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Entry
- #115150 - CARDIOFACIOCUTANEOUS SYNDROME 1; CFC1
- OMIM
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<span class="h4">#115150</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/115150"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS115150"> <strong>Phenotypic Series</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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<li role="presentation" style="margin-left: 1em">
<a href="#clinicalFeatures">Clinical 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="#otherFeatures">Other Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#history">History</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=CARDIOFACIOCUTANEOUS 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 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:0111460" 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/115150" 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:0111460" 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> 403770008<br />
<strong>ORPHA:</strong> 1340<br />
<strong>DO:</strong> 0111460<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>
115150
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
CARDIOFACIOCUTANEOUS SYNDROME 1; CFC1
</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">
CFC SYNDROME<br />
CFCS
</span>
</h4>
</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/7/742?start=-3&limit=10&highlight=742">
7q34
</a>
</span>
</td>
<td>
<span class="mim-font">
Cardiofaciocutaneous syndrome
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/115150"> 115150 </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">
BRAF
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164757"> 164757 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/115150" 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')">
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<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS115150" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="sr-only">Toggle Dropdown</span>
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&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/115150" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/115150" 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">
- 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> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- 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 />
</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, relative <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/3961000119101" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">3961000119101</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849075&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849075</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004482" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004482</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004482" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004482</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> <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 /> -
Dolichocephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/72239002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">72239002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221358&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221358</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000268</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000268</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=b49d4ad3bcb5a39e5263c4f1d7454a3e" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Dolichocephaly-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=b49d4ad3bcb5a39e5263c4f1d7454a3e&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> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Prominent forehead <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837260</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011220" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011220</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011220" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011220</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=a2091161c29564b62e12b608022a4044" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Forehead,Prominent-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=a2091161c29564b62e12b608022a4044&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 /> -
Bitemporal narrowing <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000341" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000341</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000341" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000341</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=130363281c65526c396a969f71815381" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Forehead,Narrow-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=130363281c65526c396a969f71815381&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 /> -
Hypoplastic supraorbital ridges <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861869&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861869</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009891</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009891</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=1d9991069f33e068aba646f06fe3a5cb" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Supraorbital_Ridges,Underdeveloped-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=1d9991069f33e068aba646f06fe3a5cb&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">
- 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 /> -
Thickened helices <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837732&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837732</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000391" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000391</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000391" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000391</a>]</span><br /> -
Ear pits <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/716577004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">716577004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204272007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204272007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0546969&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0546969</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004467" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004467</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">
- Sparse eyebrows <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422441003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422441003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0578682&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0578682</a>, <a href="https://bioportal.bioontology.org/search?q=C1832446&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1832446</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002223" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002223</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0045075" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0045075</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0045075" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0045075</a>]</span><br /> -
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 /> -
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 /> -
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 /> -
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 /> -
Nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/563001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">563001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/379.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">379.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</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 /> -
Optic nerve dysplasia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2676026&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2676026</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001093" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001093</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001093" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001093</a>]</span><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 nares <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> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=656ef0aca7742d97c5769f51f0dd56de" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Nares,Anteverted-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=656ef0aca7742d97c5769f51f0dd56de&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> Mouth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- 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> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=c606b0119d4a894ebd5ee0242c136e29" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Palate,High-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=c606b0119d4a894ebd5ee0242c136e29&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> Neck </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- 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 /> -
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 />
</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">
- 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 /> -
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 /> -
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 /> -
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 />
</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> Spine </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Scoliosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/298382003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">298382003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20944008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20944008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111266001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111266001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M41.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0559260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0559260</a>, <a href="https://bioportal.bioontology.org/search?q=C0036439&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036439</a>, <a href="https://bioportal.bioontology.org/search?q=C0700208&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700208</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</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 /> -
Ulnar deviation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1293023007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1293023007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/367510009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">367510009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/264748007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">264748007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0449752&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0449752</a>, <a href="https://bioportal.bioontology.org/search?q=C0231679&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0231679</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009465" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009465</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 />
</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">
- Ichthyosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/782957005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">782957005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13059002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13059002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q80.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q80.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q80" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q80</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/757.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">757.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020758</a>, <a href="https://bioportal.bioontology.org/search?q=C0020757&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020757</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008064" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008064</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008064" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008064</a>]</span><br /> -
Hyperkeratosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254666005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254666005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399955009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399955009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26996000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26996000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0870082&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0870082</a>, <a href="https://bioportal.bioontology.org/search?q=C0022593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000962" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000962</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000962" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000962</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> 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 /> -
Sparse eyebrows <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422441003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422441003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0578682&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0578682</a>, <a href="https://bioportal.bioontology.org/search?q=C1832446&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1832446</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002223" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002223</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0045075" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0045075</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0045075" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0045075</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">
- Developmental delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <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">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</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>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</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 /> -
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 /> -
Seizures (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br />
</span>
</div>
</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 />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Elevated homovanillic acid (HVA) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393026&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393026</a>]</span><br /> -
Elevated vanillylmandelic acid (VMA) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393027&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393027</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the B-Raf protooncogene, serine/threonine kinase, gene (BRAF, <a href="/entry/164757#0012">164757.0012</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Cardiofaciocutaneous syndrome
- <a href="/phenotypicSeries/PS115150">PS115150</a>
- 4 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/742?start=-3&limit=10&highlight=742"> 7q34 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/115150"> Cardiofaciocutaneous syndrome </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">
<a href="/entry/115150"> 115150 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164757"> BRAF </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164757"> 164757 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/240?start=-3&limit=10&highlight=240"> 12p12.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615278"> Cardiofaciocutaneous syndrome 2 </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>
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<a href="/entry/615278"> 615278 </a>
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<a href="/entry/190070"> KRAS </a>
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<a href="/entry/190070"> 190070 </a>
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<a href="/geneMap/15/310?start=-3&limit=10&highlight=310"> 15q22.31 </a>
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<a href="/entry/615279"> Cardiofaciocutaneous syndrome 3 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/615279"> 615279 </a>
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<a href="/entry/176872"> MAP2K1 </a>
