born to consanguineous parents. At age 11 years, this patient developed bladder carcinoma, a rare event in childhood, supporting an increased risk of malignancy in this syndrome. Gripp et al. (2000) likewise reported a case of transitional cell carcinoma of the bladder in a patient with Costello syndrome. Birth weight and birth length had been greater than the 95th centile but at the 50th centile within weeks or months. Gastrostomy tube placement was required at 6 months because of feeding problems and failure to thrive. Redundancy of skin folds of palms, labia majora, and other body areas was noted at that time. Biventricular concentric hypertrophic cardiomyopathy with asymmetric septal hypertrophy and a large pressure gradient from the left ventricle to the aorta were seen. Treatment with the beta blocker propranolol over a period of several years led to relief of the left ventricular outflow tract obstruction. Papillomata (squamous acanthomas) of the cheeks were noted at age 4; perineal papillomata developed at age 14. Hair growth was extremely slow requiring trims once a year. Nails were thin and dysplastic. Body odor was a persistent problem. The bladder cancer was discovered at the age of 14 years. </p><p>Gripp et al. (2002) reported 5 new cases of rhabdomyosarcoma in Costello syndrome, bringing the number of reported cases of solid tumors to 17. They pointed out that the frequency is in the same order of magnitude as that of solid tumors in Beckwith-Wiedemann syndrome (BWS; 130650) and may justify tumor screening. In 8 of the 10 cases of Costello syndrome with rhabdomyosarcoma, the tumor originated from the abdomen, pelvis, or urogenital areas. Prior diagnosis of Costello syndrome was a prerequisite for the implementation of any screening protocol. Conversely, the diagnosis of Costello syndrome should be considered in individuals with rhabdomyosarcoma and physical findings suggestive of Costello syndrome. DeBaun (2002) reviewed the usefulness of screening in Costello syndrome. </p><p>Ioan and Fryns (2002) described Costello syndrome in a brother and sister, with minor manifestations in their mother. The sibs had severe mental and motor retardation, feeding difficulties, failure to thrive in the first months of life, coarse facial appearance, skin hyperlaxity, and skeletal deformities. The mother presented with mild to moderate mental retardation, short stature, facial fullness, and wart-like lesions on her face. </p><p>Hennekam (2003) stated that 115 cases of Costello syndrome had been described. He summarized clinical data on 73 of the cases and illustrated the characteristic facial appearance and palm of the hand. </p><p>Kawame et al. (2003) retrospectively reviewed the clinical records and findings in 5 girls and 5 boys with Costello syndrome. All showed significant postnatal growth retardation and severe feeding difficulties leading to failure to thrive from early infancy. All required tube feeding and some needed high-calorie formulas for variable periods. Developmental quotients/IQs in 7 children were 50 or less, and 3 were in the mildly retarded range. Five had seizures. Although happy and sociable personality had previously been established as characteristic of the disorder, Kawame et al. (2003) noted that during infancy, all 10 children showed significant irritability, including hypersensitivity to sound and tactile stimuli, sleep disturbance, and excessive shyness with strangers. These symptoms usually disappeared around 2 to 4 years of age. Other clinical features were cardiac abnormalities in 8, musculoskeletal abnormalities in all 10, and ophthalmologic manifestations in 5. Only 3 girls had papillomata. </p><p>Axelrad et al. (2004) performed standardized testing on 18 individuals with Costello syndrome. The Leiter International Performance Scale-Revised, a standardized nonverbal measure of intellectual ability, revealed a mean brief-IQ score of 57 (SD 12.5), within the range of mild mental retardation. In total, 17% of the participants had IQ scores within the severe range of mental retardation, 28% had IQ scores within the moderate range, 39% within the mild range, and 17% within the borderline range of intellectual functioning. Receptive language skills as assessed by the Peabody picture vocabulary test, 3rd edition, ranged from average functioning to 4 SD below the mean. Delays found on the Vineland adaptive behavior scales in the daily living skills, communication, and motor skills domains were comparable to the results seen in the Leiter brief-IQ. However, in the adaptive area of socialization, less than 50% participants fell in the low range of delay, and 25% of participants showed no delay in this domain. Axelrad et al. (2004) concluded that their study provides evidence supporting anecdotal data that Costello patients are quite social despite their cognitive difficulties. </p><p>White et al. (2005) reviewed the clinical findings of 17 adults with Costello syndrome and found the major health problems to be bladder carcinoma, benign tumors including benign breast disease, Chiari malformations, gastroesophageal reflux, pubertal delay, and osteoporosis. Intellectual disability was mild to moderate in 14 of the patients and severe in 3. </p><p>Piccione et al. (2009) reported a premature male infant born at 29 weeks' gestation due to fetal distress who was found to have Costello syndrome confirmed by genetic analysis (G13C; 190020.0007). At birth, he was asystolic, neurologically depressed, had no spontaneous respiration, and had bilateral pneumothoraces. Further studies showed periventricular hyperechogenicity, septum pellucidum cysts, small choroid plexus hemorrhage, abdominal ascites, and atrial septal defect. At 4 months of age, he was noted to have relative macrocephaly, coarse face with hypertelorism, downslanting palpebral fissures, epicanthal folds, prominent eyes, short nose, low-set ears, large mouth, short neck, loose skin of hands and feet, sparse hair, hyperpigmented skin, deep palmar creases, joint laxity, reduced subcutaneous adipose tissue, and bilateral cryptorchidism. These features led to the clinical diagnosis of Costello syndrome. At 11 months of age, he had delayed motor development with central hypotonia, but adequate mental and speech development. Papillomata were not present. Piccione et al. (2009) noted that the distinctive features of Costello syndrome may be absent during the first months of life, especially in preterm infants who often have failure to thrive and decreased subcutaneous adipose tissue. The striking facial features of the disorder become more evident after the critical neonatal period. </p><p>Smith et al. (2009) reported a female infant with Costello syndrome born at 27 weeks' gestation in a pregnancy complicated by mild polyhydramnios and preterm labor. She had fetal overgrowth, large anterior fontanel, low-set thickened and posteriorly rotated ears, and coarse facies. She developed an arrhythmia with multiple ectopic foci (chaotic atrial rhythm) at 4 weeks of age. Cardiac examination showed a hyperdynamic precordium with a systolic heart murmur, and echocardiogram showed concentric hypertrophic cardiomyopathy with pulmonary valve stenosis. Other features included hepatomegaly, hand posturing with ulnar deviation of the wrist, and hypoplastic labia. She died at 6 months of age from complications of cardiac arrhythmia and bronchopulmonary dysplasia. Genetic