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- #163950 - NOONAN SYNDROME 1; NS1
- OMIM
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<span class="h4">#163950</span>
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<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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<li role="presentation">
<a href="/clinicalSynopsis/163950"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
<a href="/phenotypicSeries/PS163950"> <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="#otherFeatures">Other 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="#populationGenetics">Population Genetics</a>
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<a href="#mapping">Mapping</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></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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<li role="presentation">
<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=NOONAN 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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<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0060578" 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/163950" 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:0060578" 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>
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</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:163950" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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> 205684007, 205824006<br />
<strong>ICD10CM:</strong> Q87.19<br />
<strong>ORPHA:</strong> 648<br />
<strong>DO:</strong> 0060578<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>
163950
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
NOONAN SYNDROME 1; NS1
</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">
NOONAN SYNDROME<br />
MALE TURNER SYNDROME<br />
FEMALE PSEUDO-TURNER SYNDROME<br />
TURNER PHENOTYPE WITH NORMAL KARYOTYPE
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
PTERYGIUM COLLI SYNDROME, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/823?start=-3&limit=10&highlight=823">
12q24.13
</a>
</span>
</td>
<td>
<span class="mim-font">
Noonan syndrome 1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/163950"> 163950 </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">
PTPN11
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176876"> 176876 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/163950" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS163950" 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/163950" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/163950" 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 (postnatal onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849337&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849337</a>]</span> <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">[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 in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1867873&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867873</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001531" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001531</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001531" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001531</a>]</span><br /> -
Specific growth curves are available <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855200&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855200</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> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Triangular face (with age) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834125&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834125</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000325" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000325</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=9b3a4310d8279245cf752e39c5608ddf" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Face,Triangular-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=9b3a4310d8279245cf752e39c5608ddf&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Micrognathia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32958008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32958008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M26.04" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M26.04</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/524.04" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">524.04</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0025990&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025990</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000347</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000347</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=9149eccae19753e96defbd69602ab882" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Micrognathia-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=9149eccae19753e96defbd69602ab882&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Low-set posteriorly rotated ears <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857486&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857486</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000368" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000368</a>]</span><br /> -
Hearing loss, sensorineural <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/60700002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">60700002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H90.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H90.5</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018784&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018784</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000407" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000407</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000407" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000407</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">
- 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 /> -
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 /> -
Myopia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/57190000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">57190000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H52.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H52.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/367.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">367.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027092&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027092</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000545" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000545</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000545" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000545</a>]</span><br /> -
Blue-green irides <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834126&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834126</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Mouth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Deeply grooved philtrum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834127&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834127</a>]</span><br /> -
High peaks of upper lip vermilion border <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834128&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834128</a>]</span><br /> -
High arched palate <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/27272007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">27272007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q38.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q38.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240635&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240635</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000218</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000218</a>]</span> <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> Teeth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Dental malocclusion <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/707598004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">707598004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/47944004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">47944004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M26.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M26.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/524.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">524.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0024636&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024636</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000689" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000689</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000689" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000689</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Neck </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Short neck <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95427009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95427009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0521525&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0521525</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000470" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000470</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000470" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000470</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=5edf45ce6835f32360d28d26249e2531" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Neck,Short-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=5edf45ce6835f32360d28d26249e2531&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Webbed neck <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11731003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11731003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q18.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q18.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/744.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">744.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221217&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221217</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000465" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000465</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000465" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000465</a>]</span><br /> -
Cystic hygroma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399882002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399882002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40225001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40225001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0206620&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0206620</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000476" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000476</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000476" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000476</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Congenital heart defect <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13213009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13213009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q24.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/746.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">746.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018798</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001627" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001627</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001627" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001627</a>]</span><br /> -
Hypertrophic obstructive cardiomyopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <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>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <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>]</span><br /> -
Atrial septal defects <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><br /> -
Ventricular septal defects <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 />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Patent ductus arteriosus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/83330001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">83330001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q25.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q25.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/747.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">747.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013274&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013274</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001643" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001643</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001643" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001643</a>]</span><br /> -
Aortic coarctation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7305005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7305005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q25.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q25.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/747.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">747.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/747.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">747.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003492&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003492</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001680" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001680</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001680" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001680</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CHEST </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Ribs Sternum Clavicles & Scapulae </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Shield chest <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834124&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834124</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000914" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000914</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000914" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000914</a>]</span><br /> -
Pectus carinatum superiorly <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864795&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864795</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000917" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000917</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000917" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000917</a>]</span><br /> -
Pectus excavatum inferiorly <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864796&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864796</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000915" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000915</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000915" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000915</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Internal Genitalia (Male) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cryptorchidism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204878001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204878001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q53.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q53.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/752.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">752.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0010417&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010417</a>, <a href="https://bioportal.bioontology.org/search?q=C5441920&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5441920</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000028</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000028</a>]</span><br /> -
Occasional hypogonadism <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834122&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834122</a>]</span><br /> -
Male infertility (in individuals with bilateral cryptorchidism) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4538500&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4538500</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/2904007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">2904007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N46" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N46</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N46.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N46.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/606" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">606</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/606.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">606.9</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003251</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">
- Vertebral abnormalities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834129&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834129</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003468" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003468</a>]</span><br /> -
Kyphoscoliosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405771009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405771009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405772002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405772002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405773007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405773007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0600033&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0600033</a>, <a href="https://bioportal.bioontology.org/search?q=C0575158&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575158</a>, <a href="https://bioportal.bioontology.org/search?q=C0345392&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0345392</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002751" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002751</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0008453" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008453</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002751" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002751</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Limbs </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cubitus valgus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54583007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54583007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/70123009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">70123009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M21.02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M21.02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/736.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">736.01</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0265611&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265611</a>, <a href="https://bioportal.bioontology.org/search?q=C0158465&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0158465</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002967" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002967</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002967" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002967</a>]</span><br /> -
Clinodactyly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/17268007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">17268007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551485&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551485</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030084" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030084</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030084" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030084</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=6c6553591f42fb5585fec835d3e3bab3" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Clinodactyly-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=6c6553591f42fb5585fec835d3e3bab3&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 /> -
Brachydactyly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43476002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43476002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221357&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221357</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001156" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001156</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001156" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001156</a>]</span><br /> -
Blunt fingertips <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834130&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834130</a>]</span><br /> -