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<a href="/entry/176872"> 176872 </a>
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<a href="/geneMap/19/126?start=-3&limit=10&highlight=126"> 19p13.3 </a>
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<a href="/entry/615280"> Cardiofaciocutaneous syndrome 4 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/615280"> 615280 </a>
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<a href="/entry/601263"> MAP2K2 </a>
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<a href="/entry/601263"> 601263 </a>
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<p>A number sign (#) is used with this entry because cardiofaciocutaneous syndrome-1 (CFC1) is caused by heterozygous mutation in the BRAF gene (<a href="/entry/164757">164757</a>) on chromosome 7q34.</p>
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<div class="mim-changed mim-change"><p>Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects, and impaired intellectual development. The heart defects include pulmonic stenosis, atrial septal defect, and hypertrophic cardiomyopathy. Some patients have ectodermal abnormalities such as sparse and friable hair, hyperkeratotic skin lesions, and a generalized ichthyosis-like condition. Typical facial characteristics include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices (summary by <a href="#34" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. &lt;strong&gt;Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.&lt;/strong&gt; Nature Genet. 38: 294-296, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16474404/&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;16474404&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1749&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="16474404">Niihori et al., 2006</a>). Most cases occur sporadically, but autosomal dominant transmission has been rarely reported (<a href="#23" class="mim-tip-reference" title="Linden, H. C., Price, S. M. &lt;strong&gt;Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation.&lt;/strong&gt; Clin. Dysmorph. 20: 86-88, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21178588/&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;21178588&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/MCD.0b013e32833ff29d&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="21178588">Linden and Price, 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21178588+16474404" 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>
<p><a href="#41" class="mim-tip-reference" title="Roberts, A., Allanson, J., Jadico, S. K., Kavamura, M. I., Noonan, J., Opitz, J. M., Young, T., Neri, G. &lt;strong&gt;The cardiofaciocutaneous syndrome.&lt;/strong&gt; J. Med. Genet. 43: 833-842, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16825433/&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;16825433&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16825433[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/10.1136/jmg.2006.042796&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="16825433">Roberts et al. (2006)</a> provided a detailed review of CFC syndrome, including a discussion of the phenotypic overlap of CFC syndrome with Noonan syndrome (NS1; <a href="/entry/163950">163950</a>) and Costello syndrome (<a href="/entry/218040">218040</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16825433" 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>Genetic Heterogeneity of Cardiofaciocutaneous Syndrome</em></strong>
</p>
<p>Other forms of cardiofaciocutaneous syndrome include CFC2 (<a href="/entry/615278">615278</a>), caused by mutation in the KRAS gene (<a href="/entry/190070">190070</a>); CFC3 (<a href="/entry/615279">615279</a>), caused by mutation in the MAP2K1 gene (<a href="/entry/176872">176872</a>); and CFC4 (<a href="/entry/615280">615280</a>), caused by mutation in the MAP2K2 gene (<a href="/entry/601263">601263</a>). The protein products of these causative genes, including BRAF, interact in a common RAS/ERK (see <a href="/entry/601795">601795</a>) pathway that regulates cell differentiation, proliferation, and apoptosis (summary by <a href="#41" class="mim-tip-reference" title="Roberts, A., Allanson, J., Jadico, S. K., Kavamura, M. I., Noonan, J., Opitz, J. M., Young, T., Neri, G. &lt;strong&gt;The cardiofaciocutaneous syndrome.&lt;/strong&gt; J. Med. Genet. 43: 833-842, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16825433/&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;16825433&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16825433[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/10.1136/jmg.2006.042796&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="16825433">Roberts et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16825433" 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="#40" class="mim-tip-reference" title="Reynolds, J. F., Neri, G., Herrmann, J. P., Blumberg, B., Coldwell, J. G., Miles, P. V., Opitz, J. M. &lt;strong&gt;New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement--the CFC syndrome.&lt;/strong&gt; Am. J. Med. Genet. 25: 413-427, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3789005/&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;3789005&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320250303&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="3789005">Reynolds et al. (1986)</a> described 4 males and 4 females, each from a different family, with a previously undefined multiple congenital anomalies/mental retardation syndrome, which they designated the cardiofaciocutaneous syndrome. The manifestations included congenital heart defects, characteristic facial appearance, ectodermal abnormalities, and growth failure. The most common cardiac defects were pulmonic stenosis and atrial septal defect. Typical facial characteristics were high forehead with bitemporal constriction, hypoplasia of the supraorbital ridges, downslanting palpebral fissures, depressed bridge of nose, and posteriorly angulated ears with prominent helices. The hair was usually sparse and friable. Skin changes varied from patchy hyperkeratosis to a severe generalized ichthyosis-like condition. There was no history of consanguinity. <a href="#32" class="mim-tip-reference" title="Neri, G., Sabatino, G., Bertini, E., Genuardi, M. &lt;strong&gt;The CFC syndrome--report of the first two cases outside the United States.&lt;/strong&gt; Am. J. Med. Genet. 27: 767-771, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3425595/&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;3425595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320270404&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="3425595">Neri et al. (1987)</a> reported 2 cases; again, no parental consanguinity was observed. <a href="#41" class="mim-tip-reference" title="Roberts, A., Allanson, J., Jadico, S. K., Kavamura, M. I., Noonan, J., Opitz, J. M., Young, T., Neri, G. &lt;strong&gt;The cardiofaciocutaneous syndrome.&lt;/strong&gt; J. Med. Genet. 43: 833-842, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16825433/&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;16825433&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16825433[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/10.1136/jmg.2006.042796&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="16825433">Roberts et al. (2006)</a> provided follow-up on 6 of the patients originally reported by <a href="#40" class="mim-tip-reference" title="Reynolds, J. F., Neri, G., Herrmann, J. P., Blumberg, B., Coldwell, J. G., Miles, P. V., Opitz, J. M. &lt;strong&gt;New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement--the CFC syndrome.&lt;/strong&gt; Am. J. Med. Genet. 25: 413-427, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3789005/&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;3789005&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320250303&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="3789005">Reynolds et al. (1986)</a>. Three had been lost to follow-up, 1 was living independently with family, 1 was in a group home, and 1 had died of heart failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16825433+3789005+3425595" 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="Verloes, A., Le Merrer, M., Soyeur, D., Kaplan, J., Pangalos, C., Rigo, J., Briard, M.-L. &lt;strong&gt;CFC syndrome: a syndrome distinct from Noonan syndrome.&lt;/strong&gt; Ann. Genet. 31: 230-234, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3265306/&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;3265306&lt;/a&gt;]" pmid="3265306">Verloes et al. (1988)</a> reported 2 cases and pointed out the similarity to Noonan syndrome. They also suggested that the Noonan-like short stature syndrome with sparse hair described by <a href="#3" class="mim-tip-reference" title="Baraitser, M., Patton, M. A. &lt;strong&gt;A Noonan-like short stature syndrome with sparse hair.&lt;/strong&gt; J. Med. Genet. 23: 161-164, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3712393/&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;3712393&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.23.2.161&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="3712393">Baraitser and Patton (1986)</a> is the same disorder. The first of their patients had the habitus of Noonan syndrome associated with keratosis plantaris and nystagmus; the second had a somewhat Noonan-like face, macrocephaly, keratosis pilaris, and hypertrophic cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3265306+3712393" 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="Chrzanowska, K., Fryns, J. P., Van den Berghe, H. &lt;strong&gt;Cardio-facio-cutaneous (CFC) syndrome: report of a new patient.&lt;/strong&gt; Am. J. Med. Genet. 33: 471-473, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2596505/&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;2596505&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320330410&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="2596505">Chrzanowska et al. (1989)</a> described an affected girl whose twin brother died shortly after birth and may have had the same malformation syndrome. The father and mother, aged 35 and 36 years, respectively, were healthy and nonconsanguineous. <a href="#27" class="mim-tip-reference" title="Mucklow, E. S. &lt;strong&gt;A case of cardio-facio-cutaneous syndrome.&lt;/strong&gt; Am. J. Med. Genet. 33: 474-475, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2596506/&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;2596506&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320330411&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="2596506">Mucklow (1989)</a> described 1 case, and <a href="#45" class="mim-tip-reference" title="Sorge, G., Di Forti, F., Scarano, G., Ventruto, V., Zelante, L., Dallapiccola, B. &lt;strong&gt;CFC syndrome: report on three additional cases.&lt;/strong&gt; Am. J. Med. Genet. 33: 476-478, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2596507/&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;2596507&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320330412&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="2596507">Sorge et al. (1989)</a> described 3 cases. In addition to high cranial vault, bitemporal frontal constriction was noted. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2596507+2596506+2596505" 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="#15" class="mim-tip-reference" title="Gross-Tsur, V., Gross-Kieselstein, E., Amir, N. &lt;strong&gt;Cardio-facio cutaneous syndrome: neurological manifestations.&lt;/strong&gt; Clin. Genet. 38: 382-386, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2149308/&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;2149308&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1990.tb03600.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="2149308">Gross-Tsur et al. (1990)</a> described what they alleged to be the sixteenth reported case of CFC. <a href="#41" class="mim-tip-reference" title="Roberts, A., Allanson, J., Jadico, S. K., Kavamura, M. I., Noonan, J., Opitz, J. M., Young, T., Neri, G. &lt;strong&gt;The cardiofaciocutaneous syndrome.&lt;/strong&gt; J. Med. Genet. 43: 833-842, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16825433/&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;16825433&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16825433[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/10.1136/jmg.2006.042796&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="16825433">Roberts et al. (2006)</a> noted that this child had Lennox-Gastaut encephalopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16825433+2149308" 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="Fryer, A. E., Holt, P. J., Hughes, H. E. &lt;strong&gt;The cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome: are they the same?&lt;/strong&gt; Am. J. Med. Genet. 38: 548-551, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2063896/&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;2063896&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320380410&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="2063896">Fryer et al. (1991)</a> also emphasized the phenotypic overlap between the CFC syndrome and the Noonan syndrome. They presented findings in the patient reported by <a href="#29" class="mim-tip-reference" title="Navaratnam, A. E. D. &lt;strong&gt;Ulerythema ophryogenes with mental retardation.&lt;/strong&gt; Proc. Roy. Soc. Med. 66: 233-234, 1973.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4697981/&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;4697981&lt;/a&gt;]" pmid="4697981">Navaratnam (1973)</a>, published photographs spanning from infancy to age 21 years, and showed the appearance of the pectus carinatum/excavatum and the keratotic skin lesions. <a href="#25" class="mim-tip-reference" title="Matsuda, Y., Murano, I., Kondoh, O., Matsuo, K., Kajii, T. &lt;strong&gt;Cardio-facio-cutaneous (CFC) syndrome: report of two patients without hyperkeratotic skin lesions.&lt;/strong&gt; Am. J. Med. Genet. 39: 144-147, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1842204/&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;1842204&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320390206&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="1842204">Matsuda et al. (1991)</a> described 2 Japanese boys with the CFC syndrome but without hyperkeratosis of the skin. <a href="#33" class="mim-tip-reference" title="Neri, G., Zollino, M., Reynolds, J. F. &lt;strong&gt;The Noonan-CFC controversy. (Editorial)&lt;/strong&gt; Am. J. Med. Genet. 39: 367-370, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1867292/&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;1867292&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320390323&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="1867292">Neri et al. (1991)</a> concluded that the Noonan and CFC syndromes are indeed distinct and separate conditions, both falling within the broad and causally heterogeneous spectrum of the Noonan/congenital lymphedema phenotype; other members of the cluster were listed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1842204+1867292+2063896+4697981" 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="Turnpenny, P. D., Dean, J. C. S., Auchterlonie, I. A., Johnston, A. W. &lt;strong&gt;Cardiofaciocutaneous syndrome with new ectodermal manifestations.&lt;/strong&gt; J. Med. Genet. 29: 428-429, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1619641/&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;1619641&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.29.6.428&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="1619641">Turnpenny et al. (1992)</a> described a 7-year-old girl whose features were thought to satisfy the diagnosis of CFC syndrome. The ectodermal features consisted of fine and sparse hair, thin and opalescent nails, finger tip pads, generalized cutaneous pigmentation, but no hyperkeratosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1619641" 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>Although CFC syndrome is distinguished from Noonan syndrome by the presence of abnormal hair and hyperkeratotic lesions and by its usual sporadic occurrence, <a href="#49" class="mim-tip-reference" title="Ward, K. A., Moss, C., McKeown, C. &lt;strong&gt;The cardio-facio-cutaneous syndrome: a manifestation of the Noonan syndrome?&lt;/strong&gt; Brit. J. Derm. 131: 270-274, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7917994/&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;7917994&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2133.1994.tb08504.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="7917994">Ward et al. (1994)</a> supported the suggestion of <a href="#9" class="mim-tip-reference" title="Fryer, A. E., Holt, P. J., Hughes, H. E. &lt;strong&gt;The cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome: are they the same?