analysis identified a G12S mutation in the HRAS gene (190020.0003). Smith et al. (2009) emphasized the neonatal cardiac morbidity and mortality associated with Costello syndrome. </p><p>Lin et al. (2011) reviewed the cardiac features of 61 patients with Costello syndrome ranging in age from 1 month to 40 years, with 13 patients over age 18 years. Cardiovascular abnormalities were present in 85% of patients. The most common finding was hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, which was present in 37 (61%) of the 61 patients. Among these patients, HCM was chronic or progressive in 14 (38%), stabilized in 11 (37%), regressed in 4 (11%), and was unknown in 8 (22%). A congenital heart defect was present in 27 (44%) of the 61 patients, most commonly nonprogressive valvar pulmonary stenosis. Arrhythmia occurred in 34 (56%) patients, atrial tachycardia in 15 (25%), and aortic dilation in 4 (7%). The cardiac features of 85 patients with HRAS mutations from the literature were also assessed. Congenital heart disease was present in 22% of patients, HCM in 68%, arrhythmia in 40%, atrial tachycardia in 7%, and aortic dilation in 1 patient. Cardiac tissue showed myocardial fiber disarray in 7 (70%) of 10 specimens, consistent with sarcomeric dysfunction. Ten (43%) of 23 deaths among both cohorts occurred in infants less than 1 year of age, and most of these deaths were cardiac-related. The most common HRAS mutation was G12S (190020.0003), occurring in 84% of patients from the study and 71% of patients from the literature. </p><p><strong><em>Congenital Myopathy with Excess of Muscle Spindles</em></strong></p><p>
De Boode et al. (1996) reported 2 unrelated patients with progressive hypertrophic obstructive cardiomyopathy, Noonan syndrome-like facial anomalies, and increased density of muscle spindles in skeletal muscle biopsies. Both showed polyhydramnios on prenatal ultrasound and 1 had fetal hydrops. Death occurred at ages 3 weeks and 10 months, respectively. </p><p>Selcen et al. (2001) reported an infant with congenital weakness, hypotonia, arthrogryposis, atrial tachycardia, hypertrophic cardiomyopathy, and marked excess of muscle spindles on biopsy. He died at age 14 months from cardiorespiratory failure. Postmortem examination showed organomegaly. He also had bifrontal hallowing with fat pads below, triangular mouth, high-arched palate, and congenital neuroblastoma. </p><p>Stassou et al. (2005) reported a preterm neonate with arthrogryposis, hydrops fetalis, hypertrophic cardiomyopathy, and flaccid quadriplegia. Skeletal muscle biopsy showed increased muscle spindles encapsulated by fibrous tissue within most of the muscle fascicles sampled. She died at age 7 months. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Other Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Della Marca et al. (2006) found that 7 of 10 patients with Costello syndrome had obstructive sleep apnea as demonstrated by polysomnography and abnormally high apnea-hypopnea index. None of the patients were obese. All patients had 1 or more sites of narrowing in the upper airways. </p><p>Gripp et al. (2008) reported a boy with Costello syndrome and hypertrophic pyloric stenosis. A review identified pyloric stenosis in 5 (8.6%) of 58 patients with Costello syndrome, which is an increased frequency when compared to the general population (2.5 per 1,000). </p><p>Gripp et al. (2010) found abnormal brain imaging in 27 (96%) of 28 patients with Costello syndrome. All 28 had macrocephaly, and 14 (50%) of 28 had ventriculomegaly, necessitating surgical intervention in 7 (25%). Twenty-seven (96%) of 28 patients had an enlarged cerebellum causing posterior fossa crowding with cerebellar tonsillar herniation, which progressed in 10 (59%) of 17 patients who had serial studies. Cerebellar herniation was not seen in studies performed before age 6 months, but developed between 8 and 15 months of age. Herniation caused Chiari type I malformation in 9 (32%) and syrinx formation in 7 (25%) of 28 patients, and 9 (32%) needed decompression intervention. Tethered cord release was performed in 2 (7%). The symptoms associated with tonsillar herniation resembled the most common presentation of infants with Costello syndrome, including poor feeding, respiratory distress with mixed central and obstructive apnea, ocular palsy, and constant arching. Serial studies showed progression of relative macrocephaly, frontal bossing, and cerebellar tonsillar herniation, consistent with accelerated postnatal growth. Gripp et al. (2010) concluded that the findings indicated that macrocephaly and posterior fossa crowding are part of an ongoing process that occurs postnatally and results from disproportionate brain growth, rather than a static congenital anomaly. </p><p>Goodwin et al. (2014) studied 41 patients with Costello syndrome. Of the 33 patients who were examined for an enamel defect (Goodwin, 2014), 29 (88%) showed decreased enamel mineralization. Many patients had evidence of abnormal pathologic wear, suggesting that the enamel was less densely mineralized and more susceptible to abrasion than normal. Scanning electron microscopy of exfoliated teeth showed irregular or absent parallel hydroxyapatite prisms as well as absence of inter-rod crystals between enamel rods compared to controls. Similar findings were observed in a mouse model of Costello syndrome with an Hras G12V mutation (190020.0001). Ameloblasts at the labial aspect of the incisor of mutant mice were disorganized and had lost polarity compared to wildtype, and ameloblast progenitor cells were hyperproliferative. Treatment of adult mutant mice with MEK (see 176872) inhibitors rescued the enamel defect and restored normal progenitor cell proliferation and differentiation, whereas treatment with a PIK3 inhibitor only corrected the progenitor cell proliferation defect. The findings indicated that activated HRAS negatively regulates enamel formation. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Biochemical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Gripp et al. (2004) found elevated catecholamine metabolite levels (vanillylmandelic acid and/or homovanillic acid) in the urine of 8 patients with Costello syndrome. Imaging studies and clinical follow-up did not lead to the identification of neuroblastoma or another catecholamine-secreting tumor in any patient. Gripp et al. (2004) concluded that in this patient group an elevation above the normal limit for catecholamine metabolites is more likely to be a variant than a sign of a neuroblastoma, and recommended that this assay not be used as a screening test. </p>
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<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The vast majority of patients with Costello syndrome have de novo heterozygous mutations in the HRAS gene (Aoki et al., 2005; Kerr et al., 2006; Gripp et al., 2006). Studies by Lurie (1994) found a significant increase of mean paternal age (38.0 years), suggesting sporadic autosomal dominant mutations as the most likely cause. Rare reports of affected sibs born to healthy parents may be explained by gonadal mosaicism. </p><p>The molecular evidence presented by Aoki et al. (2005), viz., the finding of heterozygous mutations in the HRAS gene (190020) in patients with Costello syndrome, convincingly refuted the hypothesis of autosomal recessive inheritance and favored gonadal mosaicism as the explanation of instances of affected sibs. </p><p><strong><em>Exclusion of Autosomal Recessive Inheritance</em></strong></p><p>