Polyarticular villonodular synovitis (knees, ankles, wrists, elbows - in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3149659&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3149659</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> Hair </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Woolly-like hair <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2750363&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2750363</a>]</span><br /> -
Low posterior hairline <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855728&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855728</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002162" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002162</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002162" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002162</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=7d997573ca589e086a27f00c475ce630" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Hairline,Low_Posterior-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=7d997573ca589e086a27f00c475ce630&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> MUSCLE, SOFT TISSUES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Lymphedema <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30213001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30213001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/234097001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">234097001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0024236&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024236</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001004</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001004</a>]</span><br />
</span>
</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">
- Articulation difficulties <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834121&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834121</a>]</span><br /> -
Mental retardation (25%) <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 />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Amegakaryocytic thrombocytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/234482009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">234482009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0398639&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0398639</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004859" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004859</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004859" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004859</a>]</span><br /> -
Von Willebrand disease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128105004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128105004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D68.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D68.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D69.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D69.8</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D68.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D68.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/286.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">286.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042974&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042974</a>]</span><br /> -
Bleeding tendency <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64779008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64779008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/362970003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">362970003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248250000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248250000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D68.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D68.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">286</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0005779&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005779</a>, <a href="https://bioportal.bioontology.org/search?q=C1458140&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1458140</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001892" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001892</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0003256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003256</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001928" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001928</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001892" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001892</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEOPLASIA </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Malignant schwannoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/404037002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">404037002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/19897006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">19897006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0751690&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0751690</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100697" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100697</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100697" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100697</a>]</span><br /> -
Multiple giant cell granulomas (bones, joints, soft tissues) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969540&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969540</a>]</span><br />
</span>
</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">
- Partial deficiency of factor XI(C) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2750360&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2750360</a>]</span><br /> -
Partial deficiency of factor XII(C) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2750361&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2750361</a>]</span><br /> -
Partial deficiency of factor XIII(C) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2750362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2750362</a>]</span><br /> -
Thrombocytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/415116008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">415116008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302215000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302215000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D69.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D69.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/287.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">287.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0392386&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0392386</a>, <a href="https://bioportal.bioontology.org/search?q=C0040034&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040034</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001873" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001873</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001873" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001873</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Genetic heterogeneity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242960&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242960</a>]</span><br /> -
Allelic to LEOPARD syndrome (<a href="/entry/151100">151100</a>)<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 protein tyrosine phosphatase, nonreceptor-type, 11 gene (PTPN11, <a href="/entry/176876#0001">176876.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
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<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>
Noonan syndrome
- <a href="/phenotypicSeries/PS163950">PS163950</a>
- 16 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/1/943?start=-3&limit=10&highlight=943"> 1p13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613224"> Noonan syndrome 6 </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/613224"> 613224 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164790"> NRAS </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164790"> 164790 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/1231?start=-3&limit=10&highlight=1231"> 1q22 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615355"> Noonan syndrome 8 </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/615355"> 615355 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609591"> RIT1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609591"> 609591 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/151?start=-3&limit=10&highlight=151"> 2p23.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617506"> Noonan syndrome-like disorder with loose anagen hair 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>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/617506"> 617506 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600590"> PPP1CB </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600590"> 600590 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/200?start=-3&limit=10&highlight=200"> 2p22.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610733"> Noonan syndrome 4 </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/610733"> 610733 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/182530"> SOS1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/182530"> 182530 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/304?start=-3&limit=10&highlight=304"> 2p14 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619745"> Noonan syndrome 14 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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/619745"> 619745 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609292"> SPRED2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609292"> 609292 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/70?start=-3&limit=10&highlight=70"> 3p25.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611553"> Noonan syndrome 5 </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/611553"> 611553 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164760"> RAF1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164760"> 164760 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/718?start=-3&limit=10&highlight=718"> 3q22.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618499"> Noonan syndrome 11 </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/618499"> 618499 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608435"> MRAS </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608435"> 608435 </a>
</span>
</td>
</tr>
<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/613706"> Noonan syndrome 7 </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/613706"> 613706 </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/10/563?start=-3&limit=10&highlight=563"> 10q25.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607721"> Noonan syndrome-like with loose anagen hair 1 </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/607721"> 607721 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602775"> SHOC2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602775"> 602775 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/193?start=-3&limit=10&highlight=193"> 11p15.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618624"> Noonan syndrome 12 </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/618624"> 618624 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600098"> RRAS2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600098"> 600098 </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/609942"> Noonan syndrome 3 </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/609942"> 609942 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/190070"> KRAS </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/190070"> 190070 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/823?start=-3&limit=10&highlight=823"> 12q24.13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/163950"> Noonan syndrome 1 </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/163950"> 163950 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176876"> PTPN11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176876"> 176876 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/218?start=-3&limit=10&highlight=218"> 14q21.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616559"> Noonan syndrome 9 </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/616559"> 616559 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601247"> SOS2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601247"> 601247 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/71?start=-3&limit=10&highlight=71"> 22q11.21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605275"> Noonan syndrome 2 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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/605275"> 605275 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600574"> LZTR1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600574"> 600574 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/71?start=-3&limit=10&highlight=71"> 22q11.21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616564"> Noonan syndrome 10 </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/616564"> 616564 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600574"> LZTR1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600574"> 600574 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/85?start=-3&limit=10&highlight=85"> 22q11.22 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619087"> Noonan syndrome 13 </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/619087"> 619087 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176948"> MAPK1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/176948"> 176948 </a>
</span>
</td>
</tr>
</tbody>
</table>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>TEXT</strong>
</span>
</span>
</h4>
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<span class="mim-text-font">
<p>A number sign (#) is used with this entry because Noonan syndrome-1 (NS1) is caused by heterozygous mutation in the PTPN11 gene (<a href="/entry/176876">176876</a>) on chromosome 12q24.</p><p>Mutation in the PTPN11 gene also causes LEOPARD syndrome-1 (LPRD1; <a href="/entry/151100">151100</a>), a disorder with features overlapping those of Noonan syndrome.</p>
</span>
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<br />
</div>
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<div>
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<p>Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial dysmorphism, and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, downslanting palpebral fissures, a high-arched palate, and low-set, posteriorly rotated ears. Cardiac involvement is present in up to 90% of patients. Pulmonic stenosis and hypertrophic cardiomyopathy are the most common forms of cardiac disease, but a variety of other lesions are also observed. Additional relatively frequent features include multiple skeletal defects (chest and spine deformities), webbed neck, mental retardation, cryptorchidism, and bleeding diathesis (summary by <a href="#102" class="mim-tip-reference" title="Tartaglia, M., Kalidas, K., Shaw, A., Song, X., Musat, D. L., van der Burgt, I., Brunner, H. G., Bertola, D. R., Crosby, A., Ion, A., Kucherlapati, R. S., Jeffery, S., Patton, M. A., Gelb, B. D. &lt;strong&gt;PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.&lt;/strong&gt; Am. J. Hum. Genet. 70: 1555-1563, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11992261/&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;11992261&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11992261[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/340847&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="11992261">Tartaglia et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11992261" 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 Noonan Syndrome</em></strong></p><p>
See also NS3 (<a href="/entry/609942">609942</a>), caused by mutation in the KRAS gene (<a href="/entry/190070">190070</a>); NS4 (<a href="/entry/610733">610733</a>), caused by mutation in the SOS1 gene (<a href="/entry/182530">182530</a>); NS5 (<a href="/entry/611553">611553</a>), caused by mutation in the RAF1 gene (<a href="/entry/164760">164760</a>); NS6 (<a href="/entry/613224">613224</a>), caused by mutation in the NRAS gene (<a href="/entry/164790">164790</a>); NS7 (<a href="/entry/613706">613706</a>), caused by mutation in the BRAF gene (<a href="/entry/164757">164757</a>); NS8 (<a href="/entry/615355">615355</a>), caused by mutation in the RIT1 gene (<a href="/entry/609591">609591</a>); NS9 (<a href="/entry/616559">616559</a>), caused by mutation in the SOS2 gene (<a href="/entry/601247">601247</a>); NS10 (<a href="/entry/616564">616564</a>), caused by mutation in the LZTR1 gene (<a href="/entry/600574">600574</a>); NS11 (<a href="/entry/618499">618499</a>), caused by mutation in the MRAS gene (<a href="/entry/608435">608435</a>); NS12 (<a href="/entry/618624">618624</a>), caused by mutation in the RRAS2 gene (<a href="/entry/600098">600098</a>); and NS13 (<a href="/entry/619087">619087</a>), caused by mutation in the MAPK1 gene (<a href="/entry/176948">176948</a>).</p><p>Autosomal recessive forms of Noonan syndrome include NS2 (<a href="/entry/605275">605275</a>), caused by mutation in the LZTR1 gene (<a href="/entry/600574">600574</a>), and NS14 (<a href="/entry/619745">619745</a>), caused by mutation in the SPRED2 gene (<a href="/entry/609292">609292</a>).</p><p>See also Noonan syndrome-like disorder with loose anagen hair-1 (NSLH1; <a href="/entry/607721">607721</a>), caused by mutation in the SHOC2 gene (<a href="/entry/602775">602775</a>); Noonan syndrome-like disorder with loose anagen hair-2 (NSLH2; <a href="/entry/617506">617506</a>), caused by mutation in the PPP1CB gene (<a href="/entry/600590">600590</a>); and Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL; <a href="/entry/613563">613563</a>), caused by mutation in the CBL gene (<a href="/entry/165360">165360</a>).</p><p>Mutations in the neurofibromin gene (NF1; <a href="/entry/613113">613113</a>), which is the site of mutations causing classic neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>), have been found in neurofibromatosis-Noonan syndrome (NFNS; <a href="/entry/601321">601321</a>).</p>