&lt;/strong&gt; Am. J. Med. Genet. 38: 548-551, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2063896/&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;2063896&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320380410&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="2063896">Fryer et al. (1991)</a> that it falls 'within the clinical spectrum of the Noonan phenotype.' They described mother and daughter who had features consistent with the CFC syndrome but had other features which have been reported in the Noonan syndrome but not in the CFC syndrome, namely, hemorrhagic diathesis and ocular abnormalities. They were described as having ulerythema ophryogenes (keratosis pilaris affecting the follicles of the eyebrow hairs, associated with erythema, scarring, and atrophy). <a href="#19" class="mim-tip-reference" title="Krajewska-Walasek, M., Chrzanowska, K., Jastrzbska, M. &lt;strong&gt;The cardio-facio-cutaneous (CFC) syndrome: two possible new cases and review of the literature.&lt;/strong&gt; Clin. Dysmorph. 5: 65-72, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8867662/&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;8867662&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00019605-199601000-00010&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="8867662">Krajewska-Walasek et al. (1996)</a> reported 2 unrelated children (a boy and a girl) with CFC syndrome who had 'Noonan-like' face, sparse, thin, curly hair, and severe mental retardation. The girl also had altered sensation of the distal part of the limbs, which has been described in patients with Noonan syndrome but not in patients with CFC syndrome. <a href="#22" class="mim-tip-reference" title="Leichtman, L. G. &lt;strong&gt;Are cardio-facio-cutaneous syndrome and Noonan syndrome distinct? A case of CFC offspring of a mother with Noonan syndrome.&lt;/strong&gt; Clin. Dysmorph. 5: 61-64, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8867661/&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;8867661&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00019605-199601000-00009&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="8867661">Leichtman (1996)</a> described a family suggesting that CFC syndrome is a variable expression of Noonan syndrome. He reported a 4-year-old girl with features sufficient to meet the criteria for CFC, including developmental delay, hypotrichosis, eczematic eruption, and characteristic facial and cardiac anomalies, whose mother demonstrated typical manifestations of Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8867662+8867661+2063896+7917994" 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="#24" class="mim-tip-reference" title="Manoukian, S., Lalatta, F., Selicorni, A., Tadini, G., Cavalli, R., Neri, G. &lt;strong&gt;Cardio-facio-cutaneous (CFC) syndrome: report of an adult without mental retardation.&lt;/strong&gt; Am. J. Med. Genet. 63: 382-385, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8725790/&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;8725790&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1096-8628(19960517)63:2&lt;382::AID-AJMG11&gt;3.0.CO;2-G&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="8725790">Manoukian et al. (1996)</a> reported the case of a 25-year-old woman with typical features of CFC syndrome but without mental retardation. She had valvular and infundibular pulmonic stenosis, brittle and woolly hair with patchy alopecia, scant body hair, dry and hypohidrotic skin, and characteristic facial traits. At the age of 3 years the patient had shown fullness of periorbital tissues, ectropion of the lower palpebral fissures, malar hypoplasia, bulbous nose, and hyperplasia of the helix and earlobes. At the age of 25 she showed downslanting palpebral fissures with scant eyebrows and absent eyelashes on the nasal side, edematous eyelids, ectropion of the lower eyelids, posteriorly angulated ears with hyperplastic helix and lobes, and webbed neck. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8725790" 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="Wieczorek, D., Majewski, F., Gillessen-Kaesbach, G. &lt;strong&gt;Cardio-facio-cutaneous (CFC) syndrome--a distinct entity? Report of three patients demonstrating the diagnostic difficulties in delineation of CFC syndrome.&lt;/strong&gt; Clin. Genet. 52: 37-46, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9272711/&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;9272711&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1997.tb02512.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="9272711">Wieczorek et al. (1997)</a> described 3 patients in whom the diagnosis was considered to be CFC syndrome. They provided a detailed review of previously reported cases and discussed the differences from Noonan and Costello (<a href="/entry/218040">218040</a>) syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9272711" 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="McGaughran, J. &lt;strong&gt;Cardio-facio-cutaneous syndrome: first presentation in a 52-year-old woman. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 116A: 210-212, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12494447/&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;12494447&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10784&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="12494447">McGaughran (2003)</a> reported the diagnosis of CFC syndrome in a 52-year-old woman who had short stature, a head circumference below the 50th centile, bilateral ptosis, fine, thin hair with frontal balding, posteriorly angulated ears with tipped-up ear lobes, a high, narrow palate, lax skin, and deep palmar creases. Ptosis and lax skin had been present since childhood. <a href="#26" class="mim-tip-reference" title="McGaughran, J. &lt;strong&gt;Cardio-facio-cutaneous syndrome: first presentation in a 52-year-old woman. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 116A: 210-212, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12494447/&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;12494447&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10784&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="12494447">McGaughran (2003)</a> stated that this was the oldest person that had been described with CFC syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12494447" 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="Armour, C. M., Allanson, J. E. &lt;strong&gt;Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations. (Letter)&lt;/strong&gt; J. Med. Genet. 45: 249-254, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18039946/&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;18039946&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2007.054460&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="18039946">Armour and Allanson (2008)</a> reported the clinical features of 38 patients with genetically confirmed CFC syndrome. Polyhydramnios (77%) and prematurity (49%) were common perinatal issues. Cardiac anomaly was present in 71% of individuals with the most common being pulmonary valve stenosis (42%), hypertrophic cardiomyopathy (39%), and atrial septal defect (28%). Hair anomalies were also typical: curly hair (92%), sparse hair (84%), and absent or sparse eyebrows (86%). The most frequent cutaneous features were keratosis pilaris (73%), hyperkeratosis (61%), and nevi (76%). Significant and long-lived gastrointestinal dysmotility (71%), seizures (49%), optic nerve hypoplasia (30%), and renal anomalies, chiefly hydronephrosis (20%), were among the less well known issues reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18039946" 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 17 (52%) of 33 unrelated patients with a clinical diagnosis of CFCS, <a href="#43" class="mim-tip-reference" title="Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., and 15 others. &lt;strong&gt;Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.&lt;/strong&gt; Hum. Mutat. 30: 695-702, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19206169/&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;19206169&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19206169[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/humu.20955&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="19206169">Sarkozy et al. (2009)</a> identified heterozygous de novo mutations in the BRAF gene. The most common facial features included prominent forehead, bitemporal narrowing, hypertelorism, downslanting palpebral fissures, epicanthal folds, thick lips, and low-set ears with thick helices. Pulmonary stenosis and hypertrophic cardiomyopathy were the most common cardiac defects, occurring in 90% and 55% of patients, respectively. Ectodermal anomalies included absent or hypoplastic eyebrows, curly, sparse hair, hyperkeratosis, and keratosis pilaris; hyperhidrosis was a common feature (78%). About half of patients had short stature, and most had some degree of neonatal growth failure with poor feeding. Most also had moderate to severe mental retardation, although 2 had normal cognition. Many had hypotonia or seizures. Nine of 17 patients had pigmentary skin changes, including 2 with a high number of lentigines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206169" 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="#12" class="mim-tip-reference" title="Goodwin, A. F., Oberoi, S., Landan, M., Charles, C., Groth, J., Martinez, A., Fairley, C., Weiss, L. A., Tidyman, W. E., Klein, O. D., Rauen, K. A. &lt;strong&gt;Craniofacial and dental development in cardio-facio-cutaneous syndrome: the importance of Ras signaling homeostasis.&lt;/strong&gt; Clin. Genet. 83: 539-544, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22946697/&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;22946697&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22946697[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/10.1111/cge.12005&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="22946697">Goodwin et al. (2013)</a> evaluated the craniofacial features of 32 individuals ranging in age from 2 to 27 years with a clinical diagnosis of CFC who were ascertained from large conferences on the disorder. The most common features included relative macrocephaly (97%), high forehead (84%), bitemporal narrowing (84%), a convex facial profile (74%), and hypertelorism (65%)/telecanthus (100%). About half (52%) had hypoplasia of the superior orbital ridge, and only a few (10%) had micrognathia or a small mandible. Other common features were short nose (71%) and low-set (90%), posteriorly rotated (84%) ears with upturned lobes (52%). The patients also had a recognizable dental phenotype characterized by malocclusion, with open bite in which the anterior teeth were not in contact when the posterior teeth were in occlusion (37%). Many (19%) had a posterior crossbite, in which the maxillary posterior teeth are on the lingual side of the mandibular teeth instead of the buccal side. The majority of patients (80%) had a constricted high-arched palate and many showed tongue thrusting. However, dental development, eruption patterns, and enamel were similar to the general population. Individuals with BRAF mutations had a significantly higher incidence (92%) of high-arched palate compared with MEK1- or MEK2-positive individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22946697" 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="#4" class="mim-tip-reference" title="Bottani, A., Hammerer, I., Schinzel, A. &lt;strong&gt;The cardio-facio-cutaneous syndrome: report of a patient and review of the literature.&lt;/strong&gt; Europ. J. Pediat. 150: 486-488, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1915501/&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;1915501&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01958429&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="1915501">Bottani et al. (1991)</a> reported a patient and reviewed the cases, all sporadic, reported to date. In 20 cases for which information was available, the average age of fathers at the birth of the child was 39 years. This evidence of paternal age effect significantly supports autosomal dominant inheritance. <a href="#7" class="mim-tip-reference" title="Corsello, G., Giuffre, L. &lt;strong&gt;Cardiofaciocutaneous syndrome: notes on clinical variability and natural history. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 41: 265-266, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1785648/&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;1785648&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320410228&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="1785648">Corsello and Giuffre (1991)</a> reported 2 unrelated boys with CFC syndrome. The parents were nonconsanguineous but the fathers were 45 and 50 years old. <a href="#20" class="mim-tip-reference" title="Lecora, M., Parenti, G., Andria, G. &lt;strong&gt;CFC syndrome: report of familial cases. (Letter)&lt;/strong&gt; Clin. Genet. 50: 558-559, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9147900/&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;9147900&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1996.tb02739.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="9147900">Lecora et al. (1996)</a> reported that the mother and younger sister of a patient with CFC, originally described by <a href="#11" class="mim-tip-reference" title="Ghezzi, M., Parenti, G., de Franchis, R., Farina, V., de Leva, F., Guarino, A., Berni Canani, R., Strisciuglio, P. &lt;strong&gt;Clinical variability of cardio-facio-cutaneous syndrome: report of two additional cases.&lt;/strong&gt; Clin. Genet. 42: 206-209, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1358488/&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;1358488&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1992.tb03239.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="1358488">Ghezzi et al. (1992)</a>, also had variable phenotypes consistent with CFC syndrome, thus suggesting autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9147900+1785648+1915501+1358488" 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="#13" class="mim-tip-reference" title="Grebe, T. A., Clericuzio, C. &lt;strong&gt;Neurologic and gastrointestinal dysfunction in cardio-facio-cutaneous syndrome: identification of a severe phenotype.&lt;/strong&gt; Am. J. Med. Genet. 95: 135-143, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11078563/&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;11078563&lt;/a&gt;]" pmid="11078563">Grebe and Clericuzio (2000)</a> described 2 patients with severe manifestations of cardiofaciocutaneous syndrome. Based on these patients, diagnostic criteria for a severe phenotype of CFC syndrome were proposed. These criteria included macrocephaly; characteristic facial features; growth retardation; cardiac defect; sparse, curly hair; neurologic impairment/developmental delay; gastrointestinal dysfunction; ocular abnormalities/dysfunction; history of polyhydramnios; and hyperkeratotic skin lesions. The authors suggested that these stringent diagnostic criteria be used in future studies aimed at identifying a molecular basis for this condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11078563" 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="#18" class="mim-tip-reference" title="Kavamura, M. I., Peres, C. A., Alchorne, M. M. A., Brunoni, D. &lt;strong&gt;CFC index for the diagnosis of cardiofaciocutaneous syndrome.&lt;/strong&gt; Am. J. Med. Genet. 112: 12-16, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12239713/&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;12239713&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10681&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="12239713">Kavamura et al. (2002)</a> created a clinical and objective method, called the CFC index, for the diagnosis of CFC syndrome. The method also differentiated CFC from Noonan and Costello (<a href="/entry/218040">218040</a>) syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12239713" 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="#47" class="mim-tip-reference" title="Van Den Berg, H., Hennekam, R. C. M. &lt;strong&gt;Acute lymphoblastic leukaemia in a patient with cardiofaciocutaneous syndrome.&lt;/strong&gt; J. Med. Genet. 36: 799-800, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10528867/&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;10528867&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.36.10.799&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="10528867">Van Den Berg and Hennekam (1999)</a> reported a child with CFC who developed acute lymphoblastic leukaemia (ALL). The authors noted that malignancy had not been described previously in patients with CFC but had been in those with Noonan syndrome, and that in this group ALL was the most commonly described malignancy. <a href="#47" class="mim-tip-reference" title="Van Den Berg, H., Hennekam, R. C. M. &lt;strong&gt;Acute lymphoblastic leukaemia in a patient with cardiofaciocutaneous syndrome.