The hypothesis of autosomal recessive inheritance of Costello syndrome was based on 2 families with affected sibs (Berberich et al., 1991; Zampino et al., 1993) and 2 consanguineous matings (Borochowitz et al., 1992). Lurie (1994) reviewed 20 reported families and found that the 37 sibs of probands were all normal. In 6 families for whom pedigrees were not available, 2 affected sib pairs were born. Even if there were no normal offspring in these latter families, the occurrence of the Costello syndrome in only 2 of 39 sibs virtually excludes an autosomal recessive inheritance pattern (P = 0.999). Moreover, a significant increase of mean paternal age (38.0 years) and paternal-maternal age difference (7.36 years) suggests sporadic autosomal dominant mutations as a likely cause. The 2 reported cases of affected sibs born to healthy parents may be explained by gonadal mosaicism. </p><p>However, Franceschini et al. (1999) reported a 12-year-old boy with Costello syndrome who was born to consanguineous (first cousins once removed) parents, which could be considered consistent with autosomal recessive transmission. </p><p><strong><em>Apparent Autosomal Dominant Inheritance and Somatic Mosaicism</em></strong></p><p>
Johnson et al. (1998) described 8 patients with Costello syndrome, including an affected sib pair, and reviewed the literature on 29 previously reported patients. They emphasized an association with advanced parental age, which was considered consistent with autosomal dominant inheritance with germline mosaicism. In their study the average paternal age was 40.3 years, with a mean maternal age of 35.8 years. Features noted in the patients of Johnson et al. (1998) included cataracts in 2 patients, heat intolerance and increased sweating in 3, graying of hair in 1 (aged 8 years), and generalized amino aciduria in 3. Of all the patients reviewed, hypertrophic cardiomyopathy with valve dysfunction was found in 65% and delayed bone age in 85%. </p><p>A review of previously reported patients suggested to Van Eeghen et al. (1999) that the disorder is autosomal dominant, caused either by a mutation in a single gene or by microdeletion. Ioan and Fryns (2002) described Costello syndrome in a brother and sister, with minor manifestations in their mother. They suggested that this was further evidence for autosomal dominant inheritance. In a review of Costello syndrome, Hennekam (2003) favored autosomal dominant inheritance. </p><p>Gripp et al. (2006) reported a 15-year-old girl with Costello syndrome resulting from somatic mosaicism for the common G12S HRAS mutation (190020.0003). Clinical features included short stature, developmental delay, mild mitral valve prolapse without hypertrophic cardiomyopathy, Achilles tendon contractures, sparse, thin and brittle hair, epicanthal folds, and a wide mouth with thick lips. She also had nasal papillomata and thickened toenails. Her skin showed areas of streaky hyperpigmentation over trunk and extremities. Molecular analysis of white blood cells failed to detect a mutation, but DNA derived from buccal swabs showed the G12S mutation in 25 to 30% of cells. The wide distribution throughout the skin suggested an early somatic mutation. </p><p>Sol-Church et al. (2009) described what they said was the first documented transmission of an HRAS mutation from a parent with somatic mosaicism to a child, resulting in typical Costello syndrome in the child. The child carried a heterozygous G12S mutation on the paternal allele. The father was noted to have features suggestive of mosaic Costello syndrome, including severe failure to thrive in early childhood, developmental delay, hyperkeratosis on both hands and his left foot, papillomas on the right left perianal region and nose, hyperpigmentation, thick ear lobes, and patches of curly hair. He did not have structural cardiac defects. The father expressed awareness that he and his son had similar physical and developmental traits of the disorder. DNA testing of the father showed that he was somatic mosaic for the G12S mutation, carrying it in 7 to 8% of his alleles, whereas the mother did not have the mutation. The findings showed the importance of parental evaluation, which has implications for genetic counseling. This family had been reported in abstract form by Bodkin et al. (1999). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Smith et al. (2009) reviewed prenatal ultrasound findings of 17 patients with Costello syndrome. Seven (41%) were preterm with delivery prior to 37 weeks' gestation, and the remaining 10 (59%) were term deliveries. There were 3 main prenatal findings on ultrasound: polyhydramnios, fetal overgrowth, and relative macrocephaly. Polyhydramnios was the most commonly reported prenatal complication, affecting 100% of pregnancies. Most (65%) patients had birth weight above the 90th centile, and 41% patients had birth weights greater than the 97th centile. A fourth less common finding was cardiac arrhythmia. Smith et al. (2009) noted that the combination of polyhydramnios and fetal overgrowth often prompts evaluation for maternal diabetes mellitus, but that recognition of Costello syndrome in utero is important because of the neonatal risk of cardiac mortality and morbidity. </p><p>Kuniba et al. (2009) provided a case report of a Japanese fetus with severe Costello syndrome diagnosed using prenatal 3-dimensional ultrasonography at 23 weeks' gestation. Findings at that time included polyhydramnios, severe overgrowth (+5.3 SD using a Japanese fetal growth curve), and dysmorphic craniofacial features, such as large head, pointed chin, broad nasal bridge, and low-set ears. In addition, the wrists showed lateral deviation and flexion. Molecular analysis via amniocentesis identified an uncommon G12D mutation in the HRAS gene (190020.0013). After birth, he developed respiratory failure, severe hypoglycemia, cardiac hypertrophy, and renal failure, and died soon after birth. The phenotype was similar to that reported by Lo et al. (2008) in 2 infants with the G12D mutation, suggesting that this mutation is associated with a severe clinical outcome and death in early infancy. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Gripp et al. (2019) reported management guidelines based on expert opinion for the multisystem involvement seen in Costello syndrome. They recommended that at diagnosis, patients should have a complete cardiac evaluation, including echocardiogram, electrocardiogram, and Holter monitoring. Because hypertrophic cardiomyopathy (HCM) and non-reentrant atrial tachycardias are most often present in infancy, there should be frequent surveillance in the first 2 years of life. Abnormalities should be treated by a cardiologist or an electrophysiologist as needed. Due to risk of acquired and progressive cardiovascular abnormalities, screening for HCM, early coronary disease, lipid abnormalities and hypertension is warranted throughout life. At diagnosis, referral to neurology and an MRI of the brain (with a repeat 1 year later) and of the lower spine (for tethered cord) is recommended, with serial clinical examinations. Patients should be referred for early childhood services, and receive appropriate supportive educational, physical, and communication services. Because patients are at risk