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<p>The disorder now known as Noonan syndrome bears similarities to the disorder described by <a href="#109" class="mim-tip-reference" title="Turner, H. H. &lt;strong&gt;A syndrome of infantilism, congenital webbed neck and cubitus valgus.&lt;/strong&gt; Endocrinology 23: 566-574, 1938."None>Turner (1938)</a> and shown by <a href="#41" class="mim-tip-reference" title="Ford, C. E., Jones, K. W., Polani, P. E., de Almeida, J. C., Briggs, J. H. &lt;strong&gt;A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner&#x27;s syndrome).&lt;/strong&gt; Lancet 273: 711-713, 1959. Note: Originally Volume 1.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13642858/&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;13642858&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(59)91893-8&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="13642858">Ford et al. (1959)</a> to have its basis in a 45,X chromosomal aberration called Turner syndrome, Ullrich-Turner syndrome (<a href="#114" class="mim-tip-reference" title="Wiedemann, H.-R., Glatzl, J. &lt;strong&gt;Follow-up of Ullrich&#x27;s original patient with &#x27;Ullrich-Turner&#x27; syndrome.&lt;/strong&gt; Am. J. Med. Genet. 41: 134-136, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1951454/&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;1951454&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320410132&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="1951454">Wiedemann and Glatzl, 1991</a>), or monosomy X. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1951454+13642858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#74" class="mim-tip-reference" title="Migeon, B. R., Whitehouse, D. &lt;strong&gt;Familial occurrence of the somatic phenotype of Turner&#x27;s syndrome.&lt;/strong&gt; Johns Hopkins Med. J. 120: 78-80, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6021361/&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;6021361&lt;/a&gt;]" pmid="6021361">Migeon and Whitehouse (1967)</a> described 2 families, each with 2 sibs with somatic features of the Turner phenotype. In 1 family, 2 brothers had webbing of the neck, coarctation of the aorta, and cryptorchidism. In the second, a brother and sister were affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6021361" 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="#29" class="mim-tip-reference" title="Diekmann, L., Pfeiffer, R. A., Hilgenberg, F., Bender, F., Reploh, H. D. &lt;strong&gt;Familiaere Kardiomyopathie mit Pterygium colli.&lt;/strong&gt; Muench. Med. Wschr. 109: 2638-2645, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5632008/&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;5632008&lt;/a&gt;]" pmid="5632008">Diekmann et al. (1967)</a> described 2 brothers and a sister, with normal and unrelated parents, who had somatic characteristics of the Turner syndrome, particularly pterygium colli and deformed sternum, and had myocardiopathy leading to death at ages 12 and 10 years in 2 of them. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5632008" 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="#80" class="mim-tip-reference" title="Noonan, J. A. &lt;strong&gt;Hypertelorism with Turner phenotype: a new syndrome with associated congenital heart disease.&lt;/strong&gt; Am. J. Dis. Child. 116: 373-380, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4386970/&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;4386970&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archpedi.1968.02100020377005&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="4386970">Noonan (1968)</a> reported 19 patients of whom 17 had pulmonary stenosis and 2 had patent ductus arteriosus (see <a href="/entry/607411">607411</a>). Twelve were males and 7 were females. Deformity of the sternum with precocious closure of sutures was a frequent feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4386970" 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 95 male patients with pulmonary stenosis, <a href="#16" class="mim-tip-reference" title="Celermajer, J. M., Bowdler, J. D., Cohen, D. H. &lt;strong&gt;Pulmonary stenosis in patients with the Turner phenotype in the male.&lt;/strong&gt; Am. J. Dis. Child. 116: 351-358, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4301561/&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;4301561&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archpedi.1968.02100020355002&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="4301561">Celermajer et al. (1968)</a> found the Turner phenotype in 8. In 5 of these, karyotyping was performed. In 4 the chromosomes were normal; in 1, an extra acrocentric chromosome was present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4301561" 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="#54" class="mim-tip-reference" title="Kaplan, M. S., Opitz, J. M., Gosset, F. R. &lt;strong&gt;Noonan&#x27;s syndrome: a case with elevated serum alkaline phosphatase levels and malignant schwannoma of the left forearm.&lt;/strong&gt; Am. J. Dis. Child. 116: 359-366, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5697968/&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;5697968&lt;/a&gt;]" pmid="5697968">Kaplan et al. (1968)</a> described 2 brothers with Noonan syndrome and elevated alkaline phosphatase levels, one of whom also had malignant schwannoma of the forearm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5697968" 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="#82" class="mim-tip-reference" title="Nora, J. J., Sinha, A. K. &lt;strong&gt;Direct familial transmission of the Turner phenotype.&lt;/strong&gt; Am. J. Dis. Child. 116: 343-350, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5697967/&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;5697967&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archpedi.1968.02100020347001&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="5697967">Nora and Sinha (1968)</a> observed mother-to-offspring transmission in 3 families; in 1 family, transmission was through 3 generations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5697967" 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="#5" class="mim-tip-reference" title="Baird, P. A., De Jong, B. P. &lt;strong&gt;Noonan&#x27;s syndrome (XX and XY Turner phenotype) in three generations of a family.&lt;/strong&gt; J. Pediat. 80: 110-114, 1972.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5016336/&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;5016336&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(72)80466-9&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="5016336">Baird and De Jong (1972)</a> described 7 cases in 3 generations. One affected woman had 5 affected children (out of 6) with 2 different husbands. Seizures and anomalous upper lateral incisors may have been coincidental. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5016336" 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="#100" class="mim-tip-reference" title="Simpson, J. W., Nora, J. J., Singer, D. B., McNamara, D. G. &lt;strong&gt;Multiple valvular sclerosis in Turner phenotypes and rubella syndrome.&lt;/strong&gt; Am. J. Cardiol. 23: 94-97, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5380846/&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;5380846&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9149(69)90247-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5380846">Simpson et al. (1969)</a> reported experiences suggesting that rubella embryopathy may result in the Turner phenotype, thereby accounting for either the male Turner syndrome or the female pseudo-Turner syndrome. A particularly convincing pedigree for autosomal dominant inheritance was reported by <a href="#13" class="mim-tip-reference" title="Bolton, M. R., Pugh, D. M., Mattioli, L. F., Dunn, M. I., Schimke, R. N. &lt;strong&gt;The Noonan syndrome: a family study.&lt;/strong&gt; Ann. Intern. Med. 80: 626-629, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4823815/&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;4823815&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.7326/0003-4819-80-5-626&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="4823815">Bolton et al. (1974)</a>, who found the condition in a man and 4 sons (in a sibship of 10). Four of the 5 affected persons had pulmonic stenosis. Father-to-son transmission was reported by <a href="#87" class="mim-tip-reference" title="Qazi, Q. H., Arnon, R. G., Paydar, M. H., Mapa, H. C. &lt;strong&gt;Familial occurrence of Noonan syndrome.&lt;/strong&gt; Am. J. Dis. Child. 127: 696-698, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4151095/&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;4151095&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archpedi.1974.02110240082011&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="4151095">Qazi et al. (1974)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5380846+4823815+4151095" 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="#60" class="mim-tip-reference" title="Koretzky, E. D., Moller, J. H., Korns, M. E., Schwartz, C. J., Edwards, J. E. &lt;strong&gt;Congenital pulmonary stenosis resulting from dysplasia of valve.&lt;/strong&gt; Circulation 40: 43-53, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5792996/&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;5792996&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/01.cir.40.1.43&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="5792996">Koretzky et al. (1969)</a> described an unusual type of pulmonary valvular dysplasia which showed a familial tendency with either affected parent and offspring or affected sibs. Although some relatives had pulmonary valvular stenosis of the standard dome-shaped variety, the valvular dysplasia in others was characterized by the presence of three distinct cusps and no commissural fusion. The obstructive mechanism was related to markedly thickened, immobile cusps, with disorganized myxomatous tissue. Other features were retarded growth, abnormal facies (triangular face, hypertelorism, low-set ears and ptosis of the eyelids), absence of ejection click, and unusually marked right axis deviation by electrocardiogram. It now seems clear that the patients of <a href="#60" class="mim-tip-reference" title="Koretzky, E. D., Moller, J. H., Korns, M. E., Schwartz, C. J., Edwards, J. E. &lt;strong&gt;Congenital pulmonary stenosis resulting from dysplasia of valve.&lt;/strong&gt; Circulation 40: 43-53, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5792996/&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;5792996&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/01.cir.40.1.43&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="5792996">Koretzky et al. (1969)</a> had Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5792996" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#73" class="mim-tip-reference" title="Mendez, H. M. M., Opitz, J. M. &lt;strong&gt;Noonan syndrome: a review.&lt;/strong&gt; Am. J. Med. Genet. 21: 493-506, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3895929/&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;3895929&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320210312&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="3895929">Mendez and Opitz (1985)</a> stated that the Watson syndrome (<a href="/entry/193520">193520</a>) and the LEOPARD syndrome (<a href="/entry/151100">151100</a>) 'are essentially indistinguishable from the Noonan syndrome.' <a href="#117" class="mim-tip-reference" title="Witt, D. R., Hoyme, E., Zonana, J., Manchester, D. K., Fryns, J. P., Stevenson, J. G., Curry, C. J. R., Hall, J. G. &lt;strong&gt;Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature.&lt;/strong&gt; Am. J. Med. Genet. 27: 841-856, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3321992/&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;3321992&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320270412&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="3321992">Witt et al. (1987)</a> reviewed the occurrence of lymphedema in Noonan syndrome. When it does occur, it opens the possibility of prenatal diagnosis by imaging methods or by AFP level. Noonan syndrome was one of the causes found for posterior cervical hygroma in a series of previable fetuses studied by <a href="#53" class="mim-tip-reference" title="Kalousek, D. K., Seller, M. J. &lt;strong&gt;Differential diagnosis of posterior cervical hygroma in previable fetuses.&lt;/strong&gt; Am. J. Med. Genet. Suppl. 3: 83-92, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3130882/&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;3130882&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320280511&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="3130882">Kalousek and Seller (1987)</a>. The authors found, furthermore, that 45,X Turner syndrome lethal in the fetal period showed a constant association of 3 defects, posterior cervical cystic hygroma, generalized subcutaneous edema, and preductal aortic coarctation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3895929+3321992+3130882" 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="#36" class="mim-tip-reference" title="Evans, D. G. R., Lonsdale, R. N., Patton, M. A. &lt;strong&gt;Cutaneous lymphangioma and amegakaryocytic thrombocytopenia in Noonan syndrome.&lt;/strong&gt; Clin. Genet. 39: 228-232, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2036745/&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;2036745&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1991.tb03017.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="2036745">Evans et al. (1991)</a> found a large cutaneous lymphangioma of the right cheek and amegakaryocytic thrombocytopenia in a male infant with Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2036745" 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="#31" class="mim-tip-reference" title="Donnenfeld, A. E., Nazir, M. A., Sindoni, F., Librizzi, R. J. &lt;strong&gt;Prenatal sonographic documentation of cystic hygroma regression in Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 39: 461-465, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1877625/&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;1877625&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320390418&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="1877625">Donnenfeld et al. (1991)</a> presented a case of Noonan syndrome in which posterior nuchal cystic hygroma was diagnosed at 13 to 14 weeks of gestation by ultrasonography. The hygroma had regressed by the time of birth leaving nuchal skin fold redundancy and pterygium colli. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1877625" 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>On the basis of studies of genital tract function in 11 adult males with Noonan syndrome, <a href="#35" class="mim-tip-reference" title="Elsawi, M. M., Pryor, J. P., Klufio, G., Barnes, C., Patton, M. A. &lt;strong&gt;Genital tract function in men with Noonan syndrome.&lt;/strong&gt; J. Med. Genet. 31: 468-470, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7915331/&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;7915331&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.31.6.468&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="7915331">Elsawi et al. (1994)</a> concluded that bilateral testicular maldescent was a main factor in contributing to impairment of fertility. Four of the 11 men had fathered children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7915331" 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="#62" class="mim-tip-reference" title="Lee, N. B., Kelly, L., Sharland, M. &lt;strong&gt;Ocular manifestations of Noonan syndrome.&lt;/strong&gt; Eye 6: 328-334, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1446772/&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;1446772&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/eye.1992.66&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="1446772">Lee et al. (1992)</a> reviewed the ophthalmologic and orthoptic findings in 58 patients with Noonan syndrome. External features were hypertelorism (74%), downward sloping palpebral apertures (38%), epicanthal folds (39%), and ptosis (48%). Orthoptic examination revealed strabismus in 48%, refractive errors in 61%, amblyopia in 33%, and nystagmus in 9% of cases. Anterior segment changes, found in 63% of patients, included prominent corneal nerves (46%), anterior stromal dystrophy (4%), cataracts (8%), and panuveitis (2%). Fundal changes occurred in 20% of patients and included optic nerve head drusen, optic disc hypoplasia, colobomas, and myelinated nerve fiber layer. <a href="#62" class="mim-tip-reference" title="Lee, N. B., Kelly, L., Sharland, M. &lt;strong&gt;Ocular manifestations of Noonan syndrome.&lt;/strong&gt; Eye 6: 328-334, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1446772/&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;1446772&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/eye.1992.66&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="1446772">Lee et al. (1992)</a> recommended early ophthalmic examination of children with Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1446772" 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="#1" class="mim-tip-reference" title="Allanson, J. E., Hall, J. G., Hughes, H. E., Preus, M., Witt, R. D. &lt;strong&gt;Noonan syndrome: the changing phenotype.&lt;/strong&gt; Am. J. Med. Genet. 21: 507-514, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4025385/&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;4025385&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320210313&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="4025385">Allanson et al. (1985)</a> studied the changes in facial appearance with age. They pointed out that the manifestations may be subtle in adults. <a href="#88" class="mim-tip-reference" title="Ranke, M. B., Heidemann, P., Knupfer, C., Enders, H., Schmaltz, A. A., Bierich, J. R. &lt;strong&gt;Noonan syndrome: growth and clinical manifestations in 144 cases.&lt;/strong&gt; Europ. J. Pediat. 148: 220-227, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3215198/&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;3215198&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00441408&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="3215198">Ranke et al. (1988)</a> analyzed the clinical features of 144 patients from 2 West German centers. The size at birth was normal in both sexes. In both males and females, the mean height followed along the 3rd percentile until puberty, but decreased transiently due to an approximately 2-year delay in onset of puberty. Final height approaches the lower limits of normal at the end of the second decade of life. The mean adult height was 162.5 cm in males and 152.7 cm in females, respectively. <a href="#2" class="mim-tip-reference" title="Allanson, J. E. &lt;strong&gt;Noonan syndrome.&lt;/strong&gt; J. Med. Genet. 24: 9-13, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3543368/&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;3543368&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.24.1.9&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="3543368">Allanson (1987)</a> provided a useful review. The fetal primidone syndrome, occurring in the offspring of mothers taking this anticonvulsant, closely simulates the Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4025385+3215198+3543368" 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="#7" 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> reported 4 unrelated children (2 boys, 2 girls) with a Noonan-like syndrome associated with sparse hair as a conspicuous feature. See <a href="/entry/115150">115150</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'})"><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="#64" 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> reported a family suggesting that cardiofaciocutaneous syndrome (CFC; <a href="/entry/115150">115150</a>) is a variable expression of Noonan syndrome. He described a 4-year-old girl who had all of the manifestations of CFC syndrome (characteristic facial and cardiac anomalies, developmental delay, hypotrichosis, eczematic eruption with resistance to treatment), whose mother had typical characteristics of Noonan syndrome. <a href="#71" class="mim-tip-reference" title="Lorenzetti, M.-E., Fryns, J.-P. &lt;strong&gt;Retinitis pigmentosa in a young man with Noonan syndrome: further evidence that Noonan syndrome (NS) and the cardio-facio-cutaneous syndrome (CFC) are variable manifestations of the same entity?&lt;/strong&gt; Am. J. Med. Genet. 65: 97-99, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8911596/&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;8911596&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1096-8628(19961016)65:2&lt;97::AID-AJMG1&gt;3.0.CO;2-R&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="8911596">Lorenzetti and Fryns (1996)</a> reported a 13-year-old boy with Noonan syndrome and retinitis pigmentosa. Because similar eye defects are found in CFC syndrome, the authors suggested that CFC and Noonan syndromes might be variable manifestations of the same entity. However, <a href="#78" class="mim-tip-reference" title="Neri, G., Zollino, M. &lt;strong&gt;More on the Noonan-CFC Controversy (Editorial)&lt;/strong&gt; Am. J. Med. Genet. 65: 100-(only), 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8911597/&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;8911597&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1096-8628(19961016)65:2&lt;100::AID-AJMG2&gt;3.0.CO;2-W&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="8911597">Neri and Zollino (1996)</a> noted distinctions between the patient reported by <a href="#71" class="mim-tip-reference" title="Lorenzetti, M.-E., Fryns, J.-P. &lt;strong&gt;Retinitis pigmentosa in a young man with Noonan syndrome: further evidence that Noonan syndrome (NS) and the cardio-facio-cutaneous syndrome (CFC) are variable manifestations of the same entity?&lt;/strong&gt; Am. J. Med. Genet. 65: 97-99, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8911596/&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;8911596&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1096-8628(19961016)65:2&lt;97::AID-AJMG1&gt;3.0.CO;2-R&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="8911596">Lorenzetti and Fryns (1996)</a> and CFC syndrome, and stated that similarity of eye defects is not enough to conclude that CFC and Noonan syndromes are the same condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8867661+8911596+8911597" 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>Early feeding difficulties are common in Noonan syndrome but often go unrecognized. <a href="#95" class="mim-tip-reference" title="Shah, N., Rodriguez, M., St. Louis, D., Lindley, K., Milla, P. J. &lt;strong&gt;Feeding difficulties and foregut dysmotility in Noonan&#x27;s syndrome.&lt;/strong&gt; Arch. Dis. Child. 81: 28-31, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10373129/&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;10373129&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.81.1.28&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="10373129">Shah et al. (1999)</a> studied a consecutive series of children with Noonan syndrome whose diagnosis had been confirmed by a clinical geneticist. Sixteen had poor feeding (poor suck or refusal to take solids or liquids) and symptoms of gastrointestinal dysfunction (vomiting, constipation, abdominal pain, and bloating). All 16 had required nasogastric tube feeding. Seven of the 25 had foregut dysmotility and gastroesophageal reflux. In 4 of these, electrogastrography and antroduodenal manometry demonstrated immature gastric motility reminiscent of that of a preterm infant of 32 to 35 weeks' gestation. Other children had less severe forms of gastric dysmotility. The authors highlighted the importance of recognizing this common, treatable feature of Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10373129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#65" class="mim-tip-reference" title="Lemire, E. G. &lt;strong&gt;Noonan syndrome or new autosomal dominant condition with coarctation of the aorta, hypertrophic cardiomyopathy, and minor anomalies.