&lt;/strong&gt; J. Med. Genet. 36: 799-800, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10528867/&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;10528867&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.36.10.799&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="10528867">Van Den Berg and Hennekam (1999)</a> cited the report of <a href="#21" class="mim-tip-reference" title="Legius, E., Schollen, E., Matthijs, G., Fryns, J.-P. &lt;strong&gt;Fine mapping of Noonan/cardio-facio cutaneous syndrome in a large family.&lt;/strong&gt; Europ. J. Hum. Genet. 6: 32-37, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9781012/&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;9781012&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.ejhg.5200150&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="9781012">Legius et al. (1998)</a> and also noted that on the basis of this single case it remained uncertain whether malignancy was a manifestation of CFC or a coincidence in this child. This patient was found to carry a G469E mutation in the BRAF gene (<a href="/entry/164757#0014">164757.0014</a>) by <a href="#34" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. &lt;strong&gt;Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.&lt;/strong&gt; Nature Genet. 38: 294-296, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16474404/&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;16474404&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1749&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="16474404">Niihori et al. (2006)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9781012+10528867+16474404" 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>The phenotypic overlap among CFC syndrome, Noonan syndrome, and Costello syndrome, and the finding of causative mutations for the latter syndromes in the PTPN11 and HRAS (<a href="/entry/190020">190020</a>) genes, respectively, suggested to <a href="#34" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. &lt;strong&gt;Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.&lt;/strong&gt; Nature Genet. 38: 294-296, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16474404/&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;16474404&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1749&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="16474404">Niihori et al. (2006)</a> that the action of the RAS-MAPK pathway is the common underlying mechanism of Noonan syndrome and Costello syndrome and, hence, possibly of CFC syndrome. To elucidate the molecular basis of CFC syndrome, <a href="#34" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. &lt;strong&gt;Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.&lt;/strong&gt; Nature Genet. 38: 294-296, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16474404/&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;16474404&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1749&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="16474404">Niihori et al. (2006)</a> examined the downstream molecules of RAS in the signaling pathway and sequenced the entire 18 codons of BRAF in 40 individuals with CFC. They identified 8 mutations (e.g., <a href="/entry/164757#0012">164757.0012</a>) in 16 individuals. <a href="#34" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. &lt;strong&gt;Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.&lt;/strong&gt; Nature Genet. 38: 294-296, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16474404/&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;16474404&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1749&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="16474404">Niihori et al. (2006)</a> also sequenced the entire coding regions of 3 Ras genes, HRAS, KRAS, and NRAS (<a href="/entry/164790">164790</a>), in genomic DNA from 43 individuals with CFC syndrome and identified 2 KRAS mutations: G60R (<a href="/entry/190070#0009">190070.0009</a>) and D153V (<a href="/entry/190070#0010">190070.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474404" 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="#42" class="mim-tip-reference" title="Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A. &lt;strong&gt;Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.&lt;/strong&gt; Science 311: 1287-1290, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16439621/&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;16439621&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1124642&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="16439621">Rodriguez-Viciana et al. (2006)</a> screened 23 CFC patients for mutations in BRAF. Eighteen of 23, or 78% of individuals, had mutations in BRAF; 11 distinct missense mutations clustered in 2 regions. Five individuals had a gln257-to-arg missense mutation (<a href="/entry/164757#0013">164757.0013</a>) in the cysteine-rich domain of the conserved region 1 (CR1). The other cluster of mutations was in the protein kinase domain and involved exons 11, 12, 14, and 15. Five patients had heterogeneous missense mutations in exon 12. All parents and controls, totaling 40 phenotypically unaffected individuals, had none of these mutations, supporting the hypothesis that occurrence of CFC is sporadic. <a href="#42" class="mim-tip-reference" title="Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A. &lt;strong&gt;Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.&lt;/strong&gt; Science 311: 1287-1290, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16439621/&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;16439621&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1124642&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="16439621">Rodriguez-Viciana et al. (2006)</a> suggested that although the causative mutations in BRAF were heterogeneous, the distribution of mutations was specific and nonrandom. No frameshift, nonsense, or splice site mutations were detected in the cohort of patients; thus, BRAF haploinsufficiency is not a likely causative mechanism of CFC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16439621" 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="#8" 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="#39" 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="#39" 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>In 17 (52%) of 33 unrelated patients with a clinical diagnosis of CFCS, <a href="#43" class="mim-tip-reference" title="Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., and 15 others. &lt;strong&gt;Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.&lt;/strong&gt; Hum. Mutat. 30: 695-702, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19206169/&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;19206169&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19206169[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/humu.20955&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="19206169">Sarkozy et al. (2009)</a> identified heterozygous de novo mutations in the BRAF gene. The mutations clustered in exon 6, encoding the cysteine-rich domain, and in exons 11 to 17, encoding the kinase domain. In vitro functional expression studies of selected variants showed variable gain of function, but little transforming ability; all mutations had less activating potential than the common V600E mutation (<a href="/entry/164757#0001">164757.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206169" 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 Studies</em></strong></p><p>
Because CFC syndrome had been considered to be a more severe variant of Noonan syndrome, <a href="#17" 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> screened for PTPN11 mutations in a series of 28 CFC patients using denaturing high-performance liquid chromatography (DHPLC), but found no abnormalities in the coding region of the gene. In an analysis of the PTPN11 gene in 96 Noonan syndrome patients, <a href="#28" class="mim-tip-reference" title="Musante, L., Kehl, H. G., Majewski, F., Meinecke, P., Schweiger, S., Gillessen-Kaesbach, G., Wieczorek, D., Hinkel, G. K., Tinschert, S., Hoeltzenbein, M., Ropers, H.-H., Kalscheuer, V. M. &lt;strong&gt;Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome.&lt;/strong&gt; Europ. J. Hum. Genet. 11: 201-206, 2003. Note: Erratum: Europ. J. Hum. Genet. 11: 551 only, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12634870/&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;12634870&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.ejhg.5200935&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="12634870">Musante et al. (2003)</a> also screened 5 sporadic patients with CFC syndrome and found no mutations in the PTPN11 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12634870+12384786" 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="#34" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. &lt;strong&gt;Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.&lt;/strong&gt; Nature Genet. 38: 294-296, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16474404/&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;16474404&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1749&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="16474404">Niihori et al. (2006)</a> compared the manifestations of KRAS-positive and BRAF-positive individuals and found similar frequencies of growth and mental retardation, craniofacial appearance, abnormal hair, and heart defects. However, they observed a difference between the 2 groups in manifestations of skin abnormality, including ichthyosis, hyperkeratosis, and hemangioma, which were observed in 13 BRAF-positive individuals but in none of the KRAS-positive individuals (P less than 0.05). That somatic mutations in BRAF have been identified in 60% of malignant melanoma or nevi (<a href="#10" class="mim-tip-reference" title="Garnett, M. J., Marais, R. &lt;strong&gt;Guilty as charged: B-RAF is a human oncogene.&lt;/strong&gt; Cancer Cell 6: 313-319, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15488754/&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;15488754&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ccr.2004.09.022&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="15488754">Garnett and Marais, 2004</a>) suggested to <a href="#34" class="mim-tip-reference" title="Niihori, T., Aoki, Y., Narumi, Y., Neri, G., Cave, H., Verloes, A., Okamoto, N., Hennekam, R. C. M., Gillessen-Kaesbach, G., Wieczorek, D., Kavamura, M.I., Kurosawa, K., and 12 others. &lt;strong&gt;Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.&lt;/strong&gt; Nature Genet. 38: 294-296, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16474404/&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;16474404&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1749&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="16474404">Niihori et al. (2006)</a> that BRAF has an important role in the skin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15488754+16474404" 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="#14" 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, aged 7 weeks to 8 years, with a clinical diagnosis of Costello syndrome (<a href="/entry/218040">218040</a>), Costello-like syndrome, or an overlap CFC/Costello syndrome, who were negative for mutation 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="#14" 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="#14" 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>Among 51 patients with CFC, <a href="#44" 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 BRAF (47%), MAP2K1 (9.8%), MAP2K2 (5.9%), and KRAS (5.9%) genes. Careful assessment of facial features suggested that patients with MAP2K1 mutations showed macrostomia and horizontal shape of the palpebral fissures, whereas those with MAP2K2 mutations had a long, narrow face with a high forehead, low-set ears, severe ptosis, epicanthal folds, and prominent supraorbital ridges. <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 6 patients with a clinical diagnosis of CFC, <a href="#35" class="mim-tip-reference" title="Nystrom, A.-M., Ekvall, S., Berglund, E., Bjorkqvist, M., Braathen, G., Duchen, K., Enell, H., Holmberg, E., Holmlund, U., Olsson-Engman, M., Anneren, G., Bondeson, M.-L. &lt;strong&gt;Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders.&lt;/strong&gt; J. Med. Genet. 45: 500-506, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18456719/&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;18456719&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2008.057653&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="18456719">Nystrom et al. (2008)</a> identified mutations in the BRAF (2), KRAS (1), MEK1 (1), and MEK2 (2) genes. A seventh patient with a diagnosis of CFC had a mutation in the SOS1 gene (<a href="/entry/182530">182530</a>), which is usually associated with Noonan syndrome-4 (NS4; <a href="/entry/610733">610733</a>). An eighth patient with a diagnosis of Noonan syndrome was found to have a mutation in the BRAF gene, which is usually associated with CFC. <a href="#35" class="mim-tip-reference" title="Nystrom, A.-M., Ekvall, S., Berglund, E., Bjorkqvist, M., Braathen, G., Duchen, K., Enell, H., Holmberg, E., Holmlund, U., Olsson-Engman, M., Anneren, G., Bondeson, M.-L. &lt;strong&gt;Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders.&lt;/strong&gt; J. Med. Genet. 45: 500-506, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18456719/&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;18456719&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2008.057653&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="18456719">Nystrom et al. (2008)</a> concluded that the molecular and clinical overlap between CFC and Noonan syndrome is complex and suggested that they may even represent allelic disorders. However, <a href="#30" class="mim-tip-reference" title="Neri, G., Allanson, J., Kavamura, M. I. &lt;strong&gt;No reason yet to change diagnostic criteria for Noonan, Costello and cardio-facio-cutaneous syndromes. (Letter)&lt;/strong&gt; J. Med. Genet. 45: 832 only, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19047498/&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;19047498&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2008.063263&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="19047498">Neri et al. (2008)</a> disputed the diagnoses of 2 patients reported by <a href="#35" class="mim-tip-reference" title="Nystrom, A.-M., Ekvall, S., Berglund, E., Bjorkqvist, M., Braathen, G., Duchen, K., Enell, H., Holmberg, E., Holmlund, U., Olsson-Engman, M., Anneren, G., Bondeson, M.-L. &lt;strong&gt;Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders.&lt;/strong&gt; J. Med. Genet. 45: 500-506, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18456719/&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;18456719&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2008.057653&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="18456719">Nystrom et al. (2008)</a>. <a href="#30" class="mim-tip-reference" title="Neri, G., Allanson, J., Kavamura, M. I. &lt;strong&gt;No reason yet to change diagnostic criteria for Noonan, Costello and cardio-facio-cutaneous syndromes. (Letter)&lt;/strong&gt; J. Med. Genet. 45: 832 only, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19047498/&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;19047498&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2008.063263&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="19047498">Neri et al. (2008)</a> concluded that the SOS1 mutation-bearing CFC patient actually had typical Noonan syndrome, and that the BRAF-carrying NS patient actually had typical CFC. <a href="#30" class="mim-tip-reference" title="Neri, G., Allanson, J., Kavamura, M. I. &lt;strong&gt;No reason yet to change diagnostic criteria for Noonan, Costello and cardio-facio-cutaneous syndromes. (Letter)&lt;/strong&gt; J. Med. Genet. 45: 832 only, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19047498/&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;19047498&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2008.063263&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="19047498">Neri et al. (2008)</a> stated that NS can be caused by mutations in the PTPN11 (<a href="/entry/176876">176876</a>), SOS1, and RAF1 genes, that CFC can be caused by mutations in the BRAF, MEK1, and MEK2 genes, and that the diagnosis of Costello syndrome should be restricted to patients with HRAS mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19047498+18456719" 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="#37" class="mim-tip-reference" title="Rauen, K. A., Cotter, P. D., Bitts, S. M., Cox, V. A., Golabi, M. &lt;strong&gt;Cardio-facio-cutaneous syndrome phenotype in an individual with an interstitial deletion of 12q: identification of a candidate region for CFC syndrome.