for failure to thrive, short stature, growth hormone deficiency, hypoglycemia, and delayed or precocious puberty, they should be referred at diagnosis to an endocrinologist, with screening for hypoglycemia and appropriate hormone testing with medical management of abnormalities. Because failure to thrive and poor feeding, along with other gastrointestinal complications, are seen in almost all young children with Costello syndrome, referral should be made to a gastroenterologist and dietitian. Patients should also be assessed at diagnosis and treated appropriately for airway issues, genitourinary abnormalities, and musculoskeletal abnormalities. Ongoing care should also include assessment and management for dental and ophthalmologic concerns. Patients with Costello syndrome are at risk for benign tumors, embryonal rhabdomyosarcoma, bladder carcinoma, and neuroblastoma. If a diagnosis is made before 10 years of age, patients should have an abdominal and pelvic ultrasound at diagnosis and then every 3 months until 8-10 years of age. Annual urinalysis starting at 10 years of age is recommended, with referral for evaluation for bladder carcinoma in the case of persistent hematuria. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Cytogenetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Czeizel and Timar (1995) described the case of a Hungarian girl with Costello syndrome in association with an apparently balanced translocation: 46,XX t(1;22)(q25;q11). The patient showed excessive generalized skin, more pronounced in the palms, 'wash woman's hands,' and soles, with elastolysis confirmed by histologic examination. The long tubular bones were osteoporotic. Spina bifida occulta was demonstrated in L5 and S1. Mental retardation was mild. She had a particularly sociable and humorous personality. </p><p>Sutajova et al. (2004) studied further the female patient originally reported by Czeizel and Timar (1995) who was diagnosed with Costello syndrome and who carried an apparently balanced translocation, t(1;22). They showed that there were 2 derivative chromosomes 1 in her peripheral blood lymphocytes, in one of which the coding region of the PDGFB gene (190040), which maps to 22q13.1, was disrupted. In 18 patients with Costello syndrome, no pathogenic mutations were found in any of the genes belonging to the PDGF or PDGFR (see 173490) gene families. Reevaluation of the clinical features of the translocation patient challenged the diagnosis of Costello syndrome. Sutajova et al. (2004) speculated, however, that the biologic consequences of the mutant PDGFB allele contributed to the unique disease phenotype of the patient. </p><p>Maroti et al. (2002) defined the location of the breakpoint regions of the 1;22 translocation. FISH analysis refined the cytogenetic breakpoint from 22q11 to 22q13.1. Suri and Garrett (1998) described a patient with Costello syndrome with acoustic neurinoma and cataract, both of which are features of neurofibromatosis type 2 (NF2; 101000). Although they did not find a deletion or point mutation of the NF2 gene, located in 22q12.2, it was suggested that the gene for Costello syndrome might be close to NF2. If the Costello gene is located on 22q13.1, an inversion might have happened in the Costello/NF2 patient that escaped detection by conventional cytogenetic analysis. Maroti et al. (2002) confirmed the 1q25 location of the other breakpoint. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Disruption of elastic fiber production, such as is observed in Costello syndrome, may arise either from low production of tropoelastin (see 130160) and microfibrillar proteins, or from their inadequate secretion and extracellular assembly. Hinek et al. (2000) undertook a study to assess the major steps of elastogenesis in fibroblasts derived from 6 children with Costello syndrome and from 3 age-matched normal children. Their data indicated that fibroblasts from patients with Costello syndrome produce normal levels of soluble tropoelastin and properly deposit an extracellular microfibrillar scaffold but are unable to assemble elastic fibers, because of a secondary deficiency in the 67-kD elastin-binding protein, which the authors called EBP. EBP is an enzymatically inactive spliced variant of beta-galactosidase (see 230500) (Hinek et al., 1993; Privitera et al., 1998) that binds to the repeating hydrophobic domains on elastin. Because the normal association between tropoelastin and EBP can be disrupted by contact with galactosugar-bearing moieties, and because the fibroblasts from patients with Costello syndrome showed an unusual accumulation of chondroitin sulfate-bearing proteoglycans (CD44 (107269) and biglycan (301870)), Hinek et al. (2000) postulated that a chondroitin sulfate may induce shedding of EBP from Costello cells and prevent normal recycling of this reusable tropoelastin chaperone. This conclusion was further supported by the fact that exposure to chondroitinase ABC, an enzyme capable of chondroitin sulfate degradation, restored normal production of elastic fibers by fibroblasts from patients with Costello syndrome. </p><p>In histologic and immunohistochemical analyses of postmortem heart tissue from 3 children with Costello syndrome, Hinek et al. (2005) observed that cardiomyocytes from all 3 were characterized by pericellular and intracellular accumulation of chondroitin 6-sulfate-bearing glycosaminoglycans, with lower than normal deposition of chondroitin 4-sulfate. Their endocardia showed the presence of multiple foci of collagen-rich fibrotic tissue with a marked reduction of elastic fibers, and there were thin, short, and fragmented elastic fibers in the myocardial stroma, pericardium, and cardiac valves, coinciding with lowered expression of EBP. Hinek et al. (2005) proposed that an imbalance in sulfation of chondroitin sulfate molecules and subsequent accumulation of chondroitin 6-sulfate in cardiomyocytes contribute to the development of the hypertrophic cardiomyopathy of Costello syndrome. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Because of phenotypic overlap between Costello syndrome and Noonan syndrome (163950), and because mutations in the SHP2/PTPN11 gene (176876) had been demonstrated in the latter, Tartaglia et al. (2003) screened a cohort of 27 patients with clinically diagnosed Costello syndrome for PTPN11 mutations; they found none. The previous exclusion of PTPN11 mutations in cardiofaciocutaneous syndrome by Ion et al. (2002) indicates that these 3 syndromes are distinct. Troger et al. (2003) likewise found no mutation in the PTPN11 gene in 18 patients with Costello syndrome. </p><p>Gain-of-function mutant SHP2 proteins identified in Noonan syndrome have enhanced phosphatase activity, which results in activation of a RAS-MAPK cascade in a cell-specific manner. Aoki et al. (2005) hypothesized that genes mutated in Costello syndrome and in PTPN11-negative Noonan syndrome encode molecules that function upstream or downstream of SHP2 in signal pathways. Among these molecules, they sequenced the entire coding region of 4 RAS genes in genomic DNA from 13 individuals with Costello syndrome and 28 individuals with PTPN11-negative Noonan syndrome. In 12 of the 13 individuals with Costello syndrome, they found a heterozygous mutation in the HRAS gene (190020.0001, 190020.0003-190020.0005). All 4 of the mutations had previously been identified somatically in various tumors. Examination