&lt;/strong&gt; Am. J. Med. Genet. 113: 286-290, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12439898/&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;12439898&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.10782&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="12439898">Lemire (2002)</a> described a father, son, and daughter with an apparently autosomal dominant disorder characterized by craniofacial anomalies, coarctation of the aorta, hypertrophic cardiomyopathy, and other structural heart defects with normal psychomotor development. Some clinical features such as webbed neck, low-set ears, low posterior hairline, and widely spaced nipples suggested Noonan syndrome. Alternatively, a previously unrecognized disorder was considered. The paternal age at the father's birth was 50 years. The father presented at age 13 years when postductal coarctation of the aorta was discovered during routine physical examination. Preoperative evaluation showed hypertrophied interventricular septum with pulmonic stenosis and bicuspid aortic valve in addition to the aortic coarctation. At age 22 years, echocardiogram showed marked systolic thickening of interventricular septum and posterior wall of the left ventricle and concentric left ventricular hypertrophy. He later developed atrial flutter and congestive heart failure. His son was recognized at birth to have 2 small ventricular septal defects, mildly hypoplastic aortic arch, and coarctation of the aorta. The coarctation was repaired at age 14 days and bilateral inguinal hernias at age 5 weeks. At age 9 months, he was found to have congestive heart failure due to a restrictive cardiomyopathy. At age 10 months, studies confirmed the presence of spongy myocardium with much impaired diastolic function. He died of early acute graft failure at age 14 months after heart transplantation. Autopsy showed restrictive cardiomyopathy with generalized myocardium hypertrophy. The daughter was found at birth to have a small ventricular septal defect, small patent ductus arteriosus, aneurysm of the atrial septum, and coarctation of the aorta. Cardiomyopathy was suspected on the basis of excessive thickening of the lower two-thirds of the interventricular septum and of the free wall of the right ventricle. Coarctation of the aorta was repaired surgically at age 19 days. At age 10.5 months, she was noted to have plagiocephaly, facial asymmetry with left side smaller than the right, webbed neck, asymmetric chest with widely spaced nipples, and edema of the dorsum of the feet. At age 2 years, bicuspid aortic valve and diffuse concentric hypertrophy of the left ventricle were noted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12439898" 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="Holder-Espinasse, M., Winter, R. M. &lt;strong&gt;Type 1 Arnold-Chiari malformation and Noonan syndrome: a new diagnostic feature? (Letter)&lt;/strong&gt; Clin. Dysmorph. 12: 275 only, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14564218/&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;14564218&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00019605-200310000-00013&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="14564218">Holder-Espinasse and Winter (2003)</a> described a 6-year-old girl with clinical features of Noonan syndrome, short stature, and headache who was noted to have Arnold-Chiari malformation (<a href="/entry/207950">207950</a>) on MRI. They cited 3 previous reports of Noonan syndrome and Chiari malformation and/or syringomelia (<a href="#6" class="mim-tip-reference" title="Ball, M. J., Peiris, A. &lt;strong&gt;Chiari (type 1) malformation and syringomelia in a patient with Noonan&#x27;s syndrome. (Letter)&lt;/strong&gt; J. Neurol. Neurosurg. Psychiat. 45: 753-754, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7131003/&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;7131003&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jnnp.45.8.753&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="7131003">Ball and Peiris, 1982</a>; <a href="#43" class="mim-tip-reference" title="Gabrielli, O., Salvolini, U., Coppa, G. V., Catassi, C., Rossi, R., Manca, A., Lanza, R., Giorgi, P. L. &lt;strong&gt;Magnetic resonance imaging in the malformative syndromes with mental retardation.&lt;/strong&gt; Pediat. Radiol. 21: 16-19, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2287531/&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;2287531&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF02010806&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="2287531">Gabrielli et al., 1990</a>; <a href="#24" class="mim-tip-reference" title="Colli, R., Colombo, P., Russo, F., Sterpa, A. &lt;strong&gt;Malformazione di Arnold Chiari tipo 1 in soggetto con sindrome di Noonan.&lt;/strong&gt; Pediat. Med. Chir. 23: 61-64, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11486425/&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;11486425&lt;/a&gt;]" pmid="11486425">Colli et al., 2001</a>). <a href="#48" class="mim-tip-reference" title="Holder-Espinasse, M., Winter, R. M. &lt;strong&gt;Type 1 Arnold-Chiari malformation and Noonan syndrome: a new diagnostic feature? (Letter)&lt;/strong&gt; Clin. Dysmorph. 12: 275 only, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14564218/&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;14564218&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00019605-200310000-00013&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="14564218">Holder-Espinasse and Winter (2003)</a> concluded that Chiari malformation should be considered part of the Noonan syndrome spectrum and that brain and cervical spine MRI should be required in patients with Noonan syndrome, particularly if headaches or neurologic symptoms are present. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14564218+7131003+11486425+2287531" 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>For a comprehensive review of Turner syndrome, including clinical management, see <a href="#89" class="mim-tip-reference" title="Ranke, M. B., Saenger, P. &lt;strong&gt;Turner&#x27;s syndrome.&lt;/strong&gt; Lancet 358: 309-314, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11498234/&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;11498234&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(01)05487-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11498234">Ranke and Saenger (2001)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11498234" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#58" class="mim-tip-reference" title="Kondoh, T., Ishii, E., Aoki, Y., Shimizu, T., Zaitsu, M., Matsubara, Y., Moriuchi, H. &lt;strong&gt;Noonan syndrome with leukaemoid reaction and overproduction of catecholamines: a case report.&lt;/strong&gt; Europ. J. Pediat. 162: 548-549, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12739139/&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;12739139&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00431-003-1227-6&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="12739139">Kondoh et al. (2003)</a> described a transient leukemoid reaction and an apparently spontaneously regressing neuroblastoma in a 3-month-old Japanese patient with Noonan syndrome and a de novo missense mutation in the PTPN11 gene (<a href="/entry/176876#0007">176876.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12739139" 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="#79" class="mim-tip-reference" title="Noonan, J. A., Raaijmakers, R., Hall, B. D. &lt;strong&gt;Adult height in Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 123A: 68-71, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14556249/&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;14556249&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20502&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="14556249">Noonan et al. (2003)</a> reported their findings in 73 adults over 21 years of age with Noonan syndrome. In 30%, adult height was in the normal range between the 10th and 90th percentiles. More than half of the females and nearly 40% of males had an adult height below the third percentile. The presence or severity of heart disease was not a factor, and none of the adults with normal height had been treated with growth hormone. Serial measurements of height over many years through childhood to adulthood were available in only a few patients, but their pattern of growth suggested that catch up may occur in late adolescence. The possible benefit of growth hormone therapy could not be evaluated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14556249" 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="Croonen, E. A., van der Burgt, I., Kapusta, L., Draaisma, J. M. T. &lt;strong&gt;Electrocardiography in Noonan syndrome PTPN11 gene mutation--phenotype characterization.&lt;/strong&gt; Am. J. Med. Genet. 146A: 350-353, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18203203/&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;18203203&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32140&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="18203203">Croonen et al. (2008)</a> evaluated ECG findings and cardiographic abnormalities in 84 patients with Noonan syndrome, 54 (67%) of whom were positive for a mutation in the PTPN11 gene. As reported previously, pulmonary stenosis was the most common cardiac abnormality, followed by atrial septal defect and hypertrophic cardiomyopathy. ECG showed at least 1 characteristic finding in 50% of cases, including left axis deviation in 38 (45%), small R waves in the left precordial leads in 20 (24%), and an abnormal Q wave in 5 (6%) Noonan patients; however, these ECG findings were not associated with a PTPN11 mutation or with a specific cardiac anomaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18203203" 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 40 Italian patients with Noonan syndrome, <a href="#38" class="mim-tip-reference" title="Ferrero, G. B., Baldassarre, G., Delmonaco, A. G., Biamino, E., Banaudi, E., Carta, C., Rossi, C., Silengo, M. C. &lt;strong&gt;Clinical and molecular characterization of 40 patients with Noonan syndrome.&lt;/strong&gt; Europ. J. Med. Genet. 51: 566-572, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18678287/&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;18678287&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ejmg.2008.06.011&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="18678287">Ferrero et al. (2008)</a> found short stature in 92%, congenital heart defect in 82.5%, isolated pulmonic stenosis in 60.6%, and hypertrophic obstructive cardiomyopathy in 12.2%. Prenatal anomalies were observed in 25% of cases, with polyhydramnios being the most common. PTPN11 mutations were detected in 11 sporadic patients and 1 family, totaling 12 (31.5%) of 38 cases. One patient without a detectable mutation had a Chiari I malformation with seizures. Another of the remaining patients had a mutation in the SOS1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18678287" 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="#61" class="mim-tip-reference" title="Kruszka, P., Porras, A. R., Addissie, Y. A., Moresco, A., Medrano, S., Mok, G. T. K., Leung, G. K. C., Tekendo-Ngongang, C., Uwineza, A., Thong, M.-K., Muthukumarasamy, P., Honey, E., and 50 others. &lt;strong&gt;Noonan syndrome in diverse populations.&lt;/strong&gt; Am. J. Med. Genet. 173A: 2323-2334, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28748642/&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;28748642&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28748642[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.38362&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="28748642">Kruszka et al. (2017)</a> reviewed clinical data and images of 125 patients diagnosed with Noonan syndrome, 37 of whom were clinically diagnosed (mutation not known) and 88 of whom carried mutations in Noonan-associated genes: 61 in PTPN11, 8 in RIT1, 7 in SOS1, 4 in RAF1, 2 in BRAF, and 1 in KRAS; in addition, 3 patients carried mutations in MAP2K1 (<a href="/entry/176872">176872</a>), 1 patient in MAP2K2 (<a href="/entry/601263">601263</a>), and 1 patient in the SHOC2 gene. The authors stated that NS was phenotypically similar across the different population groups, which were from 20 countries, with widely spaced eyes and low-set ears present in more than 80% of patients, short stature in more than 70%, and pulmonary stenosis in roughly 50% of patients. Only 2 features, ptosis and webbed neck, were statistically different between the groups, with ptosis being present in 63% of African patients versus 72% of Asian patients and 94% of Latin American patients, and webbed neck being present in 36% of Asian patients versus 57% of African patients and 69% of Latin American patients. <a href="#61" class="mim-tip-reference" title="Kruszka, P., Porras, A. R., Addissie, Y. A., Moresco, A., Medrano, S., Mok, G. T. K., Leung, G. K. C., Tekendo-Ngongang, C., Uwineza, A., Thong, M.-K., Muthukumarasamy, P., Honey, E., and 50 others. &lt;strong&gt;Noonan syndrome in diverse populations.&lt;/strong&gt; Am. J. Med. Genet. 173A: 2323-2334, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28748642/&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;28748642&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28748642[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.38362&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="28748642">Kruszka et al. (2017)</a> also analyzed the usefulness of facial analysis technology in diagnosing NS, comparing 161 Caucasian, African, Asian, and Latin American NS patients with 161 gender- and age-matched controls. The sensitivity and specificity to discriminate between NS and controls was 0.88 and 0.89, respectively, when the entire cohort was evaluated concurrently. Test accuracy increased significantly when the cohort was analyzed by specific ethnic population, with sensitivities ranging from 0.94 to 0.96, and specificities from 0.90 to 0.98. However, the authors emphasized that facial analysis technology is a tool and not a substitute for clinical evaluation, since it does not consider other important features of NS such as webbed neck, chest deformities, and congenital heart disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28748642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Croonen, E. A., Essink, M., van der Burgt, I., Draaisma, J. M., Noordam, C., Nijhuis-van der Sanden, M. W. G. &lt;strong&gt;Motor performance in children with Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 173A: 2335-2345, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28627718/&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;28627718&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.38322&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="28627718">Croonen et al. (2017)</a> provided a detailed analysis of motor performance in daily life of 19 children with a phenotypic and genotypic diagnosis of Noonan syndrome (genetic diagnosis was not reported). The children ranged in age from 6 years to nearly 12 years old, with a mean age of 9.3 years. More than 60% of the parents reported that their children experienced pain, decreased muscle strength, reduced endurance, and/or clumsiness in daily functioning. Norm-referenced test results confirmed that motor performance, strength, and endurance were significantly impaired in the children, and decreased functional motor performance appeared to be related to decreased visual perception and reduced muscle strength. The authors noted the possibility of selection bias in the study, since of 29 patients invited to participate, 5 did not respond and 4 declined (1 had incomplete address data); the authors suggested that children without clinical complaints might be less likely to participate in research. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28627718" 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><strong><em>Giant Cell Lesions</em></strong></p><p>
Some patients with Noonan syndrome develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villonodular synovitis (PVNS) when occurring in the jaw or joints. Early reports described this as a separate disorder (<a href="#66" class="mim-tip-reference" title="Leszczynski, J., Huckell, J. R., Percy, J. S., LeRiche, J. C., Lentle, B. C. &lt;strong&gt;Pigmented villonodular synovitis in multiple joints: occurrence in a child with cavernous haemangioma of lip and pulmonary stenosis.&lt;/strong&gt; Ann. Rheum. Dis. 34: 269-272, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1155985/&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;1155985&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/ard.34.3.269&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="1155985">Leszczynski et al., 1975</a>; <a href="#70" class="mim-tip-reference" title="Lindenbaum, B. L., Hunt, T. &lt;strong&gt;An unusual presentation of pigmented villonodular synovitis.&lt;/strong&gt; Clin. Orthop. Relat. Res. 122: 263-267, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/837615/&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;837615&lt;/a&gt;]" pmid="837615">Lindenbaum and Hunt, 1977</a>; <a href="#112" class="mim-tip-reference" title="Wagner, M. L., Spjut, H. J., Dutton, R. V., Glassman, A. L., Askew, J. B. &lt;strong&gt;Polyarticular pigmented villonodular synovitis.&lt;/strong&gt; Am. J. Roentgen. 136: 821-823, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6784483/&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;6784483&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.2214/ajr.136.4.821&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="6784483">Wagner et al., 1981</a>); however, it is now considered part of the phenotypic spectrum of Noonan syndrome (<a href="#107" class="mim-tip-reference" title="Tartaglia, M., Zampino, G., Gelb, B. D. &lt;strong&gt;Noonan syndrome: clinical aspects and molecular pathogenesis.&lt;/strong&gt; Molec. Syndromol. 1: 2-26, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20648242/&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;20648242&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20648242[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/10.1159/000276766&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="20648242">Tartaglia et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20648242+1155985+837615+6784483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Cohen, M. M., Jr., Ruvalcaba, R. H. A., Graham, C. B., Harrison, M. T., Morgan, A. F. &lt;strong&gt;A new syndrome, and hyperparathyroidism.&lt;/strong&gt; Synd. Ident. 2: 14-17, 1974."None>Cohen et al. (1974)</a> described a patient with short stature, ocular hypertelorism, prominent posteriorly angulated ears, short webbed neck, cubitus valgus, pulmonic stenosis, multiple lentigines, and giant cell lesions of both bone and soft tissue. <a href="#22" class="mim-tip-reference" title="Cohen, M. M., Jr. &lt;strong&gt;The Child with Multiple Birth Defects.&lt;/strong&gt; New York: Raven Press (pub.) 1982. Pp. 78-85."None>Cohen (1982)</a> presented a photographic montage of the patient. <a href="#20" class="mim-tip-reference" title="Cohen, M. M., Jr., Gorlin, R. J. &lt;strong&gt;Noonan-like/multiple giant cell lesion syndrome.&lt;/strong&gt; Am. J. Med. Genet. 40: 159-166, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1897569/&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;1897569&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320400208&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="1897569">Cohen and Gorlin (1991)</a> reviewed further known cases to a total of 14. <a href="#19" class="mim-tip-reference" title="Chuong, R., Kaban, L. B., Kozakewich, H., Perez-Atayde, A. &lt;strong&gt;Central giant cell lesions of the jaws: a clinicopathologic study.&lt;/strong&gt; J. Oral Maxillofac. Surg. 44: 708-713, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3462363/&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;3462363&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0278-2391(86)90040-6&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="3462363">Chuong et al. (1986)</a> studied central giant cell lesions of the jaw in 17 patients and noted that 2 of these occurred in patients with Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3462363+1897569" 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="#110" class="mim-tip-reference" title="Ucar, B., Okten, A., Mocan, H., Ercin, C. &lt;strong&gt;Noonan syndrome associated with central giant cell granuloma.&lt;/strong&gt; Clin. Genet. 53: 411-414, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9660063/&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;9660063&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1998.tb02756.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="9660063">Ucar et al. (1998)</a> described a patient with Noonan syndrome and PVNS. As indicated by the photographs provided, the patient showed facies and sternal configuration typical of Noonan syndrome. Cubitus valgus, pulmonary valve stenosis, and patent foramen ovale, as well as cryptorchidism, were also present. A central giant cell granuloma was found originating from the lateral wall of the right maxillary sinus and caused the presenting complaint of proptosis of the right eye. (Giant cell granulomas in the head and neck region are called central when they occur in bone and peripheral when they occur in gingiva or alveolar mucosa.) In this family the patient's father also had the phenotype of Noonan syndrome, suggesting autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9660063" 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="Bertola, D. R., Kim, C. A., Pereira, A. C., Mota, G. F. A., Krieger, J. E., Vieira, I. C., Valente, M., Loreto, M. R., Magalhaes, R. P., Gonzalez, C. H. &lt;strong&gt;Are Noonan syndrome and Noonan-like/multiple giant cell lesion syndrome distinct entities?&lt;/strong&gt; Am. J. Med. Genet. 98: 230-234, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11169560/&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;11169560&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(20010122)98:3&lt;230::aid-ajmg1080&gt;3.0.co;2-k&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="11169560">Bertola et al. (2001)</a> described a family with typical clinical findings of Noonan syndrome associated with giant cell lesions in maxilla and mandible. The authors raised the possibility that Noonan syndrome and Noonan syndrome-like disorder with multiple giant cell lesions might be allelic disorders. This was indeed demonstrated to be the case by <a href="#102" class="mim-tip-reference" title="Tartaglia, M., Kalidas, K., Shaw, A., Song, X., Musat, D. L., van der Burgt, I., Brunner, H. G., Bertola, D. R., Crosby, A., Ion, A., Kucherlapati, R. S., Jeffery, S., Patton, M. A., Gelb, B. D. &lt;strong&gt;PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.&lt;/strong&gt; Am. J. Hum. Genet. 70: 1555-1563, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11992261/&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;11992261&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11992261[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/340847&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="11992261">Tartaglia et al. (2002)</a>, who found a mutation in the PTPN11 gene (<a href="/entry/176876#0004">176876.0004</a>), which is the site of mutation in about half of unrelated individuals with sporadic or familial Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11992261+11169560" 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>Hematologic Abnormalities And Leukemia</em></strong></p><p>