&lt;/strong&gt; Am. J. Med. Genet. 93: 219-222, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10925386/&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;10925386&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(20000731)93:3&lt;219::aid-ajmg12&gt;3.0.co;2-5&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="10925386">Rauen et al. (2000)</a> reported the case of a 19-month-old girl who presented with the phenotype of CFC syndrome, including characteristic minor facial anomalies, cardiac defect, ectodermal anomalies (keratosis pilaris), and developmental delay. The patient was found to have an interstitial deletion at 12q21.2-q22, proximal to the critical region for Noonan syndrome, suggesting that in this patient CFC is genetically distinct from Noonan syndrome. <a href="#36" class="mim-tip-reference" title="Rauen, K. A., Albertson, D. G., Pinkel, D., Cotter, P. D. &lt;strong&gt;Additional patient with del(12)(q21.2q22): further evidence for a candidate region for cardio-facio-cutaneous syndrome?&lt;/strong&gt; Am. J. Med. Genet. 110: 51-56, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12116271/&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;12116271&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10478&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="12116271">Rauen et al. (2002)</a> reported an additional patient with an interstitial deletion cytogenetically identical to the one reported by <a href="#37" class="mim-tip-reference" title="Rauen, K. A., Cotter, P. D., Bitts, S. M., Cox, V. A., Golabi, M. &lt;strong&gt;Cardio-facio-cutaneous syndrome phenotype in an individual with an interstitial deletion of 12q: identification of a candidate region for CFC syndrome.&lt;/strong&gt; Am. J. Med. Genet. 93: 219-222, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10925386/&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;10925386&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(20000731)93:3&lt;219::aid-ajmg12&gt;3.0.co;2-5&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="10925386">Rauen et al. (2000)</a>. The patient was of XYY sex chromosome constitution. Microarray-based comparative genomic hybridization confirmed both the deletion and the second Y chromosome. The deletion on 12q spanned at least 14 Mb as indicated by the genomic positions of the 4 BAC clones included in the deletion. While the proband did not have the classic features of CFC, he had some dysmorphic craniofacial characteristics, ectodermal anomalies, and moderate developmental delay which were suggestive of CFC syndrome. <a href="#51" class="mim-tip-reference" title="Zollino, M., Neri, G. &lt;strong&gt;Partial deletion of chromosome 12q is not usually associated with CFC syndrome.&lt;/strong&gt; Am. J. Med. Genet. 95: 296 only, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11102944/&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;11102944&lt;/a&gt;]" pmid="11102944">Zollino and Neri (2000)</a> looked for 12q21-q22 deletions in 7 patients with classic CFC syndrome using FISH with the same probe used by <a href="#37" class="mim-tip-reference" title="Rauen, K. A., Cotter, P. D., Bitts, S. M., Cox, V. A., Golabi, M. &lt;strong&gt;Cardio-facio-cutaneous syndrome phenotype in an individual with an interstitial deletion of 12q: identification of a candidate region for CFC syndrome.&lt;/strong&gt; Am. J. Med. Genet. 93: 219-222, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10925386/&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;10925386&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(20000731)93:3&lt;219::aid-ajmg12&gt;3.0.co;2-5&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="10925386">Rauen et al. (2000)</a> and found no deletions. Based on phenotypic features, <a href="#51" class="mim-tip-reference" title="Zollino, M., Neri, G. &lt;strong&gt;Partial deletion of chromosome 12q is not usually associated with CFC syndrome.&lt;/strong&gt; Am. J. Med. Genet. 95: 296 only, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11102944/&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;11102944&lt;/a&gt;]" pmid="11102944">Zollino and Neri (2000)</a> and <a href="#31" class="mim-tip-reference" title="Neri, G., Kavamura, M. I., Zollino, M., Opitz, J. M. &lt;strong&gt;CFC syndrome.&lt;/strong&gt; Am. J. Med. Genet. 116A: 410 only, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12522802/&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;12522802&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10012&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="12522802">Neri et al. (2003)</a> argued that the patients presented by Rauen et al. (<a href="#37" class="mim-tip-reference" title="Rauen, K. A., Cotter, P. D., Bitts, S. M., Cox, V. A., Golabi, M. &lt;strong&gt;Cardio-facio-cutaneous syndrome phenotype in an individual with an interstitial deletion of 12q: identification of a candidate region for CFC syndrome.&lt;/strong&gt; Am. J. Med. Genet. 93: 219-222, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10925386/&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;10925386&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(20000731)93:3&lt;219::aid-ajmg12&gt;3.0.co;2-5&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="10925386">2000</a>, <a href="#36" class="mim-tip-reference" title="Rauen, K. A., Albertson, D. G., Pinkel, D., Cotter, P. D. &lt;strong&gt;Additional patient with del(12)(q21.2q22): further evidence for a candidate region for cardio-facio-cutaneous syndrome?&lt;/strong&gt; Am. J. Med. Genet. 110: 51-56, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12116271/&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;12116271&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10478&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="12116271">2002</a>) did not have CFC. <a href="#38" class="mim-tip-reference" title="Rauen, K. A., Cotter, P. D. &lt;strong&gt;Cardio-facio-cutaneous syndrome phenotype and del(12q).&lt;/strong&gt; Am. J. Med. Genet. 116A: 411-412, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12522803/&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;12522803&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10013&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="12522803">Rauen and Cotter (2003)</a> stated that 'controversy exists as to whether CFC represents a separate entity or if CFC is part of the Noonan syndrome (NS) spectrum.' They pointed out the identification of mutations in the PTPN11 gene on chromosome 12q24.1 in patients with Noonan syndrome, which shares phenotypic features with CFC. In an Editor's Note, <a href="#5" class="mim-tip-reference" title="Carey, J. C. &lt;strong&gt;Editor&#x27;s note: regarding correspondence on CFC syndrome and interstitial 12q deletions.&lt;/strong&gt; Am. J. Med. Genet. 116A: 413 only, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12522804/&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;12522804&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10014&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="12522804">Carey (2003)</a> stated that the idea that 12q21.2-q22 is a candidate region for CFC is not a conclusion, but a hypothesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12116271+12522804+10925386+12522802+12522803+11102944" 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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<h4 href="#mimAnimalModelFold" id="mimAnimalModelToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Animal Model</strong>
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<p><a href="#1" class="mim-tip-reference" title="Anastasaki, C., Estep, A. L., Marais, R., Rauen, K. A., Patton, E. E. &lt;strong&gt;Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors.&lt;/strong&gt; Hum. Molec. Genet. 18: 2543-2554, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19376813/&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;19376813&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19376813[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/ddp186&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="19376813">Anastasaki et al. (2009)</a> expressed a panel of 28 BRAF and MEK alleles in zebrafish embryos to assess the function of human disease alleles and available chemical inhibitors of this pathway. Both kinase-activating and kinase-impaired CFC mutant alleles promoted the equivalent developmental outcome when expressed during early development. Treatment of CFC-zebrafish embryos with inhibitors of the FGF-MAPK pathway could restore normal early development. There was a developmental window in which treatment with an MEK inhibitor could restore the normal early development of the embryo without additional unwanted developmental effects of MEK inhibitor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19376813" 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="#16" class="mim-tip-reference" title="Inoue, S., Moriya, M., Watanabe, Y., Miyagawa-Tomita, S., Niihori, T., Oba, D., Ono, M., Kure, S., Ogura, T., Matsubara, Y., Aoki, Y. &lt;strong&gt;New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome.&lt;/strong&gt; Hum. Molec. Genet. 23: 6553-6566, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25035421/&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;25035421&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddu376&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="25035421">Inoue et al. (2014)</a> created heterozygous knockin mice expressing Braf with a gln241-to-arg (Q241R) mutation, which corresponds to the most frequent mutation in CFC syndrome, gln257 to arg (Q257R; <a href="/entry/164757#0013">164757.0013</a>). Braf Q241R/+ mice showed embryonic or neonatal lethality, with liver necrosis, edema, craniofacial abnormalities, and heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction, and ventricular septal defects. Braf Q241R/+ embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels. Prenatal treatment with a Mek inhibitor partly rescued embryonic lethality in Braf Q241R/+ embryos, with amelioration of craniofacial abnormalities and edema. One surviving pup was obtained following treatment with a histone-3 demethylase inhibitor. Combined treatment with Mek and histone-3 demethylase inhibitors further increased the survival rate in Braf Q241R/+ embryos and ameliorated enlarged cardiac valves. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25035421" 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="references"class="mim-anchor"></a>
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<span class="mim-font">
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Anastasaki2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Anastasaki, C., Estep, A. L., Marais, R., Rauen, K. A., Patton, E. E.
<strong>Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors.</strong>
Hum. Molec. Genet. 18: 2543-2554, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19376813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19376813</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19376813[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=19376813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/ddp186" target="_blank">Full Text</a>]
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<a id="Armour2008" class="mim-anchor"></a>
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<p class="mim-text-font">
Armour, C. M., Allanson, J. E.
<strong>Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations. (Letter)</strong>
J. Med. Genet. 45: 249-254, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18039946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18039946</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18039946" 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.2007.054460" target="_blank">Full Text</a>]
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<a id="Baraitser1986" class="mim-anchor"></a>
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Baraitser, M., Patton, M. A.
<strong>A Noonan-like short stature syndrome with sparse hair.</strong>
J. Med. Genet. 23: 161-164, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3712393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3712393</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3712393" 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.23.2.161" target="_blank">Full Text</a>]
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<a id="Bottani1991" class="mim-anchor"></a>
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<p class="mim-text-font">
Bottani, A., Hammerer, I., Schinzel, A.
<strong>The cardio-facio-cutaneous syndrome: report of a patient and review of the literature.</strong>
Europ. J. Pediat. 150: 486-488, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1915501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1915501</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1915501" 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/BF01958429" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
<a id="Carey2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Carey, J. C.
<strong>Editor's note: regarding correspondence on CFC syndrome and interstitial 12q deletions.</strong>
Am. J. Med. Genet. 116A: 413 only, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522804</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12522804" 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.10014" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
<a id="Chrzanowska1989" class="mim-anchor"></a>
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Chrzanowska, K., Fryns, J. P., Van den Berghe, H.
<strong>Cardio-facio-cutaneous (CFC) syndrome: report of a new patient.</strong>
Am. J. Med. Genet. 33: 471-473, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2596505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2596505</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2596505" 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.1320330410" target="_blank">Full Text</a>]
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<a id="Corsello1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Corsello, G., Giuffre, L.
<strong>Cardiofaciocutaneous syndrome: notes on clinical variability and natural history. (Letter)</strong>
Am. J. Med. Genet. 41: 265-266, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1785648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1785648</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1785648" 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.1320410228" target="_blank">Full Text</a>]
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<a id="Estep2006" class="mim-anchor"></a>
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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: <a href="https://pubmed.ncbi.nlm.nih.gov/16372351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16372351</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16372351" 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.31078" target="_blank">Full Text</a>]
</p>
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<a id="9" class="mim-anchor"></a>
<a id="Fryer1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Fryer, A. E., Holt, P. J., Hughes, H. E.
<strong>The cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome: are they the same?</strong>
Am. J. Med. Genet. 38: 548-551, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2063896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2063896</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2063896" 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.1320380410" target="_blank">Full Text</a>]
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<a id="Garnett2004" class="mim-anchor"></a>
<div class="">
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Garnett, M. J., Marais, R.
<strong>Guilty as charged: B-RAF is a human oncogene.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15488754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15488754</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15488754" 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/j.ccr.2004.09.022" target="_blank">Full Text</a>]
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<a id="Ghezzi1992" class="mim-anchor"></a>
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Ghezzi, M., Parenti, G., de Franchis, R., Farina, V., de Leva, F., Guarino, A., Berni Canani, R., Strisciuglio, P.