of genomic DNA from unaffected parents in 4 families identified no mutations, suggesting that mutations in the affected individuals arose de novo, although the possibility of germline mosaicism in a parent could not be excluded. No mutations in KRAS (190070), NRAS (164790), HRAS, or ERAS (300437) were observed in the 28 individuals with Noonan syndrome or in 1 individual with Costello syndrome. The observations suggested that germline mutations in HRAS perturb human development and increase susceptibility to tumors. </p><p>Gripp et al. (2006) and Estep et al. (2006) simultaneously analyzed the HRAS gene in samples collected at International Costello Syndrome meetings over several years and identified heterozygous mutations in 33 of 40 and 33 of 36 patients diagnosed with Costello syndrome, respectively (20 patients participated in both studies, for a total of 56 different patients). All mutations were in codons 12 and 13; the majority in both studies (91% and 91%, respectively) were a G12S substitution (190020.0003). Gripp et al. (2006) analyzed 19 sets of parents, none of whom carried the mutation, confirming the de novo nature of mutations in Costello syndrome patients. Estep et al. (2006) also analyzed 8 well-characterized patients diagnosed with cardiofaciocutaneous syndrome (CFC; 115150) and found no mutations in the HRAS coding region, supporting a distinct etiology between the Costello and CFC syndromes. In a detailed review of these reports, Lin et al. (2008) noted that Gripp et al. (2006) and Estep et al. (2006) had described a total of 49 patients, not 56 as originally stated. Lin et al. (2008) also provided a detailed list of the clinical features of these patients and emphasized the need for a central registry in order to keep track of biologic material. </p><p>In 2 patients originally diagnosed with Costello syndrome but with features overlapping those of CFC, in whom no HRAS mutations were found (Estep et al., 2006), Rauen (2006) identified missense mutations in the BRAF gene (164757.0020 and 164757.0021, respectively). Rauen (2006) stated that Costello syndrome and CFC can be distinguished by mutation analysis of genes in the RAS/MAPK pathway. </p><p>Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%). The mutations were de novo in all cases in which DNA samples were available from the parents. The most common mutation was G12S, which was found in 30 of 37 mutation-positive patients. All of the mutation-positive cases had failure to thrive as well as the facial appearance and hands characteristic of Costello syndrome; macrocephaly was found in 32 mutation-positive cases. In a patient with autistic features and microretrognathism, Kerr et al. (2006) identified a substitution in a novel region of HRAS (K117R; 190020.0006). Kerr et al. (2006) stated that, together with previously published series (Aoki et al., 2005 and Gripp et al., 2006), mutations in HRAS had been found in 82 (85%) of 96 patients with a clinical diagnosis of Costello syndrome and that overall, the frequency of malignancy in the published mutation-positive cases was 11%. </p><p>Zampino et al. (2007) identified the common G12S mutation in 8 of 9 unrelated patients with Costello syndrome; the ninth child had a different mutation (190020.0008). All mutations were de novo, paternally inherited and associated with advanced paternal age. None of 36 patients with Noonan syndrome or 4 with CFC syndrome had a mutation in the HRAS gene. </p><p>Zenker et al. (2007) identified 2 different heterozygous mutations in the KRAS gene (190070.0017-190070.0018) in 2 unrelated infants with Costello syndrome. Both patients had coarse facies, loose and redundant skin with deep palmar creases, heart defects, failure to thrive, and moderate mental retardation. Zenker et al. (2007) noted that the patients may later develop features of CFC, which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders. </p><p>In a 20-year-old woman with clinical features typical of Costello syndrome and additional findings seen in Noonan syndrome, who was negative for mutations in the PTPN11 and HRAS genes, Bertola et al. (2007) identified a mutation in the KRAS gene (K5E; 190070.0019) that was not found in her unaffected mother or brother or in 100 controls. The patient was diagnosed with hypertrophic cardiomyopathy soon after birth, and evolved with severe developmental delay; lymphedema began in her lower extremities at age 15 years, and at age 18 years she developed nasal papillomata. The initial diagnosis was Noonan syndrome, but the presence of relative macrocephaly, coarse facial features, loose skin in the hands and feet with deep creases, dark skin, and particularly the development of nasal papillomata led to the diagnosis of Costello syndrome. Bertola et al. (2007) noted that this mutation was in the same codon as that of 1 of the patients reported by Zenker et al. (2007) (K5N; 190070.0017). </p><p>Van der Burgt et al. (2007) identified mutations in the HRAS gene (see, e.g., 190020.0001; 190020.0003; 190020.0009; 190020.0010) in patients with congenital myopathy with excess muscle spindles, a variant of Costello syndrome. Three of the patients had been reported by de Boode et al. (1996), Selcen et al. (2001), and Stassou et al. (2005). </p><p>Schulz et al. (2008) identified mutations in the HRAS gene in 28 (90.3%) of 31 patients with Costello syndrome. All mutations occurred in codons 12 or 13, and the HRAS mutations in 14 informative families could all be traced to the paternal allele. G12S was the most common mutation, occurring in 82.1% of patients. The phenotype was relatively homogeneous. </p><p>In 2 unrelated patients with Costello syndrome, Gripp et al. (2008) identified 2 different novel mutations in the HRAS gene (190020.0011; 190020.0012). The facial features of both patients were less coarse than typically seen in Costello syndrome. </p><p>Lo et al. (2008) described 4 infants with an unusually severe Costello syndrome, in whom they identified 3 mutations in the HRAS gene (190020.0003, 190020.0013, and 190020.0014, respectively). The authors stated that hypoglycemia, renal abnormalities, severe early cardiomyopathy, congenital lung and airway abnormalities, pleural and pericardial effusion, chylous ascites, and pulmonary lymphangectasia are part of the clinical spectrum seen in Costello syndrome, and noted that lung pathology resembling alveolar capillary dysplasia was reported in 1 case. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Gripp et al. (2007) reported 13 unrelated patients ages 0 to 8 years with a clinical diagnosis of Costello syndrome, Costello-like syndrome, or thought to have either CFC syndrome or Costello syndrome who were negative for mutations in the HRAS gene. De novo heterozygous BRAF or MEK1 mutations were identified in 8 and 5 patients, respectively. In a comparison to a group of previously published patients with HRAS mutations, Gripp et al. (2007) found several significant clinical differences between the 2 groups. Patients with an HRAS mutation and Costello syndrome tended to have polyhydramnios, ulnar deviation, growth hormone deficiency, and tachycardia more frequently than patients with BRAF or MEK1 mutations. Those with BRAF or MEK1 mutations had more cardiovascular malformations. Although the presence of more than 1 papilloma strongly suggested Costello syndrome over CFC, the authors noted that these lesions typically develop over time and thus may not be very helpful in the differential diagnosis of younger children. Gripp et al. (2007) concluded that the 13 patients in their study had CFC syndrome and not Costello syndrome, based on the clinical and molecular findings. The authors noted the phenotypic overlap between the 2 disorders, but suggested that Costello syndrome be reserved for patients with HRAS mutations. </p><p>Gripp et al. (2011) examined 12 individuals with Costello syndrome due to the HRAS G13C (190020.0007) mutation and compared the phenotype to those with the HRAS G12S (190020.0003) mutation. Individuals with G13C had many typical findings including polyhydramnios, failure to thrive, hypertrophic cardiomyopathy, macrocephaly, posterior fossa crowding, and developmental delay. Their facial features were less coarse and short stature was less severe. Statistically significant differences included the absence of several common features, including multifocal atrial tachycardia, ulnar deviation of the wrist, and papillomata; a noteworthy absence of malignant tumors did not reach statistical significance. There were some novel ectodermal findings associated with the G13C mutation, including loose anagen hair and long eyelashes requiring trimming (termed 'dolichocilia'). </p><p>McCormick et al. (2013) developed a severity score for Costello syndrome based on various criteria, including feeding difficulties, cardiac abnormalities, orthopedic abnormalities, neurologic abnormalities, malignancies, bone density, and stature as well as mortality, and assessed 78 individuals blind to genotype. They then compared this to genotypes of the individuals and found that individuals with the G12A (190020.0004) and the G12C (190020.0014) HRAS mutations were more severely affected than those with other HRAS mutations. </p><p>Lorenz et al. (2013) reported an 18-year-old girl, born of consanguineous Turkish parents, with a relatively mild form of Costello syndrome. The patient had mildly delayed psychomotor development as a child, as well as hypertrophic cardiomyopathy, osteoporosis, coarse facial features, short stature, hyperkeratotic skin lesions, pigmentary anomalies, and mild intellectual disability. Genetic analysis identified a de novo heterozygous 21-bp duplication in the HRAS gene, resulting in the duplication of amino acids 63 to 69 (E63_D69dup; 190020.0018). Five of these residues are an integral part of the HRAS switch II domain that mediates binding of HRAS with various regulator and effector proteins. In vitro cellular functional expression studies showed that the E63_D69dup mutation increased HRAS coprecipitation with certain effector proteins, but not with PIK3CA (171834). Overexpression of the mutant protein increased steady-state phosphorylation of downstream effectors MEK1/2 and ERK1/2, but not AKT. The mutant protein had some residual response to epidermal growth factor (EGF) stimulus compared to constitutively active HRAS mutations. The findings indicated that this duplication mutant has a gain-of-function effect for some effectors, but this is counteracted by a normal effect on PIK3CA signaling. Lorenz et al. (2013) concluded that the attenuated phenotype in this patient was due to impaired regulator and effector binding of the E63_D69dup mutant. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Schuhmacher et al. (2008) generated a mouse model of Costello syndrome by introduction of an oncogenic gly12-to-val mutation (190020.0001) in the mouse Hras gene. Mutant mice developed hyperplasia of the mammary gland, but tumor development was rare. The mice showed some phenotypic features similar to those of Costello syndrome, including facial dysmorphism and cardiomyopathy. Mutant mice also developed systemic hypertension, extensive vascular remodeling, and fibrosis in both the heart and the kidneys resulting from abnormal upregulation of the renin-angiotensin II system, which responded to treatment with captopril. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Aoki, Y., Niihori, T., Kawame, H., Kurosawa, K., Ohashi, H., Tanaka, Y., Filocamo, M., Kato, K., Suzuki, Y., Kure, S., Matsubara, Y.
<strong>Germline mutations in HRAS proto-oncogene cause Costello syndrome.</strong>
Nature Genet. 37: 1038-1040, 2005.
[PubMed: 16170316]
[Full Text: https://doi.org/10.1038/ng1641]
</p>
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<p class="mim-text-font">
Axelrad, M. E., Glidden, R., Nicholson, L., Gripp, K. W.
<strong>Adaptive skills, cognitive, and behavioral characteristics of Costello syndrome.</strong>
Am. J. Med. Genet. 128A: 396-400, 2004.
[PubMed: 15264285]
[Full Text: https://doi.org/10.1002/ajmg.a.30140]
</p>
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<li>
<p class="mim-text-font">
Berberich, M. S., Carey, J. C., Hall, B. D.
<strong>Resolution of the perinatal and infantile failure to thrive in a new autosomal recessive syndrome with the phenotype of a storage disorder and furrowing of palmar creases. (Abstract)</strong>
Proc. Greenwood Genet. Center 10: 78 only, 1991.
</p>
</li>
<li>
<p class="mim-text-font">
Bertola, D. R., Pereira, A. C., Brasil, A. S., Albano, L. M. J., Kim, C. A., Krieger, J. E.
<strong>Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene.</strong>
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[PubMed: 17468812]
[Full Text: https://doi.org/10.1007/s10038-007-0146-1]
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<p class="mim-text-font">
Bodkin, N. M., Mortimer, E. S., Demmer, L. A.
<strong>Male to male transmission of Costello syndrome consistent with autosomal dominant inheritance. (Abstract)</strong>
Am. J. Hum. Genet. 65: A143, 1999.
</p>
</li>
<li>
<p class="mim-text-font">
Borochowitz, Z., Pavone, L., Mazor, G., Rizzo, R., Dar, H.
<strong>New multiple congenital anomalies: mental retardation syndrome (MCA/MR) with facio-cutaneous-skeletal involvement.</strong>
Am. J. Med. Genet. 43: 678-685, 1992.
[PubMed: 1621757]
[Full Text: https://doi.org/10.1002/ajmg.1320430405]
</p>
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<li>
<p class="mim-text-font">
Borochowitz, Z., Pavone, L., Mazor, G., Rizzo, R., Dar, H.
<strong>Facio-cutaneous-skeletal syndrome: new nosological entity or Costello syndrome? (Letter)</strong>
Am. J. Med. Genet. 47: 173 only, 1993.
</p>
</li>
<li>
<p class="mim-text-font">
Costello, J. M.
<strong>A new syndrome: mental subnormality and nasal papillomata.</strong>
Aust. Paediat. J. 13: 114-118, 1977.
[PubMed: 907573]
[Full Text: https://doi.org/10.1111/j.1440-1754.1977.tb01135.x]
</p>
</li>
<li>
<p class="mim-text-font">
Costello, J. M.
<strong>Costello syndrome: update on the original cases and commentary. (Letter)</strong>
Am. J. Med. Genet. 62: 199-201, 1996.
[PubMed: 8882404]
[Full Text: https://doi.org/10.1002/ajmg.1320620203]
</p>
</li>
<li>
<p class="mim-text-font">
Czeizel, A. E., Timar, L.
<strong>Hungarian case with Costello syndrome and translocation t(1,22). (Letter)</strong>
Am. J. Med. Genet. 57: 501-503, 1995.
[PubMed: 7677162]
[Full Text: https://doi.org/10.1002/ajmg.1320570331]
</p>
</li>
<li>
<p class="mim-text-font">
Davies, S. J., Hughes, H. E.
<strong>Costello syndrome: natural history and differential diagnosis of cutis laxa.</strong>
J. Med. Genet. 31: 486-489, 1994.
[PubMed: 7520945]
[Full Text: https://doi.org/10.1136/jmg.31.6.486]
</p>
</li>
<li>
<p class="mim-text-font">
Davies, S. J., Hughes, H. E.