Thrombocytopenia occurs in some cases of the Noonan syndrome (<a href="#45" class="mim-tip-reference" title="Goldstein, J. L. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Dallas, Tex. 1/25/1979."None>Goldstein, 1979</a>). Partial deficiency of factor XI was described by <a href="#56" class="mim-tip-reference" title="Kitchens, C. S., Alexander, J. A. &lt;strong&gt;Partial deficiency of coagulation factor XI as a newly recognized feature of Noonan syndrome.&lt;/strong&gt; J. Pediat. 102: 224-227, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6822926/&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;6822926&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(83)80525-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6822926">Kitchens and Alexander (1983)</a>. Out of 9 patients with Noonan syndrome, <a href="#27" class="mim-tip-reference" title="de Haan, M., van de Kamp, J. J. P., Briet, E., Dubbeldam, J. &lt;strong&gt;Noonan syndrome: partial factor XI deficiency.&lt;/strong&gt; Am. J. Med. Genet. 29: 277-282, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3354599/&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;3354599&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320290205&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="3354599">de Haan et al. (1988)</a> found 4 with partial deficiency of factor XI (30-65% of normal). They reviewed the other reports of bleeding tendency associated with thrombocytopenia or with abnormal platelet function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3354599+6822926" 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="#118" class="mim-tip-reference" title="Witt, D. R., McGillivray, B. C., Allanson, J. E., Hughes, H. E., Hathaway, W. E., Zipursky, A., Hall, J. G. &lt;strong&gt;Bleeding diathesis in Noonan syndrome: a common association.&lt;/strong&gt; Am. J. Med. Genet. 31: 305-317, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3232698/&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;3232698&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320310208&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="3232698">Witt et al. (1988)</a> described bleeding diathesis in 19 patients with Noonan syndrome. Several different defects were identified in the coagulation and platelet systems, occurring singly or in combination; for example, 2 patients had factor XI deficiency, 3 had presumptive von Willebrand disease, and 1 had thrombocytopenia. In 5 of the patients an unusually pungent odor of urine and sweat was noted by parents. One of these patients was reported by <a href="#49" class="mim-tip-reference" title="Humbert, J. R., Hammond, K. B., Hathaway, W. E., Marcoux, J. G., O&#x27;Brien, D. &lt;strong&gt;Trimethylaminuria: the fish-odour syndrome. (Letter)&lt;/strong&gt; Lancet 296: 770-771, 1970. Note: Originally Volume II.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4195988/&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;4195988&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(70)90241-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4195988">Humbert et al. (1970)</a> as a case of trimethylaminuria (<a href="/entry/136131">136131</a>) and another patient was suspected of having this condition. <a href="#97" class="mim-tip-reference" title="Sharland, M., Patton, M., Chittolie, A., Talbot, S., Bevan, D. &lt;strong&gt;Coagulation factor abnormalities in Noonan syndrome. (Abstract)&lt;/strong&gt; J. Med. Genet. 27: 646 only, 1990."None>Sharland et al. (1990)</a> also described a variety of coagulation factor deficiencies. The most common abnormality was a partial factor XI deficiency in the heterozygote range, found in 21 of 31 patients. Of 72 patients studied (37 male, 35 female, mean age 11.4 years) by <a href="#96" class="mim-tip-reference" title="Sharland, M., Patton, M. A., Talbot, S., Chitolie, A., Bevan, D. H. &lt;strong&gt;Coagulation-factor deficiencies and abnormal bleeding in Noonan&#x27;s syndrome.&lt;/strong&gt; Lancet 339: 19-21, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1345952/&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;1345952&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(92)90141-o&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="1345952">Sharland et al. (1992)</a>, 47 (65%) had a history of abnormal bruising or bleeding. In 29 patients (40%), prolonged activated partial thromboplastin time was found. In 36 patients (50%) specific abnormalities were found in the intrinsic pathway of coagulation, i.e., partial deficiency of factor XI:C, XII:C, and VIII:C. Multiple abnormalities among these 36 patients included combined deficiencies of factors XI and XII (4 patients), of factors XI and VIII (4 patients), and of factors VIII, XI, and XII (1 patient). In 5 families, similar coagulation-factor deficiencies were present in first-degree relatives. <a href="#96" class="mim-tip-reference" title="Sharland, M., Patton, M. A., Talbot, S., Chitolie, A., Bevan, D. H. &lt;strong&gt;Coagulation-factor deficiencies and abnormal bleeding in Noonan&#x27;s syndrome.&lt;/strong&gt; Lancet 339: 19-21, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1345952/&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;1345952&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(92)90141-o&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="1345952">Sharland et al. (1992)</a> suggested that because of the involvement of several factors, either singly or in combination, there are likely to be regulatory factors that control the intrinsic (contact activation) system; that these factors are under chromosomal genetic control; and that abnormalities of this regulation occur in Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1345952+4195988+3232698" 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="#28" class="mim-tip-reference" title="Derbent, M., Oncel, Y., Tokel, K., Varan, B., Haberal, A., Yazici, A. C., Legius, E., Ozbek, N. &lt;strong&gt;Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations.&lt;/strong&gt; Am. J. Med. Genet. 152A: 2768-2774, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20954246/&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;20954246&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33713&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="20954246">Derbent et al. (2010)</a> examined the hematologic profile of 30 patients with Noonan syndrome, of whom 11 (36.7%) had proven PTPN11 mutations. There were no statistically significant differences between the mutation-positive and mutation-negative groups with respect to any of the hematology results or the presence of moderate mental retardation, pulmonic stenosis, chest deformity, genitourinary anomalies, or sensorineural hearing loss. However, short stature and mild mental retardation were more common in PTPN11 carriers. Only 1 of the patients had a history of easy bruising; however, his hematologic and coagulation tests were normal. None of the other patients had clinical coagulation problems. Noonan syndrome patients had significantly lower values for platelet count, activity of factors XI, XII, and protein C (<a href="/entry/612283">612283</a>) compared to controls. Patient values for PT, aPTT, INR, and bleeding time were also statistically different from the corresponding control findings, but the absence of clinical problems rendered the tests diagnostically inconclusive. Two patients had low protein C activity (about 50% of normal), but neither had a thrombotic event or any complication during about 3 years of follow-up. <a href="#28" class="mim-tip-reference" title="Derbent, M., Oncel, Y., Tokel, K., Varan, B., Haberal, A., Yazici, A. C., Legius, E., Ozbek, N. &lt;strong&gt;Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations.&lt;/strong&gt; Am. J. Med. Genet. 152A: 2768-2774, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20954246/&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;20954246&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33713&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="20954246">Derbent et al. (2010)</a> concluded that patients with Noonan syndrome should have a thorough coagulation evaluation, but complications related to coagulation are unlikely and extensive testing is unnecessary. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20954246" 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>Juvenile myelomonocytic leukemia (JMML; <a href="/entry/607785">607785</a>) has been observed in some cases of Noonan syndrome (<a href="#4" class="mim-tip-reference" title="Bader-Meunier, B., Tchernia, G., Mielot, F., Fontaine, J. L., Thomas, C., Lyonnet, S., Lavergne, J. M., Dommergues, J. P. &lt;strong&gt;Occurrence of myeloproliferative disorder in patients with Noonan syndrome.&lt;/strong&gt; J. Pediat. 130: 885-889, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9202609/&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;9202609&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(97)70273-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9202609">Bader-Meunier et al., 1997</a>; <a href="#42" class="mim-tip-reference" title="Fukuda, M., Horibe, K., Miyajima, Y., Matsumoto, K., Nagashima, M. &lt;strong&gt;Spontaneous remission of juvenile chronic myelomonocytic leukemia in an infant with Noonan syndrome. (Letter)&lt;/strong&gt; J. Pediat. Hemat. Oncol. 19: 177-179, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9149755/&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;9149755&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00043426-199703000-00019&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="9149755">Fukuda et al., 1997</a>; <a href="#18" class="mim-tip-reference" title="Choong, K., Freedman, M. H., Chitayat, D., Kelly, E. N., Taylor, G., Zipursky, A. &lt;strong&gt;Juvenile myelomonocytic leukemia and Noonan syndrome.&lt;/strong&gt; J. Pediat. Hemat. Oncol. 21: 523-527, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10598665/&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;10598665&lt;/a&gt;]" pmid="10598665">Choong et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9149755+10598665+9202609" 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="#101" class="mim-tip-reference" title="Strullu, M., Caye, A., Lachenaud, J., Cassinat, B., Gazal, S., Fenneteau, O., Pouvreau, N., Pereira, S., Baumann, C., Contet, A., Sirvent, N., Mechinaud, F., and 10 others. &lt;strong&gt;Juvenile myelomonocytic leukaemia and Noonan syndrome.&lt;/strong&gt; J. Med. Genet. 51: 689-697, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25097206/&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;25097206&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmedgenet-2014-102611&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="25097206">Strullu et al. (2014)</a> found that 36 (5.6%) of 641 NS1 patients with a confirmed germline PTPN11 mutation developed a myeloproliferative disorder (MPD in 16) or juvenile myelomonocytic leukemia (JMML in 20). Hematologic abnormalities most often appeared in the neonatal period, earlier than in patients with sporadic JMML. None of the MPD patients required chemotherapy, and all were alive at a median follow-up of 3 years. In contrast, 12 (60%) of those with JMML had life-threatening complications, and 10 of the 12 died soon after diagnosis. Almost all (11 of 12) patients with severe neonatal JMML were males. Some PTPN11 mutations were preferentially associated with myeloproliferation, particularly mutations in codon Asp61 or a T73I mutation (<a href="/entry/176876#0011">176876.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25097206" 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="inheritance" class="mim-anchor"></a>
<h4 href="#mimInheritanceFold" id="mimInheritanceToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Inheritance</strong>
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<p>Noonan syndrome is inherited in an autosomal dominant pattern (<a href="#107" class="mim-tip-reference" title="Tartaglia, M., Zampino, G., Gelb, B. D. &lt;strong&gt;Noonan syndrome: clinical aspects and molecular pathogenesis.&lt;/strong&gt; Molec. Syndromol. 1: 2-26, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20648242/&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;20648242&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20648242[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/10.1159/000276766&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="20648242">Tartaglia et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20648242" 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="#113" class="mim-tip-reference" title="Wendt, R. G., Wolfe, F., McQueen, D., Murphy, P., Solomon, H., Housholder, M. &lt;strong&gt;Polyarticular pigmented villonodular synovitis in children: evidence for a genetic contribution.&lt;/strong&gt; J. Rheum. 13: 921-926, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3820202/&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;3820202&lt;/a&gt;]" pmid="3820202">Wendt et al. (1986)</a> reported a man with polyarticular pigmented villonodular synovitis who had an affected son and daughter. <a href="#33" class="mim-tip-reference" title="Dunlap, C., Neville, B., Vickers, R. A., O&#x27;Neil, D., Barker, B. &lt;strong&gt;The Noonan syndrome/cherubism association.&lt;/strong&gt; Oral Surg. 67: 698-705, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2740093/&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;2740093&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0030-4220(89)90012-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2740093">Dunlap et al. (1989)</a> made reference to the fact that the father of one of his cases was affected with Noonan syndrome and PVNS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2740093+3820202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Elalaoui, S. C., Kraoua, L., Liger, C., Ratbi, I., Cave, H., Sefiani, A. &lt;strong&gt;Germinal mosaicism in Noonan syndrome: a family with two affected siblings of normal parents.&lt;/strong&gt; Am. J. Med. Genet. 152A: 2850-2853, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20979190/&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;20979190&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33685&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="20979190">Elalaoui et al. (2010)</a> reported 2 sibs, born of unrelated Moroccan parents, with Noonan syndrome resulting from the same heterozygous mutation in the PTPN11 gene (<a href="/entry/176876#0003">176876.0003</a>). Both had characteristic features of Noonan syndrome, including pulmonic stenosis and facial anomalies, but neither parent showed any signs of the disorder. Molecular analysis did not detect the mutation in multiple tissues of either parent, excluding somatic mosaicism. Both affected children inherited the same haplotypes from their mother and father, whereas their unaffected brother inherited distinct haplotypes. This suggested that a common somatic germ cell event in 1 of the parents was responsible for the mutation, likely the father as he was 45 years of age, but the parental origin could not be definitively determined. <a href="#34" class="mim-tip-reference" title="Elalaoui, S. C., Kraoua, L., Liger, C., Ratbi, I., Cave, H., Sefiani, A. &lt;strong&gt;Germinal mosaicism in Noonan syndrome: a family with two affected siblings of normal parents.&lt;/strong&gt; Am. J. Med. Genet. 152A: 2850-2853, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20979190/&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;20979190&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33685&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="20979190">Elalaoui et al. (2010)</a> suggested an empirical recurrence rate of less than 1% in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20979190" 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>Population Genetics</strong>
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<p>Noonan syndrome has an estimated incidence of 1 in 1,000 to 2,500 live births (<a href="#104" class="mim-tip-reference" title="Tartaglia, M., Mehler, E. L., Goldberg, R., Zampino, G., Brunner, H. G., Kremer, H., van der Burgt, I., Crosby, A. H., Ion, A., Jeffery, S., Kalidas, K., Patton, M. A., Kucherlapati, R. S., Gelb, B. D. &lt;strong&gt;Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.&lt;/strong&gt; Nature Genet. 29: 465-468, 2001. Note: Erratum: Nature Genet. 29: 491 only, 2001; Nature Genet. 30: 123 only, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11704759/&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;11704759&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng772&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="11704759">Tartaglia et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704759" 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="mapping" class="mim-anchor"></a>
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<strong>Mapping</strong>