<strong>Clinical variability of cardio-facio-cutaneous syndrome: report of two additional cases.</strong>
Clin. Genet. 42: 206-209, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1358488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1358488</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1358488" 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.1399-0004.1992.tb03239.x" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
<a id="Goodwin2013" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Goodwin, A. F., Oberoi, S., Landan, M., Charles, C., Groth, J., Martinez, A., Fairley, C., Weiss, L. A., Tidyman, W. E., Klein, O. D., Rauen, K. A.
<strong>Craniofacial and dental development in cardio-facio-cutaneous syndrome: the importance of Ras signaling homeostasis.</strong>
Clin. Genet. 83: 539-544, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22946697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22946697</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22946697[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=22946697" 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/cge.12005" target="_blank">Full Text</a>]
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<a id="Grebe2000" class="mim-anchor"></a>
<div class="">
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Grebe, T. A., Clericuzio, C.
<strong>Neurologic and gastrointestinal dysfunction in cardio-facio-cutaneous syndrome: identification of a severe phenotype.</strong>
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[<a href="https://doi.org/10.1002/ajmg.a.31815" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1990.tb03600.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddu376" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-002-0803-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.10681" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00019605-199601000-00010" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1996.tb02739.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200150" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00019605-199601000-00009" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/MCD.0b013e32833ff29d" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1096-8628(19960517)63:2&lt;382::AID-AJMG11&gt;3.0.CO;2-G" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320390206" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.10784" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320330411" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200935" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.063263" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.10012" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320270404" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320390323" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.057653" target="_blank">Full Text</a>]
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<div class="">
<p class="mim-text-font">
Rauen, K. A., Albertson, D. G., Pinkel, D., Cotter, P. D.
<strong>Additional patient with del(12)(q21.2q22): further evidence for a candidate region for cardio-facio-cutaneous syndrome?</strong>
Am. J. Med. Genet. 110: 51-56, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12116271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12116271</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12116271" 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.10478" target="_blank">Full Text</a>]
</p>
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<a id="37" class="mim-anchor"></a>
<a id="Rauen2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rauen, K. A., Cotter, P. D., Bitts, S. M., Cox, V. A., Golabi, M.
<strong>Cardio-facio-cutaneous syndrome phenotype in an individual with an interstitial deletion of 12q: identification of a candidate region for CFC syndrome.</strong>
Am. J. Med. Genet. 93: 219-222, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10925386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10925386</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10925386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/1096-8628(20000731)93:3&lt;219::aid-ajmg12&gt;3.0.co;2-5" target="_blank">Full Text</a>]
</p>
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<a id="38" class="mim-anchor"></a>
<a id="Rauen2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rauen, K. A., Cotter, P. D.
<strong>Cardio-facio-cutaneous syndrome phenotype and del(12q).</strong>
Am. J. Med. Genet. 116A: 411-412, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522803</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12522803" 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.10013" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="39" class="mim-anchor"></a>
<a id="Rauen2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rauen, K. A.
<strong>Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. (Letter)</strong>
Am. J. Med. Genet. 140A: 1681-1683, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804887</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16804887" 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.31315" target="_blank">Full Text</a>]
</p>
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<li>
<a id="40" class="mim-anchor"></a>
<a id="Reynolds1986" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Reynolds, J. F., Neri, G., Herrmann, J. P., Blumberg, B., Coldwell, J. G., Miles, P. V., Opitz, J. M.
<strong>New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement--the CFC syndrome.</strong>
Am. J. Med. Genet. 25: 413-427, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3789005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3789005</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3789005" 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.1320250303" target="_blank">Full Text</a>]
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<a id="41" class="mim-anchor"></a>
<a id="Roberts2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Roberts, A., Allanson, J., Jadico, S. K., Kavamura, M. I., Noonan, J., Opitz, J. M., Young, T., Neri, G.
<strong>The cardiofaciocutaneous syndrome.</strong>
J. Med. Genet. 43: 833-842, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825433[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=16825433" 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.2006.042796" target="_blank">Full Text</a>]
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<a id="42" class="mim-anchor"></a>
<a id="Rodriguez-Viciana2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A.
<strong>Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.</strong>
Science 311: 1287-1290, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16439621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16439621</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16439621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.1124642" target="_blank">Full Text</a>]
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<a id="43" class="mim-anchor"></a>
<a id="Sarkozy2009" class="mim-anchor"></a>
<div class="">
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Sarkozy, A., Carta, C., Moretti, S., Zampino, G., Digilio, M. C., Pantaleoni, F., Scioletti, A. P., Esposito, G., Cordeddu, V., Lepri, F., Petrangeli, V., Dentici, M. L., and 15 others.
<strong>Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.</strong>
Hum. Mutat. 30: 695-702, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206169</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19206169[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=19206169" 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.20955" target="_blank">Full Text</a>]
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<a id="44" class="mim-anchor"></a>
<a id="Schulz2008" class="mim-anchor"></a>
<div class="">
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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.
<strong>Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome</strong>
Clin. Genet. 73: 62-70, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18042262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18042262</a>, <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'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.2007.00931.x" target="_blank">Full Text</a>]
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<a id="45" class="mim-anchor"></a>
<a id="Sorge1989" class="mim-anchor"></a>
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Sorge, G., Di Forti, F., Scarano, G., Ventruto, V., Zelante, L., Dallapiccola, B.
<strong>CFC syndrome: report on three additional cases.</strong>
Am. J. Med. Genet. 33: 476-478, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2596507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2596507</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2596507" 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.1320330412" target="_blank">Full Text</a>]
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<a id="46" class="mim-anchor"></a>
<a id="Turnpenny1992" class="mim-anchor"></a>
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Turnpenny, P. D., Dean, J. C. S., Auchterlonie, I. A., Johnston, A. W.
<strong>Cardiofaciocutaneous syndrome with new ectodermal manifestations.</strong>
J. Med. Genet. 29: 428-429, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1619641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1619641</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1619641" 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.29.6.428" target="_blank">Full Text</a>]
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<a id="47" class="mim-anchor"></a>
<a id="Van Den Berg1999" class="mim-anchor"></a>
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Van Den Berg, H., Hennekam, R. C. M.
<strong>Acute lymphoblastic leukaemia in a patient with cardiofaciocutaneous syndrome.</strong>
J. Med. Genet. 36: 799-800, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10528867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10528867</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10528867" 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.36.10.799" target="_blank">Full Text</a>]
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<a id="48" class="mim-anchor"></a>
<a id="Verloes1988" class="mim-anchor"></a>
<div class="">
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Verloes, A., Le Merrer, M., Soyeur, D., Kaplan, J., Pangalos, C., Rigo, J., Briard, M.-L.
<strong>CFC syndrome: a syndrome distinct from Noonan syndrome.</strong>
Ann. Genet. 31: 230-234, 1988.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3265306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3265306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3265306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="49" class="mim-anchor"></a>
<a id="Ward1994" class="mim-anchor"></a>
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Ward, K. A., Moss, C., McKeown, C.
<strong>The cardio-facio-cutaneous syndrome: a manifestation of the Noonan syndrome?</strong>
Brit. J. Derm. 131: 270-274, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7917994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7917994</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7917994" 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.1365-2133.1994.tb08504.x" target="_blank">Full Text</a>]
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<a id="Wieczorek1997" class="mim-anchor"></a>
<div class="">
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Wieczorek, D., Majewski, F., Gillessen-Kaesbach, G.
<strong>Cardio-facio-cutaneous (CFC) syndrome--a distinct entity? Report of three patients demonstrating the diagnostic difficulties in delineation of CFC syndrome.</strong>
Clin. Genet. 52: 37-46, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9272711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9272711</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9272711" 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.1399-0004.1997.tb02512.x" target="_blank">Full Text</a>]
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<a id="51" class="mim-anchor"></a>
<a id="Zollino2000" class="mim-anchor"></a>
<div class="">
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Zollino, M., Neri, G.