<strong>Cutis laxa: a feature of Costello syndrome. (Letter)</strong>
J. Med. Genet. 31: 85, 1994.
[PubMed: 7512146]
[Full Text: https://doi.org/10.1136/jmg.31.1.85]
</p>
</li>
<li>
<p class="mim-text-font">
de Boode, W. P., Semmekrot, B. A., ter Laak, H. J., van der Burgt, C. J. A. M, Draaisma, J. M. T., Lommen, E. J. P, Sengers, R. C. A., van Wijk-Hoek, J. M.
<strong>Myopathology in patients with a Noonan phenotype.</strong>
Acta Neuropath. 92: 597-602, 1996.
[PubMed: 8960317]
[Full Text: https://doi.org/10.1007/s004010050566]
</p>
</li>
<li>
<p class="mim-text-font">
DeBaun, M. R.
<strong>Screening for cancer in children with Costello syndrome.</strong>
Am. J. Med. Genet. 108: 88-90, 2002.
[PubMed: 11857557]
[Full Text: https://doi.org/10.1002/ajmg.10242]
</p>
</li>
<li>
<p class="mim-text-font">
Della Marca, G., Vasta, I., Scarano, E., Rigante, M., De Feo, E., Mariotti, P., Rubino, M., Vollono, C., Mennuni, G. F., Tonali, P., Zampino, G.
<strong>Obstructive sleep apnea in Costello syndrome.</strong>
Am. J. Med. Genet. 140A: 257-262, 2006.
[PubMed: 16419102]
[Full Text: https://doi.org/10.1002/ajmg.a.31076]
</p>
</li>
<li>
<p class="mim-text-font">
Der Kaloustian, V. M., Moroz, B., McIntosh, N., Watters, A. K., Blaichman, S.
<strong>Costello syndrome.</strong>
Am. J. Med. Genet. 41: 69-73, 1991.
[PubMed: 1951465]
[Full Text: https://doi.org/10.1002/ajmg.1320410118]
</p>
</li>
<li>
<p class="mim-text-font">
Der Kaloustian, V. M.
<strong>Not a new MCA/MR syndrome but probably Costello syndrome? (Letter)</strong>
Am. J. Med. Genet. 47: 170-171, 1993.
[PubMed: 8213900]
[Full Text: https://doi.org/10.1002/ajmg.1320470206]
</p>
</li>
<li>
<p class="mim-text-font">
Di Rocco, M., Gatti, R., Gandullia, P., Barabino, A., Picco, P., Borrone, C.
<strong>Report on two patients with Costello syndrome and sialuria.</strong>
Am. J. Med. Genet. 47: 1135-1140, 1993.
[PubMed: 8291534]
[Full Text: https://doi.org/10.1002/ajmg.1320470737]
</p>
</li>
<li>
<p class="mim-text-font">
Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D., Rauen, K. A.
<strong>HRAS mutation in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.</strong>
Am. J. Med. Genet. 140A: 8-16, 2006.
[PubMed: 16372351]
[Full Text: https://doi.org/10.1002/ajmg.a.31078]
</p>
</li>
<li>
<p class="mim-text-font">
Feingold, M.
<strong>Costello syndrome and rhabdomyosarcoma. (Letter)</strong>
J. Med. Genet. 36: 582-583, 1999.
[PubMed: 10424828]
</p>
</li>
<li>
<p class="mim-text-font">
Franceschini, P., Licata, D., Di Cara, G., Guala, A., Bianchi, M., Ingrosso, G., Franceschini, D.
<strong>Bladder carcinoma in Costello syndrome: report on a patient born to consanguineous parents and review.</strong>
Am. J. Med. Genet. 86: 174-179, 1999.
[PubMed: 10449656]
</p>
</li>
<li>
<p class="mim-text-font">
Fryns, J. P., Vogels, A., Haegeman, J., Eggermont, E., Van Den Berghe, H.
<strong>Costello syndrome: a postnatal growth retardation syndrome with distinct phenotype.</strong>
Genet. Counsel. 5: 337-343, 1994.
[PubMed: 7888135]
</p>
</li>
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<p class="mim-text-font">
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Suri, M., Garrett, C.
<strong>Costello syndrome with acoustic neuroma and cataract. Is the Costello locus linked to neurofibromatosis type 2 on 22q?</strong>
Clin. Dysmorph. 7: 149-151, 1998.
[PubMed: 9571289]
[Full Text: https://doi.org/10.1097/00019605-199804000-00014]
</p>
</li>
<li>
<p class="mim-text-font">
Sutajova, M., Neukirchen, U., Meinecke, P., Czeizel, A. E., Timar, L., Solyom, E., Gal, A., Kutsche, K.
<strong>Disruption of the PDGFB gene in a 1;22 translocation patient does not cause Costello syndrome.</strong>
Genomics 83: 883-892, 2004.
[PubMed: 15081117]
[Full Text: https://doi.org/10.1016/j.ygeno.2003.10.012]
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</li>
<li>
<p class="mim-text-font">
Tartaglia, M., Cotter, P. D., Zampino, G., Gelb, B. D., Rauen, K. A.
<strong>Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous and Costello syndromes.</strong>
Clin. Genet. 63: 423-426, 2003.
[PubMed: 12752577]
[Full Text: https://doi.org/10.1034/j.1399-0004.2003.00076.x]
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</li>
<li>
<p class="mim-text-font">
Teebi, A. S., Shaabani, I. S.
<strong>Further delineation of Costello syndrome.</strong>
Am. J. Med. Genet. 47: 166-168, 1993.
[PubMed: 8213898]
[Full Text: https://doi.org/10.1002/ajmg.1320470204]
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<li>
<p class="mim-text-font">
Teebi, A. S.
<strong>Costello or facio-cutaneous-skeletal syndrome? (Letter)</strong>
Am. J. Med. Genet. 47: 172, 1993.
[PubMed: 8213901]
[Full Text: https://doi.org/10.1002/ajmg.1320470207]
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</li>
<li>
<p class="mim-text-font">
Torrelo, A., Lopez-Avila, A., Mediero, I. G., Zambrano, A.
<strong>Costello syndrome.</strong>
J. Am. Acad. Derm. 32: 904-907, 1995.
[PubMed: 7722055]
[Full Text: https://doi.org/10.1016/0190-9622(95)91559-1]
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<li>
<p class="mim-text-font">
Troger, B., Kutsche, K., Bolz, H., Luttgen, S., Gal, A., Almassy, Z., Caliebe, A., Freisinger, P., Hobbiebrunken, E., Morlot, M., Stefanova, M., Streubel, B., Wieczorek, D., Meinecke, P.