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<p>By means of a genomewide linkage analysis in a large Dutch kindred with autosomal dominant Noonan syndrome, <a href="#51" class="mim-tip-reference" title="Jamieson, C. R., van der Burgt, I., Brady, A. F., van Reen, M., Elsawi, M. M., Hol, F., Jeffery, S., Patton, M. A., Mariman, E. &lt;strong&gt;Mapping a gene for Noonan syndrome to the long arm of chromosome 12.&lt;/strong&gt; Nature Genet. 8: 357-360, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7894486/&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;7894486&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1294-357&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="7894486">Jamieson et al. (1994)</a> localized the gene to chromosome 12; maximum lod = 4.04 at theta = 0.0. Linkage analysis using chromosome 12 markers in 20 smaller, 2-generation families gave a maximum lod of 2.89 at theta = 0.07, but haplotype analysis showed nonlinkage in 1 family. These data suggested that a gene for Noonan syndrome is located in the 12q22-qter region between markers D12S84 and D12S366. Clinical studies in this kindred were reported by <a href="#111" class="mim-tip-reference" title="van der Burgt, I., Berends, E., Lommen, E., van Beersum, S., Hamel, B., Mariman, E. &lt;strong&gt;Clinical and molecular studies in a large Dutch family with Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 53: 187-191, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7856646/&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;7856646&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320530213&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="7856646">van der Burgt et al. (1994)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7856646+7894486" 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="Brady, A. F., Jamieson, C. R., van der Burgt, I., Crosby, A., van Reen, M., Kremer, H., Mariman, E., Patton, M. A., Jeffery, S. &lt;strong&gt;Further delineation of the critical region for Noonan syndrome on the long arm of chromosome 12.&lt;/strong&gt; Europ. J. Hum. Genet. 5: 336-337, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9412792/&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;9412792&lt;/a&gt;]" pmid="9412792">Brady et al. (1997)</a> further analyzed the 3-generation Dutch family studied by <a href="#51" class="mim-tip-reference" title="Jamieson, C. R., van der Burgt, I., Brady, A. F., van Reen, M., Elsawi, M. M., Hol, F., Jeffery, S., Patton, M. A., Mariman, E. &lt;strong&gt;Mapping a gene for Noonan syndrome to the long arm of chromosome 12.&lt;/strong&gt; Nature Genet. 8: 357-360, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7894486/&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;7894486&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1294-357&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="7894486">Jamieson et al. (1994)</a> using newly isolated CA-repeat markers derived from the interval between D12S84 and D12S366. In this way they were able to reduce the localization to an interval bounded by markers D12S105 and NOS1 (<a href="/entry/163731">163731</a>), which has been mapped to 12q24.2-q24.31. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7894486+9412792" 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="#63" 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> performed linkage analysis in a 4-generation Belgian family with Noonan syndrome in some individuals and CFC syndrome in others. Clinical and linkage data in this family indicated that the 2 syndromes result from variable expression of the same genetic defect. They found a maximum lod score of 4.43 at zero recombination for marker D12S84 in 12q24. A crossover in this pedigree narrowed the candidate gene region to a 5-cM interval between D12S84 and D12S1341. A remarkable feature of the family studied by <a href="#63" 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> was the presence of 3 dizygotic twins in the offspring of 2 affected females. A dizygotic twin pair was observed in the offspring of an affected female in the family in which linkage was studied by <a href="#51" class="mim-tip-reference" title="Jamieson, C. R., van der Burgt, I., Brady, A. F., van Reen, M., Elsawi, M. M., Hol, F., Jeffery, S., Patton, M. A., Mariman, E. &lt;strong&gt;Mapping a gene for Noonan syndrome to the long arm of chromosome 12.&lt;/strong&gt; Nature Genet. 8: 357-360, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7894486/&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;7894486&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1294-357&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="7894486">Jamieson et al. (1994)</a>. It is possible that an increased frequency of dizygotic twinning is associated with NS1/CFC linked to 12q24. The fragile X syndrome (<a href="/entry/300624">300624</a>) is another mendelian disorder with a possibly increased frequency of dizygotic twinning (<a href="#85" class="mim-tip-reference" title="Partington, M. W., Moore, D. Y., Turner, G. M. &lt;strong&gt;Confirmation of early menopause in fragile X carriers.&lt;/strong&gt; Am. J. Med. Genet. 64: 370-372, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8844083/&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;8844083&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1096-8628(19960809)64:2&lt;370::AID-AJMG27&gt;3.0.CO;2-B&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="8844083">Partington et al., 1996</a>; <a href="#94" class="mim-tip-reference" title="Schwartz, C. E., Dean, J., Howard-Peebles, P. N., Bugge, M., Mikkelson, M., Tommerup, N., Hull, C., Hagerman, R., Holden, J. J., Stevenson, R. E. &lt;strong&gt;Obstetrical and gynecological complications in fragile X carriers: a multicenter study.&lt;/strong&gt; Am. J. Med. Genet. 51: 400-402, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7943006/&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;7943006&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320510419&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="7943006">Schwartz et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9781012+7894486+8844083+7943006" 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>
Using a number of probes at the neurofibromatosis type I locus in the study of 11 families with Noonan syndrome in 2 or 3 generations, <a href="#96" class="mim-tip-reference" title="Sharland, M., Patton, M. A., Talbot, S., Chitolie, A., Bevan, D. H. &lt;strong&gt;Coagulation-factor deficiencies and abnormal bleeding in Noonan&#x27;s syndrome.&lt;/strong&gt; Lancet 339: 19-21, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1345952/&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;1345952&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(92)90141-o&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="1345952">Sharland et al. (1992)</a> excluded proximal 17q as the location of the gene. Studying six 2-generation families with classic Noonan syndrome, <a href="#40" class="mim-tip-reference" title="Flintoff, W. F., Bahuau, M., Lyonnet, S., Gilgenkrantz, S., Lacombe, D., Marcon, F., Levilliers, J., Kachaner, J., Munnich, A., Le Merrer, M. &lt;strong&gt;No evidence for linkage to the type 1 or type 2 neurofibromatosis loci in Noonan syndrome families.&lt;/strong&gt; Am. J. Med. Genet. 46: 700-705, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8362913/&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;8362913&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320460621&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="8362913">Flintoff et al. (1993)</a> could find no evidence of linkage of this disorder to NF1 on 17q or to NF2 (<a href="/entry/101000">101000</a>) on 22q. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1345952+8362913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of candidate genes, <a href="#50" class="mim-tip-reference" title="Ion, A., Crosby, A. H., Kremer, H., Kenmochi, N., Van Reen, M., Fenske, C., Van Der Burgt, I., Brunner, H. G., Montgomery, K. &lt;strong&gt;Detailed mapping, mutation analysis, and intragenic polymorphism identification in candidate Noonan syndrome genes MYL2, DCN, EPS8, and RPL6.&lt;/strong&gt; J. Med. Genet. 37: 884-886, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11185075/&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;11185075&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.37.11.884&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="11185075">Ion et al. (2000)</a> excluded the genes EPS8 (<a href="/entry/600206">600206</a>) and DCN (<a href="/entry/125255">125255</a>) from the critical region by FISH analysis. They also excluded the MYL2 (<a href="/entry/160781">160781</a>) and RPL6 (<a href="/entry/603703">603703</a>) genes by mutation analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11185075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="cytogenetics" class="mim-anchor"></a>
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<p><a href="#91" class="mim-tip-reference" title="Robin, N. H., Sellinger, B., McDonald-McGinn, D., Zackai, E. H., Emanuel, B. S., Driscoll, D. A. &lt;strong&gt;Classical Noonan syndrome is not associated with deletions of 22q11.&lt;/strong&gt; Am. J. Med. Genet. 56: 94-96, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7747795/&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;7747795&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320560121&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="7747795">Robin et al. (1995)</a> described 6 patients with Noonan syndrome who underwent molecular evaluation for submicroscopic deletion of chromosome 22q11. None of these patients presented with conotruncal heart defects. Evidence for 22q11 hemizygosity was demonstrated in only 1 patient. This patient had Noonan-like manifestations without clinical manifestations of DiGeorge (<a href="/entry/188400">188400</a>) or velocardiofacial (<a href="/entry/192430">192430</a>) syndromes. <a href="#30" class="mim-tip-reference" title="Digilio, M. C., Marino, B., Giannotti, A., Dallapiccola, B. &lt;strong&gt;Exclusion of 22q11 deletion in Noonan syndrome with tetralogy of Fallot. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 62: 413-414, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8723074/&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;8723074&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320620404&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="8723074">Digilio et al. (1996)</a> studied 4 patients with Noonan syndrome and tetralogy of Fallot. Chromosome analysis was normal in all 4 patients. DNA analysis showed no hemizygosity for the 22q11 region in any of the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7747795+8723074" 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>Duplication of Chromosome 12q24.13</em></strong></p><p>
<a href="#99" class="mim-tip-reference" title="Shchelochkov, O. A., Patel, A., Weissenberger, G. M., Chinault, A. C., Wiszniewska, J., Fernandes, P. H., Eng, C., Kukolich, M. K., Sutton, V. R. &lt;strong&gt;Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 146A: 1042-1048, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18348260/&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;18348260&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32215&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="18348260">Shchelochkov et al. (2008)</a> described a 3-year-old girl with clinical features consistent with Noonan syndrome. She presented with postnatal-onset failure to thrive, microcephaly, velopalatal incompetence, pectus excavatum, aortic coarctation, and atrial and ventricular septal defects. Facial features included ptosis, hypertelorism, epicanthal folds, cupped simple ears, and wide mouth with downturned corners. Speech and fine and gross motor development were at the level of a 12- to 18-month-old child, atypical for a child with Noonan syndrome. Array CGH showed an interstitial 10-Mb duplication, 12q24.11-q24.23, that includes the genes PTPN11 (<a href="/entry/176876">176876</a>), TBX5 (<a href="/entry/601620">601620</a>), and TBX3 (<a href="/entry/601621">601621</a>). This was confirmed by FISH analysis and chromosome analysis. Sequencing of PTPN11, KRAS (<a href="/entry/190070">190070</a>), SOS1 (<a href="/entry/182530">182530</a>), and the coding region of RAF1 (<a href="/entry/164760">164760</a>) did not reveal any pathogenic mutations. <a href="#99" class="mim-tip-reference" title="Shchelochkov, O. A., Patel, A., Weissenberger, G. M., Chinault, A. C., Wiszniewska, J., Fernandes, P. H., Eng, C., Kukolich, M. K., Sutton, V. R. &lt;strong&gt;Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 146A: 1042-1048, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18348260/&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;18348260&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32215&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="18348260">Shchelochkov et al. (2008)</a> proposed that duplications of the region containing PTPN11 may result in a Noonan syndrome phenotype and may account for the basis of Noonan syndrome in some of the 15 to 30% of patients for whom no mutations can be detected by sequencing of components of the RAS/MAPK signaling pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18348260" 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="Graham, J. M., Jr., Kramer, N., Bejjani, B. A., Thiel, C. T., Carta, C., Neri, G., Tartaglia, M., Zenker, M. &lt;strong&gt;Genomic duplication of PTPN11 is an uncommon cause of Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 149A: 2122-2128, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19760651/&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;19760651&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19760651[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32992&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="19760651">Graham et al. (2009)</a> reported another patient with Noonan syndrome caused by an 8.98-Mb duplication on chromosome 12q24.13 encompassing the PTPN11 gene, which was confirmed by FISH analysis. However, duplications were not observed in a screening of more than 250 Noonan syndrome cases without mutations in known disease-causing genes. Changes affecting the 3-prime untranslated region of the PTPN11 transcript were also not found in 36 patients without disease-causing mutations. In contrast to <a href="#99" class="mim-tip-reference" title="Shchelochkov, O. A., Patel, A., Weissenberger, G. M., Chinault, A. C., Wiszniewska, J., Fernandes, P. H., Eng, C., Kukolich, M. K., Sutton, V. R. &lt;strong&gt;Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 146A: 1042-1048, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18348260/&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;18348260&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32215&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="18348260">Shchelochkov et al. (2008)</a>, <a href="#46" class="mim-tip-reference" title="Graham, J. M., Jr., Kramer, N., Bejjani, B. A., Thiel, C. T., Carta, C., Neri, G., Tartaglia, M., Zenker, M. &lt;strong&gt;Genomic duplication of PTPN11 is an uncommon cause of Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 149A: 2122-2128, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19760651/&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;19760651&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19760651[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32992&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="19760651">Graham et al. (2009)</a> concluded that duplication of PTPN11 represents an uncommon cause of Noonan syndrome. However, the rare observation of NS in individuals with duplications involving the PTPN11 locus suggested that increased dosage of this gene may have dysregulating effects on intracellular signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18348260+19760651" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="diagnosis" class="mim-anchor"></a>
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<p><a href="#15" class="mim-tip-reference" title="Butler, M. G., Kumar, R., Davis, M. F., Gale, D. D., Dahir, G. A., Meaney, F. J. &lt;strong&gt;Metacarpophalangeal pattern profile analysis in Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 92: 128-131, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10797437/&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;10797437&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10797437[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;]" pmid="10797437">Butler et al. (2000)</a> used metacarpophalangeal pattern profile (MCPP) analysis to evaluate 15 individuals with Noonan syndrome. Discriminant analysis resulted in the correct classification of 93% of Noonan syndrome patients based on 2 MCPP variables (metacarpal 1 and middle phalanx 3). The authors suggested that MCPP analysis may be useful as a diagnostic tool in screening subjects for Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10797437" 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="#72" class="mim-tip-reference" title="MacFarlane, C. E., Brown, D. C., Johnston, L. B., Patton, M. A., Dunger, D. B., Savage, M. O., McKenna, W. J., Kelnar, C. J. H. &lt;strong&gt;Growth hormone therapy and growth in children with Noonan&#x27;s syndrome: results of 3 years&#x27; follow-up.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 1953-1956, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11344190/&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;11344190&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.5.7468&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="11344190">MacFarlane et al. (2001)</a> reported growth data from the first 3 years of a multicenter study examining the efficacy and safety of recombinant human GH in 23 children with Noonan syndrome. Sixteen male and 7 female patients (aged 9.3 +/- 2.6 years at onset of GH therapy, mean +/- SD; range 4.8-13.7) were each assessed at 1, 2, and 3 years after starting treatment. Comparisons were made with a group of 8 subjects (6 males and 2 females, aged 9.0 +/- 4.1 years; range 4.1-14.8) with Noonan syndrome and not treated with recombinant GH, and measured over the same period. All treated subjects underwent annual cardiac assessment. Height SD score increased from -2.7 +/- 0.4 at the start of GH therapy to -1.9 +/- 0.9 three years later. This corresponded to an increase in height from 116.1 +/- 13.2 to 137.3 +/- 14.0 cm. Height velocity increased from 4.4 +/- 1.7 cm/year in the year before treatment to 8.4 +/- 1.7, 6.2 +/- 1.7, and 5.8 +/- 1.8 during the first, second, and third years of GH treatment, respectively. Height acceleration was not significant during the second or third years when pubertal subjects were excluded. The authors concluded that the increase in growth rate in Noonan syndrome resulting from 1 year of GH therapy seems to be maintained during the second year, although height velocity shows a less significant increase over pretherapy values. Possible abnormal anabolic effects of recombinant GH on myocardial thickness were not confirmed, and no treated patient developed features of hypertrophic cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11344190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Kirk, J. M. W., Betts, P. R., Butler, G. E., Donaldson, M. D. C., Dunger, D. B., Johnston, D. I., Kelnar, C. J. H., Price, D. A., Wilton, P. &lt;strong&gt;Short stature in Noonan syndrome: response to growth hormone therapy.&lt;/strong&gt; Arch. Dis. Child. 84: 440-443, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11316696/&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;11316696&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.84.5.440&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="11316696">Kirk et al. (2001)</a> presented data on 66 Noonan syndrome patients (54 males) treated with growth hormone. Treatment improved height velocity in the short term, but longer-term therapy resulted in a waning of effect. The study indicated that final height is not substantially improved in most patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11316696" 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>From a study of 14 children with Noonan syndrome who were treated with human growth hormone, half of whom had a missense mutation in the PTPN11 gene, <a href="#37" class="mim-tip-reference" title="Ferreira, L. V., Souza, S. A. L., Arnhold, I. J. P., Mendonca, B. B., Jorge, A. A. L. &lt;strong&gt;PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome.&lt;/strong&gt; J. Clin. Endocr. Metab. 90: 5156-5160, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15956085/&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;15956085&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2004-2559&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="15956085">Ferreira et al. (2005)</a> found that those with a PTPN11 mutation had a lower increase in IGF-I (<a href="/entry/147440">147440</a>) levels during treatment and a significantly lower gain in height SD score after 3 years of treatment compared with those without mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15956085" 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="Binder, G., Neuer, K., Ranke, M. B., Wittekindt, N. E. &lt;strong&gt;PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome.&lt;/strong&gt; J. Clin. Endocr. Metab. 90: 5377-5381, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15985475/&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;15985475&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2005-0995&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="15985475">Binder et al. (2005)</a> compared GH secretion and IGF-I/IGFBP3 (<a href="/entry/146732">146732</a>) levels of the PTPN11 mutation-positive (mut+ group) versus the mutation-negative individuals (mut- group). IGF-I and IGFBP3 levels were significantly lower in the mut+ group. In contrast, GH levels showed a tendency to be higher in the mut+ group during spontaneous secretion at night and arginine stimulation. The mean change in height SDS after 1 year of rhGH therapy was +0.66 + 0.21 in the mut+ group (8 individuals), but +1.26 + 0.36 in the mut- group (3 individuals; p = 0.007). The authors concluded that PTPN11 mutations in Noonan syndrome cause mild GH resistance by a post-receptor signaling defect, which seems to be partially compensated for by elevated GH secretion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15985475" 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="molecularGenetics" class="mim-anchor"></a>