<strong>Partial deletion of chromosome 12q is not usually associated with CFC syndrome.</strong>
Am. J. Med. Genet. 95: 296 only, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11102944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11102944</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11102944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Patricia A. Hartz - updated : 3/26/2015
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Anne M. Stumpf - reorganized : 6/20/2013<br>Cassandra L. Kniffin - updated : 6/4/2013<br>Cassandra L. Kniffin - updated : 6/28/2012<br>Cassandra L. Kniffin - updated : 4/28/2011<br>Cassandra L. Kniffin - updated : 1/21/2011<br>Cassandra L. Kniffin - updated : 11/11/2010<br>George E. Tiller - updated : 3/31/2010<br>Cassandra L. Kniffin - updated : 2/10/2009<br>Cassandra L. Kniffin - updated : 8/15/2008<br>Cassandra L. Kniffin - updated : 3/17/2008<br>Cassandra L. Kniffin - updated : 12/13/2006<br>Marla J. F. O'Neill - updated : 9/26/2006<br>Ada Hamosh - updated : 4/19/2006<br>Victor A. McKusick - updated : 2/24/2006<br>Marla J. F. O'Neill - updated : 9/29/2005<br>Marla J. F. O'Neill - updated : 5/12/2004<br>Victor A. McKusick - updated : 11/13/2002<br>Victor A. McKusick - updated : 10/7/2002<br>Deborah L. Stone - updated : 9/11/2002<br>Victor A. McKusick - updated : 6/12/2002<br>Sonja A. Rasmussen - updated : 12/12/2000<br>Victor A. McKusick - updated : 8/17/2000<br>Michael J. Wright - updated : 2/4/2000<br>Victor A. McKusick - updated : 4/30/1998<br>Victor A. McKusick - updated : 8/26/1997<br>Iosif W. Lurie - updated : 7/26/1996
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Creation Date:
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Victor A. McKusick : 11/13/1987
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carol : 02/19/2025
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<h3>
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<strong>#</strong> 115150
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CARDIOFACIOCUTANEOUS SYNDROME 1; CFC1
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<em>Alternative titles; symbols</em>
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CFC SYNDROME<br />
CFCS
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<p>
<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 403770008; &nbsp;
<strong>ORPHA:</strong> 1340; &nbsp;
<strong>DO:</strong> 0111460; &nbsp;
</span>
</p>
</div>
<div>
<br />
</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">
7q34
</span>
</td>
<td>
<span class="mim-font">
Cardiofaciocutaneous syndrome
</span>
</td>
<td>
<span class="mim-font">
115150
</span>
</td>
<td>
<span class="mim-font">
Autosomal dominant
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
BRAF
</span>
</td>
<td>
<span class="mim-font">
164757
</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 cardiofaciocutaneous syndrome-1 (CFC1) is caused by heterozygous mutation in the BRAF gene (164757) on chromosome 7q34.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects, and impaired intellectual development. The heart defects include pulmonic stenosis, atrial septal defect, and hypertrophic cardiomyopathy. Some patients have ectodermal abnormalities such as sparse and friable hair, hyperkeratotic skin lesions, and a generalized ichthyosis-like condition. Typical facial characteristics include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices (summary by Niihori et al., 2006). Most cases occur sporadically, but autosomal dominant transmission has been rarely reported (Linden and Price, 2011). </p><p>Roberts et al. (2006) provided a detailed review of CFC syndrome, including a discussion of the phenotypic overlap of CFC syndrome with Noonan syndrome (NS1; 163950) and Costello syndrome (218040). </p><p><strong><em>Genetic Heterogeneity of Cardiofaciocutaneous Syndrome</em></strong></p><p>
Other forms of cardiofaciocutaneous syndrome include CFC2 (615278), caused by mutation in the KRAS gene (190070); CFC3 (615279), caused by mutation in the MAP2K1 gene (176872); and CFC4 (615280), caused by mutation in the MAP2K2 gene (601263). The protein products of these causative genes, including BRAF, interact in a common RAS/ERK (see 601795) pathway that regulates cell differentiation, proliferation, and apoptosis (summary by Roberts et al., 2006). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Reynolds et al. (1986) described 4 males and 4 females, each from a different family, with a previously undefined multiple congenital anomalies/mental retardation syndrome, which they designated the cardiofaciocutaneous syndrome. The manifestations included congenital heart defects, characteristic facial appearance, ectodermal abnormalities, and growth failure. The most common cardiac defects were pulmonic stenosis and atrial septal defect. Typical facial characteristics were high forehead with bitemporal constriction, hypoplasia of the supraorbital ridges, downslanting palpebral fissures, depressed bridge of nose, and posteriorly angulated ears with prominent helices. The hair was usually sparse and friable. Skin changes varied from patchy hyperkeratosis to a severe generalized ichthyosis-like condition. There was no history of consanguinity. Neri et al. (1987) reported 2 cases; again, no parental consanguinity was observed. Roberts et al. (2006) provided follow-up on 6 of the patients originally reported by Reynolds et al. (1986). Three had been lost to follow-up, 1 was living independently with family, 1 was in a group home, and 1 had died of heart failure. </p><p>Verloes et al. (1988) reported 2 cases and pointed out the similarity to Noonan syndrome. They also suggested that the Noonan-like short stature syndrome with sparse hair described by Baraitser and Patton (1986) is the same disorder. The first of their patients had the habitus of Noonan syndrome associated with keratosis plantaris and nystagmus; the second had a somewhat Noonan-like face, macrocephaly, keratosis pilaris, and hypertrophic cardiomyopathy. </p><p>Chrzanowska et al. (1989) described an affected girl whose twin brother died shortly after birth and may have had the same malformation syndrome. The father and mother, aged 35 and 36 years, respectively, were healthy and nonconsanguineous. Mucklow (1989) described 1 case, and Sorge et al. (1989) described 3 cases. In addition to high cranial vault, bitemporal frontal constriction was noted. </p><p>Gross-Tsur et al. (1990) described what they alleged to be the sixteenth reported case of CFC. Roberts et al. (2006) noted that this child had Lennox-Gastaut encephalopathy. </p><p>Fryer et al. (1991) also emphasized the phenotypic overlap between the CFC syndrome and the Noonan syndrome. They presented findings in the patient reported by Navaratnam (1973), published photographs spanning from infancy to age 21 years, and showed the appearance of the pectus carinatum/excavatum and the keratotic skin lesions. Matsuda et al. (1991) described 2 Japanese boys with the CFC syndrome but without hyperkeratosis of the skin. Neri et al. (1991) concluded that the Noonan and CFC syndromes are indeed distinct and separate conditions, both falling within the broad and causally heterogeneous spectrum of the Noonan/congenital lymphedema phenotype; other members of the cluster were listed. </p><p>Turnpenny et al. (1992) described a 7-year-old girl whose features were thought to satisfy the diagnosis of CFC syndrome. The ectodermal features consisted of fine and sparse hair, thin and opalescent nails, finger tip pads, generalized cutaneous pigmentation, but no hyperkeratosis. </p><p>Although CFC syndrome is distinguished from Noonan syndrome by the presence of abnormal hair and hyperkeratotic lesions and by its usual sporadic occurrence, Ward et al. (1994) supported the suggestion of Fryer et al. (1991) that it falls 'within the clinical spectrum of the Noonan phenotype.' They described mother and daughter who had features consistent with the CFC syndrome but had other features which have been reported in the Noonan syndrome but not in the CFC syndrome, namely, hemorrhagic diathesis and ocular abnormalities. They were described as having ulerythema ophryogenes (keratosis pilaris affecting the follicles of the eyebrow hairs, associated with erythema, scarring, and atrophy). Krajewska-Walasek et al. (1996) reported 2 unrelated children (a boy and a girl) with CFC syndrome who had 'Noonan-like' face, sparse, thin, curly hair, and severe mental retardation. The girl also had altered sensation of the distal part of the limbs, which has been described in patients with Noonan syndrome but not in patients with CFC syndrome. Leichtman (1996) described a family suggesting that CFC syndrome is a variable expression of Noonan syndrome. He reported a 4-year-old girl with features sufficient to meet the criteria for CFC, including developmental delay, hypotrichosis, eczematic eruption, and characteristic facial and cardiac anomalies, whose mother demonstrated typical manifestations of Noonan syndrome. </p><p>Manoukian et al. (1996) reported the case of a 25-year-old woman with typical features of CFC syndrome but without mental retardation. She had valvular and infundibular pulmonic stenosis, brittle and woolly hair with patchy alopecia, scant body hair, dry and hypohidrotic skin, and characteristic facial traits. At the age of 3 years the patient had shown fullness of periorbital tissues, ectropion of the lower palpebral fissures, malar hypoplasia, bulbous nose, and hyperplasia of the helix and earlobes. At the age of 25 she showed downslanting palpebral fissures with scant eyebrows and absent eyelashes on the nasal side, edematous eyelids, ectropion of the lower eyelids, posteriorly angulated ears with hyperplastic helix and lobes, and webbed neck. </p><p>Wieczorek et al. (1997) described 3 patients in whom the diagnosis was considered to be CFC syndrome. They provided a detailed review of previously reported cases and discussed the differences from Noonan and Costello (218040) syndromes. </p><p>McGaughran (2003) reported the diagnosis of CFC syndrome in a 52-year-old woman who had short stature, a head circumference below the 50th centile, bilateral ptosis, fine, thin hair with frontal balding, posteriorly angulated ears with tipped-up ear lobes, a high, narrow palate, lax skin, and deep palmar creases. Ptosis and lax skin had been present since childhood. McGaughran (2003) stated that this was the oldest person that had been described with CFC syndrome. </p><p>Armour and Allanson (2008) reported the clinical features of 38 patients with genetically confirmed CFC syndrome. Polyhydramnios (77%) and prematurity (49%) were common perinatal issues. Cardiac anomaly was present in 71% of individuals with the most common being pulmonary valve stenosis (42%), hypertrophic cardiomyopathy (39%), and atrial septal defect (28%). Hair anomalies were also typical: curly hair (92%), sparse hair (84%), and absent or sparse eyebrows (86%). The most frequent cutaneous features were keratosis pilaris (73%), hyperkeratosis (61%), and nevi (76%). Significant and long-lived gastrointestinal dysmotility (71%), seizures (49%), optic nerve hypoplasia (30%), and renal anomalies, chiefly hydronephrosis (20%), were among the less well known issues reported. </p><p>In 17 (52%) of 33 unrelated patients with a clinical diagnosis of CFCS, Sarkozy et al. (2009) identified heterozygous de novo mutations in the BRAF gene. The most common facial features included prominent forehead, bitemporal narrowing, hypertelorism, downslanting palpebral fissures, epicanthal folds, thick lips, and low-set ears with thick helices. Pulmonary stenosis and hypertrophic cardiomyopathy were the most common cardiac defects, occurring in 90% and 55% of patients, respectively. Ectodermal anomalies included absent or hypoplastic eyebrows, curly, sparse hair, hyperkeratosis, and keratosis pilaris; hyperhidrosis was a common feature (78%). About half of patients had short stature, and most had some degree of neonatal growth failure with poor feeding. Most also had moderate to severe mental retardation, although 2 had normal cognition. Many had hypotonia or seizures. Nine of 17 patients had pigmentary skin changes, including 2 with a high number of lentigines. </p><p>Goodwin et al. (2013) evaluated the craniofacial features of 32 individuals ranging in age from 2 to 27 years with a clinical diagnosis of CFC who were ascertained from large conferences on the disorder. The most common features included relative macrocephaly (97%), high forehead (84%), bitemporal narrowing (84%), a convex facial profile (74%), and hypertelorism (65%)/telecanthus (100%). About half (52%) had hypoplasia of the superior orbital ridge, and only a few (10%) had micrognathia or a small mandible. Other common features were short nose (71%) and low-set (90%), posteriorly rotated (84%) ears with upturned lobes (52%). The patients also had a recognizable dental phenotype characterized by malocclusion, with open bite in which the anterior teeth were not in contact when the posterior teeth were in occlusion (37%). Many (19%) had a posterior crossbite, in which the maxillary posterior teeth are on the lingual side of the mandibular teeth instead of the buccal side. The majority of patients (80%) had a constricted high-arched palate and many showed tongue thrusting. However, dental development, eruption patterns, and enamel were similar to the general population. Individuals with BRAF mutations had a significantly higher incidence (92%) of high-arched palate compared with MEK1- or MEK2-positive individuals. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Bottani et al. (1991) reported a patient and reviewed the cases, all sporadic, reported to date. In 20 cases for which information was available, the average age of fathers at the birth of the child was 39 years. This evidence of paternal age effect significantly supports autosomal dominant inheritance. Corsello and Giuffre (1991) reported 2 unrelated boys with CFC syndrome. The parents were nonconsanguineous but the fathers were 45 and 50 years old. Lecora et al. (1996) reported that the mother and younger sister of a patient with CFC, originally described by Ghezzi et al. (1992), also had variable phenotypes consistent with CFC syndrome, thus suggesting autosomal dominant inheritance. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Grebe and Clericuzio (2000) described 2 patients with severe manifestations of cardiofaciocutaneous syndrome. Based on these patients, diagnostic criteria for a severe phenotype of CFC syndrome were proposed. These criteria included macrocephaly; characteristic facial features; growth retardation; cardiac defect; sparse, curly hair; neurologic impairment/developmental delay; gastrointestinal dysfunction; ocular abnormalities/dysfunction; history of polyhydramnios; and hyperkeratotic skin lesions. The authors suggested that these stringent diagnostic criteria be used in future studies aimed at identifying a molecular basis for this condition. </p><p>Kavamura et al. (2002) created a clinical and objective method, called the CFC index, for the diagnosis of CFC syndrome. The method also differentiated CFC from Noonan and Costello (218040) syndromes. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Other Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Van Den Berg and Hennekam (1999) reported a child with CFC who developed acute lymphoblastic leukaemia (ALL). The authors noted that malignancy had not been described previously in patients with CFC but had been in those with Noonan syndrome, and that in this group ALL was the most commonly described malignancy. Van Den Berg and Hennekam (1999) cited the report of Legius et al. (1998) and also noted that on the basis of this single case it remained uncertain whether malignancy was a manifestation of CFC or a coincidence in this child. This patient was found to carry a G469E mutation in the BRAF gene (164757.0014) by Niihori et al. (2006). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The phenotypic overlap among CFC syndrome, Noonan syndrome, and Costello syndrome, and the finding of causative mutations for the latter syndromes in the PTPN11 and HRAS (190020) genes, respectively, suggested to Niihori et al. (2006) that the action of the RAS-MAPK pathway is the common underlying mechanism of Noonan syndrome and Costello syndrome and, hence, possibly of CFC syndrome. To elucidate the molecular basis of CFC syndrome, Niihori et al. (2006) examined the downstream molecules of RAS in the signaling pathway and sequenced the entire 18 codons of BRAF in 40 individuals with CFC. They identified 8 mutations (e.g., 164757.0012) in 16 individuals. Niihori et al. (2006) also sequenced the entire coding regions of 3 Ras genes, HRAS, KRAS, and NRAS (164790), in genomic DNA from 43 individuals with CFC syndrome and identified 2 KRAS mutations: G60R (190070.0009) and D153V (190070.0010). </p><p>Rodriguez-Viciana et al. (2006) screened 23 CFC patients for mutations in BRAF. Eighteen of 23, or 78% of individuals, had mutations in BRAF; 11 distinct missense mutations clustered in 2 regions. Five individuals had a gln257-to-arg missense mutation (164757.0013) in the cysteine-rich domain of the conserved region 1 (CR1). The other cluster of mutations was in the protein kinase domain and involved exons 11, 12, 14, and 15. Five patients had heterogeneous missense mutations in exon 12. All parents and controls, totaling 40 phenotypically unaffected individuals, had none of these mutations, supporting the hypothesis that occurrence of CFC is sporadic. Rodriguez-Viciana et al. (2006) suggested that although the causative mutations in BRAF were heterogeneous, the distribution of mutations was specific and nonrandom. No frameshift, nonsense, or splice site mutations were detected in the cohort of patients; thus, BRAF haploinsufficiency is not a likely causative mechanism of CFC. </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>In 17 (52%) of 33 unrelated patients with a clinical diagnosis of CFCS, Sarkozy et al. (2009) identified heterozygous de novo mutations in the BRAF gene. The mutations clustered in exon 6, encoding the cysteine-rich domain, and in exons 11 to 17, encoding the kinase domain. In vitro functional expression studies of selected variants showed variable gain of function, but little transforming ability; all mutations had less activating potential than the common V600E mutation (164757.0001). </p><p><strong><em>Exclusion Studies</em></strong></p><p>
Because CFC syndrome had been considered to be a more severe variant of Noonan syndrome, Ion et al. (2002) screened for PTPN11 mutations in a series of 28 CFC patients using denaturing high-performance liquid chromatography (DHPLC), but found no abnormalities in the coding region of the gene. In an analysis of the PTPN11 gene in 96 Noonan syndrome patients, Musante et al. (2003) also screened 5 sporadic patients with CFC syndrome and found no mutations in the PTPN11 gene. </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>Niihori et al. (2006) compared the manifestations of KRAS-positive and BRAF-positive individuals and found similar frequencies of growth and mental retardation, craniofacial appearance, abnormal hair, and heart defects. However, they observed a difference between the 2 groups in manifestations of skin abnormality, including ichthyosis, hyperkeratosis, and hemangioma, which were observed in 13 BRAF-positive individuals but in none of the KRAS-positive individuals (P less than 0.05). That somatic mutations in BRAF have been identified in 60% of malignant melanoma or nevi (Garnett and Marais, 2004) suggested to Niihori et al. (2006) that BRAF has an important role in the skin. </p><p>Gripp et al. (2007) reported 13 unrelated patients, aged 7 weeks to 8 years, with a clinical diagnosis of Costello syndrome (218040), Costello-like syndrome, or an overlap CFC/Costello syndrome, who were negative for mutation 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>Among 51 patients with CFC, Schulz et al. (2008) identified mutations in the BRAF (47%), MAP2K1 (9.8%), MAP2K2 (5.9%), and KRAS (5.9%) genes. Careful assessment of facial features suggested that patients with MAP2K1 mutations showed macrostomia and horizontal shape of the palpebral fissures, whereas those with MAP2K2 mutations had a long, narrow face with a high forehead, low-set ears, severe ptosis, epicanthal folds, and prominent supraorbital ridges. </p><p>In 6 patients with a clinical diagnosis of CFC, Nystrom et al. (2008) identified mutations in the BRAF (2), KRAS (1), MEK1 (1), and MEK2 (2) genes. A seventh patient with a diagnosis of CFC had a mutation in the SOS1 gene (182530), which is usually associated with Noonan syndrome-4 (NS4; 610733). An eighth patient with a diagnosis of Noonan syndrome was found to have a mutation in the BRAF gene, which is usually associated with CFC. Nystrom et al. (2008) concluded that the molecular and clinical overlap between CFC and Noonan syndrome is complex and suggested that they may even represent allelic disorders. However, Neri et al. (2008) disputed the diagnoses of 2 patients reported by Nystrom et al. (2008). Neri et al. (2008) concluded that the SOS1 mutation-bearing CFC patient actually had typical Noonan syndrome, and that the BRAF-carrying NS patient actually had typical CFC. Neri et al. (2008) stated that NS can be caused by mutations in the PTPN11 (176876), SOS1, and RAF1 genes, that CFC can be caused by mutations in the BRAF, MEK1, and MEK2 genes, and that the diagnosis of Costello syndrome should be restricted to patients with HRAS mutations. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Rauen et al. (2000) reported the case of a 19-month-old girl who presented with the phenotype of CFC syndrome, including characteristic minor facial anomalies, cardiac defect, ectodermal anomalies (keratosis pilaris), and developmental delay. The patient was found to have an interstitial deletion at 12q21.2-q22, proximal to the critical region for Noonan syndrome, suggesting that in this patient CFC is genetically distinct from Noonan syndrome. Rauen et al. (2002) reported an additional patient with an interstitial deletion cytogenetically identical to the one reported by Rauen et al. (2000). The patient was of XYY sex chromosome constitution. Microarray-based comparative genomic hybridization confirmed both the deletion and the second Y chromosome. The deletion on 12q spanned at least 14 Mb as indicated by the genomic positions of the 4 BAC clones included in the deletion. While the proband did not have the classic features of CFC, he had some dysmorphic craniofacial characteristics, ectodermal anomalies, and moderate developmental delay which were suggestive of CFC syndrome. Zollino and Neri (2000) looked for 12q21-q22 deletions in 7 patients with classic CFC syndrome using FISH with the same probe used by Rauen et al. (2000) and found no deletions. Based on phenotypic features, Zollino and Neri (2000) and Neri et al. (2003) argued that the patients presented by Rauen et al. (2000, 2002) did not have CFC. Rauen and Cotter (2003) stated that 'controversy exists as to whether CFC represents a separate entity or if CFC is part of the Noonan syndrome (NS) spectrum.' They pointed out the identification of mutations in the PTPN11 gene on chromosome 12q24.1 in patients with Noonan syndrome, which shares phenotypic features with CFC. In an Editor's Note, Carey (2003) stated that the idea that 12q21.2-q22 is a candidate region for CFC is not a conclusion, but a hypothesis. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Anastasaki et al. (2009) expressed a panel of 28 BRAF and MEK alleles in zebrafish embryos to assess the function of human disease alleles and available chemical inhibitors of this pathway. Both kinase-activating and kinase-impaired CFC mutant alleles promoted the equivalent developmental outcome when expressed during early development. Treatment of CFC-zebrafish embryos with inhibitors of the FGF-MAPK pathway could restore normal early development. There was a developmental window in which treatment with an MEK inhibitor could restore the normal early development of the embryo without additional unwanted developmental effects of MEK inhibitor. </p><p>Inoue et al. (2014) created heterozygous knockin mice expressing Braf with a gln241-to-arg (Q241R) mutation, which corresponds to the most frequent mutation in CFC syndrome, gln257 to arg (Q257R; 164757.0013). Braf Q241R/+ mice showed embryonic or neonatal lethality, with liver necrosis, edema, craniofacial abnormalities, and heart defects, including cardiomegaly, enlarged cardiac valves, ventricular noncompaction, and ventricular septal defects. Braf Q241R/+ embryos also showed massively distended jugular lymphatic sacs and subcutaneous lymphatic vessels. Prenatal treatment with a Mek inhibitor partly rescued embryonic lethality in Braf Q241R/+ embryos, with amelioration of craniofacial abnormalities and edema. One surviving pup was obtained following treatment with a histone-3 demethylase inhibitor. Combined treatment with Mek and histone-3 demethylase inhibitors further increased the survival rate in Braf Q241R/+ embryos and ameliorated enlarged cardiac valves. </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">
Anastasaki, C., Estep, A. L., Marais, R., Rauen, K. A., Patton, E. E.
<strong>Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors.</strong>
Hum. Molec. Genet. 18: 2543-2554, 2009.
[PubMed: 19376813]
[Full Text: https://doi.org/10.1093/hmg/ddp186]
</p>
</li>
<li>
<p class="mim-text-font">
Armour, C. M., Allanson, J. E.
<strong>Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations. (Letter)</strong>
J. Med. Genet. 45: 249-254, 2008.
[PubMed: 18039946]
[Full Text: https://doi.org/10.1136/jmg.2007.054460]
</p>
</li>
<li>
<p class="mim-text-font">
Baraitser, M., Patton, M. A.
<strong>A Noonan-like short stature syndrome with sparse hair.</strong>
J. Med. Genet. 23: 161-164, 1986.
[PubMed: 3712393]
[Full Text: https://doi.org/10.1136/jmg.23.2.161]
</p>
</li>
<li>
<p class="mim-text-font">
Bottani, A., Hammerer, I., Schinzel, A.
<strong>The cardio-facio-cutaneous syndrome: report of a patient and review of the literature.</strong>
Europ. J. Pediat. 150: 486-488, 1991.
[PubMed: 1915501]
[Full Text: https://doi.org/10.1007/BF01958429]
</p>
</li>
<li>
<p class="mim-text-font">
Carey, J. C.
<strong>Editor&#x27;s note: regarding correspondence on CFC syndrome and interstitial 12q deletions.</strong>
Am. J. Med. Genet. 116A: 413 only, 2003.
[PubMed: 12522804]
[Full Text: https://doi.org/10.1002/ajmg.a.10014]
</p>
</li>
<li>
<p class="mim-text-font">
Chrzanowska, K., Fryns, J. P., Van den Berghe, H.
<strong>Cardio-facio-cutaneous (CFC) syndrome: report of a new patient.</strong>
Am. J. Med. Genet. 33: 471-473, 1989.
[PubMed: 2596505]
[Full Text: https://doi.org/10.1002/ajmg.1320330410]
</p>
</li>
<li>
<p class="mim-text-font">
Corsello, G., Giuffre, L.
<strong>Cardiofaciocutaneous syndrome: notes on clinical variability and natural history. (Letter)</strong>
Am. J. Med. Genet. 41: 265-266, 1991.
[PubMed: 1785648]
[Full Text: https://doi.org/10.1002/ajmg.1320410228]
</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">
Fryer, A. E., Holt, P. J., Hughes, H. E.
<strong>The cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome: are they the same?</strong>
Am. J. Med. Genet. 38: 548-551, 1991.
[PubMed: 2063896]
[Full Text: https://doi.org/10.1002/ajmg.1320380410]
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Garnett, M. J., Marais, R.
<strong>Guilty as charged: B-RAF is a human oncogene.</strong>
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