<strong>No mutation in the gene for Noonan syndrome, PTPN11, in 18 patients with Costello syndrome. (Letter)</strong>
Am. J. Med. Genet. 121A: 82-84, 2003.
[PubMed: 12900909]
[Full Text: https://doi.org/10.1002/ajmg.a.20122]
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Umans, S., Decock, P., Fryns, J. P.
<strong>Costello syndrome: the natural history of a true postnatal growth retardation syndrome.</strong>
Genet. Counsel. 6: 121-125, 1995.
[PubMed: 7546454]
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van der Burgt, I., Kupsky, W., Stassou, S., Nadroo, A., Barroso, C., Diem, A., Kratz, C. P., Dvorsky, R., Ahmadian, M. R., Zenker, M.
<strong>Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive Hras activation. (Letter)</strong>
J. Med. Genet. 44: 459-462, 2007.
[PubMed: 17412879]
[Full Text: https://doi.org/10.1136/jmg.2007.049270]
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<li>
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van Eeghen, A. M., van Gelderen, I., Hennekam, R.C.M.
<strong>Costello syndrome: report and review.</strong>
Am. J. Med. Genet. 82: 187-193, 1999.
[PubMed: 9934987]
[Full Text: https://doi.org/10.1002/(sici)1096-8628(19990115)82:2&lt;187::aid-ajmg17&gt;3.0.co;2-2]
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<li>
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White, S. M., Graham, J. M., Jr., Kerr, B., Gripp, K., Weksberg, R., Cytrynbaum, C., Reeder, J. L., Stewart, F. J., Edwards, M., Wilson, M., Bankier, A.
<strong>The adult phenotype in Costello syndrome.</strong>
Am. J. Med. Genet. 136A: 128-135, 2005. Note: Erratum: Am. J. Med. Genet. 139A: 55 only, 2005.
[PubMed: 15940703]
[Full Text: https://doi.org/10.1002/ajmg.a.30747]
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Yoshida, R., Fukushima, Y., Ohashi, H., Asoh, M., Fukuyama, Y.
<strong>The Costello syndrome: are nasal papillomata essential?</strong>
Jpn. J. Hum. Genet. 38: 437-444, 1993.
[PubMed: 8186422]
[Full Text: https://doi.org/10.1007/BF01907992]
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<li>
<p class="mim-text-font">
Zampino, G., Mastroiacovo, P., Ricci, R., Zollino, M., Segni, G., Martini-Neri, M. E., Neri, G.
<strong>Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology.</strong>
Am. J. Med. Genet. 47: 176-183, 1993.
[PubMed: 8213903]
[Full Text: https://doi.org/10.1002/ajmg.1320470210]
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<li>
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Zampino, G., Pantaleoni, F., Carta, C., Cobellis, G., Vasta, I., Neri, C., Pogna, E. A., De Feo, E., Delogu, A., Sarkozy, A., Atzeri, F., Selicorni, A., Rauen, K. A., Cytrynbaum, C. S., Weksberg, R., Dallapiccola, B., Ballabio, A., Gelb, B. D., Neri, G., Tartaglia, M.
<strong>Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.</strong>
Hum. Mutat. 28: 265-272, 2007.
[PubMed: 17054105]
[Full Text: https://doi.org/10.1002/humu.20431]
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<p class="mim-text-font">
Zenker, M., Lehmann, K., Schulz, A. L., Barth, H., Hansmann, D., Koenig, R., Korinthenberg, R., Kreiss-Nachtsheim, M., Meinecke, P., Morlot, S., Mundlos, S., Quante, A. S., Raskin, S., Schnabel, D., Wehner, L.-E., Kratz, C. P., Horn, D., Kutsche, K.
<strong>Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.</strong>
J. Med. Genet. 44: 131-135, 2007.
[PubMed: 17056636]
[Full Text: https://doi.org/10.1136/jmg.2006.046300]
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Contributors:
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Hilary J. Vernon - updated : 11/13/2020<br>Cassandra L. Kniffin - updated : 8/27/2014<br>Cassandra L. Kniffin - updated : 3/19/2014<br>Ada Hamosh - updated : 11/12/2013<br>Cassandra L. Kniffin - updated : 3/13/2013<br>Cassandra L. Kniffin - updated : 9/11/2012<br>Cassandra L. Kniffin - updated : 6/28/2011<br>Cassandra L. Kniffin - updated : 4/16/2010<br>Cassandra L. Kniffin - updated : 2/16/2010<br>Marla J. F. O&#x27;Neill - updated : 6/1/2009<br>Cassandra L. Kniffin - updated : 3/3/2009<br>Marla J. F. O&#x27;Neill - updated : 11/12/2008<br>Cassandra L. Kniffin - updated : 6/25/2008<br>Cassandra L. Kniffin - updated : 4/14/2008<br>Cassandra L. Kniffin - updated : 3/24/2008<br>Cassandra L. Kniffin - updated : 8/28/2007<br>Cassandra L. Kniffin - updated : 5/16/2007<br>Cassandra L. Kniffin - updated : 3/2/2007<br>Marla J. F. O&#x27;Neill - updated : 9/26/2006<br>Marla J. F. O&#x27;Neill - updated : 6/20/2006<br>Cassandra L. Kniffin - updated : 2/8/2006<br>Marla J. F. O&#x27;Neill - updated : 1/25/2006<br>Marla J. F. O&#x27;Neill - updated : 12/28/2005<br>Kelly A. Przylepa - updated : 11/8/2005<br>Marla J. F. O&#x27;Neill - updated : 10/19/2005<br>Victor A. McKusick - updated : 9/21/2005<br>Marla J. F. O&#x27;Neill - updated : 7/20/2004<br>Victor A. McKusick - updated : 5/6/2004<br>Victor A. McKusick - updated : 8/25/2003<br>Victor A. McKusick - updated : 6/4/2003<br>Victor A. McKusick - updated : 4/16/2003<br>Victor A. McKusick - updated : 3/7/2003<br>Victor A. McKusick - updated : 12/31/2002<br>Deborah L. Stone - updated : 10/25/2002<br>Victor A. McKusick - updated : 5/21/2002<br>Victor A. McKusick - updated : 2/8/2002<br>Ada Hamosh - updated : 2/6/2001<br>Victor A. McKusick - updated : 3/22/2000<br>Victor A. McKusick - updated : 2/24/2000<br>Sonja A. Rasmussen - updated : 10/5/1999<br>Michael J. Wright - updated : 8/13/1999<br>Victor A. McKusick - updated : 2/14/1999<br>Michael J. Wright - updated : 2/12/1999<br>Victor A. McKusick - updated : 1/25/1999<br>Ada Hamosh - updated : 6/15/1998<br>Victor A. McKusick - updated : 2/19/1998<br>Iosif W. Lurie - updated : 10/2/1996
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Victor A. McKusick : 11/20/1991
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