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<p>In more than 50% of patients with Noonan syndrome, <a href="#104" class="mim-tip-reference" title="Tartaglia, M., Mehler, E. L., Goldberg, R., Zampino, G., Brunner, H. G., Kremer, H., van der Burgt, I., Crosby, A. H., Ion, A., Jeffery, S., Kalidas, K., Patton, M. A., Kucherlapati, R. S., Gelb, B. D. &lt;strong&gt;Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.&lt;/strong&gt; Nature Genet. 29: 465-468, 2001. Note: Erratum: Nature Genet. 29: 491 only, 2001; Nature Genet. 30: 123 only, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11704759/&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;11704759&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng772&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="11704759">Tartaglia et al. (2001)</a> identified mutations in the PTPN11 gene (see, e.g., <a href="/entry/176876#0001">176876.0001</a>-<a href="/entry/176876#0003">176876.0003</a>). All the PTPN11 missense mutations were clustered in the interacting portions of the amino N-SH2 (Src homology 2) domain and the phosphotyrosine phosphatase (PTP) domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of 2 N-SH2 mutants indicated that in these cases there may be a significant shift of the equilibrium favoring the active conformation. The findings suggested that gain-of-function changes resulting in excessive SHP2 activity underlie the pathogenesis of Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704759" 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>After germline mutations in PTPN11 (<a href="/entry/176876">176876</a>) were demonstrated in the Noonan syndrome, <a href="#105" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. &lt;strong&gt;Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.&lt;/strong&gt; Nature Genet. 34: 148-150, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12717436/&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;12717436&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1156&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="12717436">Tartaglia et al. (2003)</a> investigated defects in PTPN11 in myeloid disorders including cases of juvenile myelomonocytic leukemia (JMML; <a href="/entry/607785">607785</a>) in children with Noonan syndrome. Specific mutations in PTPN11 associated with isolated JMML occurred as somatic changes and had never been observed as germline defects, leading <a href="#105" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. &lt;strong&gt;Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.&lt;/strong&gt; Nature Genet. 34: 148-150, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12717436/&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;12717436&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1156&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="12717436">Tartaglia et al. (2003)</a> to speculate that these molecular defects are stronger and associated with embryonic lethality. Conversely, most mutations in PTPN11 associated with Noonan syndrome, which were sufficient to perturb developmental processes, were not fully leukemogenic, suggesting a milder gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717436" 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 10 affected members from a large 4-generation Belgian family with Noonan syndrome and some features suggestive of CFC syndrome, <a href="#92" class="mim-tip-reference" title="Schollen, E., Matthijs, G., Gewillig, M., Fryns, J.-P., Legius, E. &lt;strong&gt;PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning.&lt;/strong&gt; Europ. J. Hum. Genet. 11: 85-88, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12529711/&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;12529711&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.ejhg.5200915&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="12529711">Schollen et al. (2003)</a> identified a missense mutation in the PTPN11 gene (<a href="/entry/176876#0018">176876.0018</a>). The mutation was not found in 7 unaffected relatives or 3 spouses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12529711" 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="#76" 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> screened the PTPN11 gene for mutations in 96 familial or sporadic Noonan syndrome patients and identified 15 missense mutations in 32 patients (33%). No obvious clinical differences were detected between subgroups of patients with mutations in different PTPN11 domains. Analysis of the clinical features of their patients revealed that several patients with facial abnormalities thought to be pathognomonic for NS did not have a mutation in the PTPN11 gene. Widely varying phenotypes among the 64 patients without PTPN11 mutations indicated further genetic heterogeneity. <a href="#76" 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/?cmd=link&linkname=pubmed_pubmed&from_uid=12634870" 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="#10" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., de Oliveira, P. S. L., Kim, C. A., Krieger, J. E. &lt;strong&gt;Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation.&lt;/strong&gt; Am. J. Med. Genet. 130A: 378-383, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15384080/&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;15384080&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30270&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="15384080">Bertola et al. (2004)</a> described a young woman with clinical features of Noonan syndrome but with some characteristics of CFC as well, including prominent ectodermal involvement (sparse and very coarse hair, and sparse eyebrows and eyelashes), developmental delay, and mental retardation. They identified a T411M mutation in the PTPN11 gene (<a href="/entry/176876#0019">176876.0019</a>); the same mutation was found in her mother and older sister, not initially considered to be affected but who had subtle clinical findings compatible with the diagnosis of Noonan syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies. <a href="#10" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., de Oliveira, P. S. L., Kim, C. A., Krieger, J. E. &lt;strong&gt;Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation.&lt;/strong&gt; Am. J. Med. Genet. 130A: 378-383, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15384080/&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;15384080&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30270&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="15384080">Bertola et al. (2004)</a> suggested that all first-degree relatives of patients with confirmed Noonan syndrome, even those with no signs of the disorder, be screened for PTPN11 mutations in order to provide accurate assessments of recurrence risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15384080" 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="#119" class="mim-tip-reference" title="Yoshida, R., Hasegawa, T., Hasegawa, Y., Nagai, T., Kinoshita, E., Tanaka, Y., Kanegane, H., Ohyama, K., Onishi, T., Hanew, K., Okuyama, T., Horikawa, R., Tanaka, T., Ogata, T. &lt;strong&gt;Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.&lt;/strong&gt; J. Clin. Endocr. Metab. 89: 3359-3364, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15240615/&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;15240615&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2003-032091&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="15240615">Yoshida et al. (2004)</a> reported PTPN11 mutation analysis and clinical assessment in 45 Japanese patients with Noonan syndrome. Sequence analysis of the coding exons 1 through 15 of PTPN11 revealed a novel 3-bp deletion (<a href="/entry/176876#0024">176876.0024</a>) and 10 recurrent missense mutations in 18 patients. The authors estimated that PTPN11 mutations account for approximately 40% of Japanese Noonan syndrome patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15240615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Jongmans, M., Sistermans, E. A., Rikken, A., Nillesen, W. M., Tamminga, R., Patton, M., Maier, E. M., Tartaglia, M., Noordam, K., van der Burgt, I. &lt;strong&gt;Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature.&lt;/strong&gt; Am. J. Med. Genet. 134A: 165-170, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15723289/&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;15723289&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30598&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="15723289">Jongmans et al. (2005)</a> performed mutation analysis of the PTPN11 gene in 170 Noonan syndrome patients and identified a mutation in 76 (45%) of them. They described the distribution of these mutations, as well as genotype-phenotype relationships. The usefulness of the Noonan syndrome scoring system developed by <a href="#111" class="mim-tip-reference" title="van der Burgt, I., Berends, E., Lommen, E., van Beersum, S., Hamel, B., Mariman, E. &lt;strong&gt;Clinical and molecular studies in a large Dutch family with Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 53: 187-191, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7856646/&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;7856646&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320530213&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="7856646">van der Burgt et al. (1994)</a> was demonstrated; when physicians based their diagnosis on the scoring system, the percentage of mutation-positive patients was higher. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7856646+15723289" 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>Mutations in the KRAS gene (<a href="/entry/190070">190070</a>) can also cause Noonan syndrome (NS3; <a href="/entry/609942">609942</a>). One patient with a T58I mutation (<a href="/entry/190070#0011">190070.0011</a>) also had a myeloproliferative disorder resembling juvenile myelomonocytic leukemia (JMML) (<a href="#93" class="mim-tip-reference" title="Schubbert, S., Zenker, M., Rowe, S. L., Boll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.-E., Nguyen, H., West, B., Zhang, K. Y. J., Sistermans, E., Rauch, A., Niemeyer, C. M., Shannon, K., Kratz, C. P. &lt;strong&gt;Germline KRAS mutations cause Noonan syndrome.&lt;/strong&gt; Nature Genet. 38: 331-336, 2006. Note: Erratum: Nature Genet. 38: 598 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16474405/&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;16474405&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1748&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="16474405">Schubbert et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474405" 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="#103" class="mim-tip-reference" title="Tartaglia, M., Martinelli, S., Stella, L., Bocchinfuso, G., Flex, E., Cordeddu, V., Zampino, G., van der Burgt, I., Palleschi, A., Petrucci, T. C., Sorcini, M., Schoch, C., Foa, R., Emanuel, P. D., Gelb, B. D. &lt;strong&gt;Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.&lt;/strong&gt; Am. J. Hum. Genet. 78: 279-290, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16358218/&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;16358218&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/499925&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="16358218">Tartaglia et al. (2006)</a> proposed a model that splits NS- and leukemia-associated PTPN11 mutations in the 2 major classes of activating lesions with differential perturbing effects on development and hematopoiesis. The results documented a strict correlation between the identity of the lesion and disease, and demonstrated that NS-causative mutations have less potency for promoting SHP2 gain of function than do leukemia-associated ones. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16358218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#90" class="mim-tip-reference" title="Roberts, A. E., Araki, T., Swanson, K. D., Montgomery, K. T., Schiripo, T. A., Joshi, V. A., Li, L., Yassin, Y., Tamburino, A. M., Neel, B. G., Kucherlapati, R. S. &lt;strong&gt;Germline gain-of-function mutations in SOS1 cause Noonan syndrome.&lt;/strong&gt; Nature Genet. 39: 70-74, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17143285/&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;17143285&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1926&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="17143285">Roberts et al. (2007)</a> and <a href="#106" class="mim-tip-reference" title="Tartaglia, M., Pennacchio, L. A., Zhao, C., Yadav, K. K., Fodale, V., Sarkozy, A., Pandit, B., Oishi, K., Martinelli, S., Schackwitz, W., Ustaszewska, A., Martin, J., and 13 others. &lt;strong&gt;Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.&lt;/strong&gt; Nature Genet. 39: 75-79, 2007. Note: Erratum: Nature Genet. 39: 276 only, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17143282/&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;17143282&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1939&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="17143282">Tartaglia et al. (2007)</a> investigated sizable groups of patients with Noonan syndrome but no mutation in PTPN11, which accounts for approximately 50% of such cases. They found that many had missense mutations in the SOS1 gene (<a href="/entry/182530">182530</a>) and that the SOS1-positive case patients represented approximately 20% of cases of Noonan syndrome. The phenotype of Noonan syndrome caused by SOS1 mutation, while within the Noonan syndrome spectrum, appears to be distinctive (see NS4, <a href="/entry/610733">610733</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17143282+17143285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#59" class="mim-tip-reference" title="Kontaridis, M. I., Swanson, K. D., David, F. S., Barford, D., Neel, B. G. &lt;strong&gt;PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.&lt;/strong&gt; J. Biol. Chem. 281: 6785-6792, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16377799/&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;16377799&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M513068200&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="16377799">Kontaridis et al. (2006)</a> examined the enzymatic properties of mutations in PTPN11 causing LEOPARD syndrome and found that, in contrast to the activating mutations that cause Noonan syndrome and neoplasia, LEOPARD syndrome mutants are catalytically defective and act as dominant-negative mutations that interfere with growth factor/ERK-MAPK (see <a href="/entry/176948">176948</a>)-mediated signaling. <a href="#59" class="mim-tip-reference" title="Kontaridis, M. I., Swanson, K. D., David, F. S., Barford, D., Neel, B. G. &lt;strong&gt;PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.&lt;/strong&gt; J. Biol. Chem. 281: 6785-6792, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16377799/&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;16377799&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M513068200&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="16377799">Kontaridis et al. (2006)</a> concluded that the pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16377799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a prospective multicenter study in 35 Noonan syndrome patients with growth retardation, <a href="#68" class="mim-tip-reference" title="Limal, J. M., Parfait, B., Cabrol, S., Bonnet, D., Leheup, B., Lyonnet, S., Vidaud, M., Le Bouc, Y. &lt;strong&gt;Noonan syndrome: relationships between genotype, growth, and growth factors.&lt;/strong&gt; J. Clin. Endocr. Metab. 91: 300-306, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16263833/&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;16263833&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2005-0983&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="16263833">Limal et al. (2006)</a> compared growth and hormonal growth factors before and during recombinant human GH therapy in patients with and without PTPN11 mutations. Sequencing of the PTPN11 coding sequence revealed 12 different heterozygous missense mutations in 20 of the 35 patients (57%). The results showed that among NS1 patients with short stature, some neonates had birth length less than -2 SDS. Growth of patients with mutations was reduced and responded less efficiently to GH than that of patients without mutations. <a href="#68" class="mim-tip-reference" title="Limal, J. M., Parfait, B., Cabrol, S., Bonnet, D., Leheup, B., Lyonnet, S., Vidaud, M., Le Bouc, Y. &lt;strong&gt;Noonan syndrome: relationships between genotype, growth, and growth factors.&lt;/strong&gt; J. Clin. Endocr. Metab. 91: 300-306, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16263833/&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;16263833&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2005-0983&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="16263833">Limal et al. (2006)</a> concluded that the association of low IGF1 (<a href="/entry/147440">147440</a>) and insulin-like growth factor-binding protein, acid-labile subunit (IGFALS; <a href="/entry/601489">601489</a>) with normal IGFBP3 (<a href="/entry/146732">146732</a>) levels could explain growth impairment of children with mutations and could suggest a GH resistance by a late postreceptor signaling defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16263833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a case of fetal demise at 12 weeks' gestation, <a href="#8" class="mim-tip-reference" title="Becker, K., Hughes, H., Howard, K., Armstrong, M., Roberts, D., Lazda, E. J., Short, J. P., Shaw, A., Patton, M. A., Tartaglia, M. &lt;strong&gt;Early fetal death associated with compound heterozygosity for Noonan syndrome-causative PTPN11 mutations.&lt;/strong&gt; Am. J. Med. Genet. 143A: 1249-1252, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17497712/&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;17497712&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31738&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="17497712">Becker et al. (2007)</a> identified compound heterozygosity for the N308S (<a href="/entry/176876#0004">176876.0004</a>) and Y63C (<a href="/entry/176876#0008">176876.0008</a>) mutations in the PTPN11 gene. The mother and father, who exhibited facial features of Noonan syndrome and had both undergone surgical correction of pulmonary valve stenosis, were heterozygous for N308S and Y63C, respectively. A second pregnancy resulted in the birth of a boy with Noonan syndrome carrying the paternal Y63C mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17497712" 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="#38" class="mim-tip-reference" title="Ferrero, G. B., Baldassarre, G., Delmonaco, A. G., Biamino, E., Banaudi, E., Carta, C., Rossi, C., Silengo, M. C. &lt;strong&gt;Clinical and molecular characterization of 40 patients with Noonan syndrome.&lt;/strong&gt; Europ. J. Med. Genet. 51: 566-572, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18678287/&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;18678287&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ejmg.2008.06.011&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="18678287">Ferrero et al. (2008)</a> identified PTPN11 mutations in 31.5% of 37 sporadic patients and 1 family with a clinical diagnosis of Noonan syndrome. One of the remaining patients had a mutation in the SOS1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18678287" 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>Cooccurrence of NF1 and PTPN11 Mutations</em></strong></p><p>
<a href="#11" class="mim-tip-reference" title="Bertola, D. R., Pereira, A. C., Passetti, F., de Oliveira, P. S. L., Messiaen, L., Gelb, B. D., Kim, C. A., Krieger, J. E. &lt;strong&gt;Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient.&lt;/strong&gt; Am. J. Med. Genet. 136A: 242-245, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15948193/&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;15948193&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30813&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="15948193">Bertola et al. (2005)</a> provided molecular evidence of the concurrence of neurofibromatosis and Noonan syndrome in a patient with a de novo missense mutation in the NF1 gene (<a href="/entry/613113#0043">613113.0043</a>) and a mutation in the PTPN11 gene (<a href="/entry/176876#0023">176876.0023</a>) inherited from her father. The proposita was noted to have cafe-au-lait spots at birth. Valvar and infundibular pulmonary stenosis and aortic coarctation were diagnosed at 20 months of age and surgically corrected at 3 years of age. As illustrated, the patient had marked hypertelorism and proptosis as well as freckling and cafe-au-lait spots. Lisch nodules were present. At the age of 8 years, a pilocytic astrocytoma in the suprasellar region involving the optic chiasm (first presenting symptomatically at 2 years of age), was partially resected. The father, who was diagnosed with Noonan syndrome, had downslanting palpebral fissures and prominent nasal labial folds. He was of short stature (159 cm) and had pectus excavatum. Electrocardiogram showed left-anterior hemiblock and complete right bundle branch block. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15948193" 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="#108" class="mim-tip-reference" title="Thiel, C., Wilken, M., Zenker, M., Sticht, H., Fahsold, R., Gusek-Schneider, G.-C., Rauch, A. &lt;strong&gt;Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 149A: 1263-1267, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19449407/&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;19449407&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32837&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="19449407">Thiel et al. (2009)</a> reported a patient with features of both neurofibromatosis I and Noonan syndrome who was compound heterozygous for mutations in both the NF1 (<a href="/entry/162200#0044">162200.0044</a>) and PTPN11 (<a href="/entry/176876#0027">176876.0027</a>) genes. The PTPN11 mutation occurred de novo, and the NF1 mutation was inherited from the patient's mother, who had mild features of neurofibromatosis I, including the absence of optic gliomas. The proband developed bilateral optic gliomas before age 2 years, suggesting an additive effect of the 2 mutations on the Ras pathway. The proband also had short stature, delayed development, sternal abnormalities, and valvular pulmonary stenosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19449407" 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>Reviews</em></strong></p><p>
<a href="#107" class="mim-tip-reference" title="Tartaglia, M., Zampino, G., Gelb, B. D. &lt;strong&gt;Noonan syndrome: clinical aspects and molecular pathogenesis.&lt;/strong&gt; Molec. Syndromol. 1: 2-26, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20648242/&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;20648242&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20648242[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/10.1159/000276766&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="20648242">Tartaglia et al. (2010)</a> provided a detailed review of the clinical and molecular features of Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20648242" 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="nomenclature" class="mim-anchor"></a>
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<p><a href="#33" class="mim-tip-reference" title="Dunlap, C., Neville, B., Vickers, R. A., O&#x27;Neil, D., Barker, B. &lt;strong&gt;The Noonan syndrome/cherubism association.&lt;/strong&gt; Oral Surg. 67: 698-705, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2740093/&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;2740093&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0030-4220(89)90012-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2740093">Dunlap et al. (1989)</a> referred to Noonan syndrome with multiple giant cells lesions as the Noonan syndrome-cherubism association. <a href="#20" class="mim-tip-reference" title="Cohen, M. M., Jr., Gorlin, R. J. &lt;strong&gt;Noonan-like/multiple giant cell lesion syndrome.&lt;/strong&gt; Am. J. Med. Genet. 40: 159-166, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1897569/&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;1897569&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320400208&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="1897569">Cohen and Gorlin (1991)</a> recommended that it not be called Noonan syndrome, pigmented villonodular synovitis, central giant cell granuloma, or cherubism, because each of these is a specific diagnostic entity sui generis and the use of such terms results in nosologic blinders that tend to limit the workup of patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2740093+1897569" 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>In a mouse model of Noonan syndrome in which transgenic mice carried a cardiomyocyte-specific gain-of-function Q79R mutation in the PTPN11 gene (<a href="/entry/176876#0018">176876.0018</a>), <a href="#77" class="mim-tip-reference" title="Nakamura, T., Colbert, M., Krenz, M., Molkentin, J. D., Hahn, H. S., Dorn, G. W., II, Robbins, J. &lt;strong&gt;Mediating ERK1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome.&lt;/strong&gt; J. Clin. Invest. 117: 2123-2132, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17641779/&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;17641779&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17641779[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI30756&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="17641779">Nakamura et al. (2007)</a> demonstrated that the developmental effects of Q79R cardiac expression are stage-specific and that ablation of subsequent ERK1/2 (see <a href="/entry/176948">176948</a>) activation prevented the development of cardiac abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17641779" 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="#23" class="mim-tip-reference" title="Cole, R. B. &lt;strong&gt;Noonan&#x27;s syndrome: a historical perspective.&lt;/strong&gt; Pediatrics 66: 468-469, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6999448/&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;6999448&lt;/a&gt;]" pmid="6999448">Cole (1980)</a> pointed out that the blacksmith in the famous painting 'Among Those Left' by Ivan Le Lorraine Albright appears to have had Noonan syndrome. The contour of the sternum, the low-set ears, and the short stature are suggestive. Genetic confirmation was provided by studies of a great-grandson with general features of the Noonan syndrome and cardiac abnormalities consistent with that diagnosis (pulmonic stenosis and regurgitation, abnormal architecture of the left ventricular musculature). <a href="#83" class="mim-tip-reference" title="Opitz, J. M., Pallister, P. D. &lt;strong&gt;Brief historical note: the concept of &#x27;gonadal dysgenesis.&#x27;.&lt;/strong&gt; Am. J. Med. Genet. 4: 333-343, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/395846/&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;395846&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320040404&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="395846">Opitz and Pallister (1979)</a> reproduced the first published illustration of the Noonan syndrome by <a href="#57" class="mim-tip-reference" title="Kobylinski, O. &lt;strong&gt;Ueber eine flughautahnliche Ausbreitung am Halse.&lt;/strong&gt; Arch. Anthrop. 14: 343-348, 1883."None>Kobylinski (1883)</a>, and <a href="#84" class="mim-tip-reference" title="Opitz, J. M. &lt;strong&gt;The Noonan syndrome. (Editorial)&lt;/strong&gt; Am. J. Med. Genet. 21: 515-518, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3895930/&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;3895930&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320210314&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="3895930">Opitz (1985)</a> republished the photograph of Rickey E., the first patient with 'her' syndrome studied at the State University of Iowa by Jacqueline A. Noonan. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=395846+6999448+3895930" 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>See Also:</strong>
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<a href="#Alslev1958" class="mim-tip-reference" title="Alslev, J., Reinwein, H. &lt;strong&gt;Ueber das familiaere Vorkommen des sogenannten Ullrich-Turner-Syndromes und das Vorhandensein eines pterygium colli, eines Kryptorchismus und des Meige-Syndromes bei zwei Bruedern mit kongenitalen Vitien.&lt;/strong&gt; Dtsch. Med. Wschr. 83: 601-604, 1958.">Alslev and Reinwein (1958)</a>; <a href="#Char1972" class="mim-tip-reference" title="Char, F., Rodriquez-Fernandez, H. L., Scott, C. I., Jr., Borgaonkar, D. S., Bell, B. B., Rowe, R. D. &lt;strong&gt;The Noonan syndrome--a clinical study of forty-five cases.&lt;/strong&gt; Birth Defects Orig. Art. Ser. VIII(5): 110-118, 1972.">Char et al. (1972)</a>; <a href="#Duncan1981" class="mim-tip-reference" title="Duncan, W. J., Fowler, R. S., Farkas, L. G., Ross, R. B., Wright, A. W., Bloom, K. R., Huot, D. J., Sondheimer, H. M., Rowe, R. D. &lt;strong&gt;A comprehensive scoring system for evaluating Noonan syndrome.&lt;/strong&gt; Am. J. Med. Genet. 10: 37-50, 1981.">Duncan et al. (1981)</a>; <a href="#Fisher1982" class="mim-tip-reference" title="Fisher, E., Weiss, E. B., Michals, K., DuBrow, I. W., Hastrieter, A. R., Matalon, R. &lt;strong&gt;Spontaneous chylothorax in Noonan&#x27;s syndrome.&lt;/strong&gt; Europ. J. Pediat. 138: 282-284, 1982.">Fisher et al. (1982)</a>; <a href="#Golabi1985" class="mim-tip-reference" title="Golabi, M., Hall, B. D., Clericuzio, C., Johnston, K. &lt;strong&gt;Fetal primidone syndrome: a distinct pattern of malformations. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 37: A54 only, 1985.">Golabi et al. (1985)</a>; <a href="#Hall1982" class="mim-tip-reference" title="Hall, J. G., Reed, S. D., Greene, G. &lt;strong&gt;The distal arthrogryposes: delineation of new entities--review and nosologic discussion.&lt;/strong&gt; Am. J. Med. Genet. 11: 185-239, 1982.">Hall et al. (1982)</a>; <a href="#Levy1970" class="mim-tip-reference" title="Levy, E. P., Pashayan, H., Fraser, F. C., Pinsky, L. &lt;strong&gt;XX and XY Turner phenotypes in a family.&lt;/strong&gt; Am. J. Dis. Child. 120: 36-43, 1970.">Levy
et al. (1970)</a>; <a href="#Linde1973" class="mim-tip-reference" title="Linde, L. M., Turner, S. W., Sparkes, R. S. &lt;strong&gt;Pulmonary valvular dysplasia, a cardiofacial syndrome.&lt;/strong&gt; Brit. Heart J. 35: 301-304, 1973.">Linde et al. (1973)</a>; <a href="#Miller1978" class="mim-tip-reference" title="Miller, M., Motulsky, A. &lt;strong&gt;Noonan syndrome in an adult family presenting with chronic lymphedema.&lt;/strong&gt; Am. J. Med. 65: 379-383, 1978.">Miller and Motulsky (1978)</a>; <a href="#Nora1974" class="mim-tip-reference" title="Nora, J. J., Nora, A. H., Sinha, A. K., Spangler, R. D., Lubs, H. A., Jr. &lt;strong&gt;The Ullrich-Noonan syndrome (Turner phenotype).&lt;/strong&gt; Am. J. Dis. Child. 127: 48-55, 1974.">Nora
et al. (1974)</a>; <a href="#Pierini1979" class="mim-tip-reference" title="Pierini, D. O., Pierini, A. M. &lt;strong&gt;Keratosis pilaris atrophicans faciei (ulerythema ophryogenes) a cutaneous marker in the Noonan syndrome.&lt;/strong&gt; Brit. J. Derm. 100: 409-416, 1979.">Pierini and Pierini (1979)</a>; <a href="#Sharland1992" class="mim-tip-reference" title="Sharland, M., Taylor, R., Patton, M. A., Jeffery, S. &lt;strong&gt;Absence of linkage of Noonan syndrome to the neurofibromatosis type 1 locus.&lt;/strong&gt; J. Med. Genet. 29: 188-190, 1992.">Sharland et al. (1992)</a>; <a href="#Wiedemann1991" class="mim-tip-reference" title="Wiedemann, H.-R. &lt;strong&gt;Otto Ullrich and his syndromes.&lt;/strong&gt; Am. J. Med. Genet. 41: 128-133, 1991.">Wiedemann (1991)</a>; <a href="#Witt1985" class="mim-tip-reference" title="Witt, D., Allanson, J., Wadsworth, L., Hall, J. G. &lt;strong&gt;Bleeding disorders in 7 cases of Noonan syndrome; further evidence of heterogeneity. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 37: A83 only, 1985.">Witt et al. (1985)</a>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Allanson1985" class="mim-anchor"></a>
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Allanson, J. E., Hall, J. G., Hughes, H. E., Preus, M., Witt, R. D.
<strong>Noonan syndrome: the changing phenotype.</strong>
Am. J. Med. Genet. 21: 507-514, 1985.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4025385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4025385</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4025385" 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.1320210313" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
<a id="Allanson1987" class="mim-anchor"></a>
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<p class="mim-text-font">
Allanson, J. E.
<strong>Noonan syndrome.</strong>
J. Med. Genet. 24: 9-13, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3543368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3543368</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3543368" 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.24.1.9" target="_blank">Full Text</a>]
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<a id="Alslev1958" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Alslev, J., Reinwein, H.
<strong>Ueber das familiaere Vorkommen des sogenannten Ullrich-Turner-Syndromes und das Vorhandensein eines pterygium colli, eines Kryptorchismus und des Meige-Syndromes bei zwei Bruedern mit kongenitalen Vitien.</strong>
Dtsch. Med. Wschr. 83: 601-604, 1958.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13537698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13537698</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13537698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1055/s-0028-1114324" target="_blank">Full Text</a>]
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<a id="Bader-Meunier1997" class="mim-anchor"></a>
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Bader-Meunier, B., Tchernia, G., Mielot, F., Fontaine, J. L., Thomas, C., Lyonnet, S., Lavergne, J. M., Dommergues, J. P.
<strong>Occurrence of myeloproliferative disorder in patients with Noonan syndrome.</strong>
J. Pediat. 130: 885-889, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9202609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9202609</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9202609" 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/s0022-3476(97)70273-7" target="_blank">Full Text</a>]
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<a id="Baird1972" class="mim-anchor"></a>
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Baird, P. A., De Jong, B. P.
<strong>Noonan's syndrome (XX and XY Turner phenotype) in three generations of a family.</strong>
J. Pediat. 80: 110-114, 1972.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5016336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5016336</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5016336" 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/s0022-3476(72)80466-9" target="_blank">Full Text</a>]
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<a id="Ball1982" class="mim-anchor"></a>
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Ball, M. J., Peiris, A.
<strong>Chiari (type 1) malformation and syringomelia in a patient with Noonan's syndrome. (Letter)</strong>
J. Neurol. Neurosurg. Psychiat. 45: 753-754, 1982.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7131003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7131003</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7131003" 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/jnnp.45.8.753" 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="Becker2007" class="mim-anchor"></a>
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Becker, K., Hughes, H., Howard, K., Armstrong, M., Roberts, D., Lazda, E. J., Short, J. P., Shaw, A., Patton, M. A., Tartaglia, M.
<strong>Early fetal death associated with compound heterozygosity for Noonan syndrome-causative PTPN11 mutations.</strong>
Am. J. Med. Genet. 143A: 1249-1252, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17497712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17497712</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17497712" 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.31738" target="_blank">Full Text</a>]
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<a id="Bertola2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bertola, D. R., Kim, C. A., Pereira, A. C., Mota, G. F. A., Krieger, J. E., Vieira, I. C., Valente, M., Loreto, M. R., Magalhaes, R. P., Gonzalez, C. H.
<strong>Are Noonan syndrome and Noonan-like/multiple giant cell lesion syndrome distinct entities?</strong>
Am. J. Med. Genet. 98: 230-234, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11169560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11169560</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11169560" 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(20010122)98:3&lt;230::aid-ajmg1080&gt;3.0.co;2-k" target="_blank">Full Text</a>]
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<a id="Bertola2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bertola, D. R., Pereira, A. C., de Oliveira, P. S. L., Kim, C. A., Krieger, J. E.
<strong>Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation.</strong>
Am. J. Med. Genet. 130A: 378-383, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15384080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15384080</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15384080" 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.30270" target="_blank">Full Text</a>]
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<a id="Bertola2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bertola, D. R., Pereira, A. C., Passetti, F., de Oliveira, P. S. L., Messiaen, L., Gelb, B. D., Kim, C. A., Krieger, J. E.
<strong>Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient.</strong>
Am. J. Med. Genet. 136A: 242-245, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15948193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15948193</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15948193" 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.30813" target="_blank">Full Text</a>]
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<a id="Binder2005" class="mim-anchor"></a>
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Binder, G., Neuer, K., Ranke, M. B., Wittekindt, N. E.
<strong>PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome.</strong>
J. Clin. Endocr. Metab. 90: 5377-5381, 2005.
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[<a href="https://doi.org/10.1210/jc.2005-0995" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320400208" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.38322" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32140" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320290205" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.33713" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.31.6.468" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2004-2559" target="_blank">Full Text</a>]
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Fisher, E., Weiss, E. B., Michals, K., DuBrow, I. W., Hastrieter, A. R., Matalon, R.
<strong>Spontaneous chylothorax in Noonan's syndrome.</strong>
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[<a href="https://doi.org/10.1007/BF00441221" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320460621" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(59)91893-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00043426-199703000-00019" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF02010806" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32992" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00019605-200310000-00013" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(70)90241-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.37.11.884" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1294-357" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30598" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320280511" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/adc.84.5.440" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(83)80525-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.38362" 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/10.1002/ajmg.10782" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/ard.34.3.269" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archpedi.1970.02100060070009" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2005-0983" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/hrt.35.3.301" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.86.5.7468" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320210312" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9343(78)90836-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20502" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archpedi.1968.02100020377005" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archpedi.1968.02100020347001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320210314" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1365-2133.1979.tb01641.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1748" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320510419" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/adc.81.1.28" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0140-6736(92)90141-o" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.29.3.188" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2014-102611" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/499925" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng772" target="_blank">Full Text</a>]
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<strong>Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.</strong>
Nature Genet. 39: 75-79, 2007. Note: Erratum: Nature Genet. 39: 276 only, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17143282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17143282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17143282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng1939" target="_blank">Full Text</a>]
</p>
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<a id="107" class="mim-anchor"></a>
<a id="Tartaglia2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Tartaglia, M., Zampino, G., Gelb, B. D.
<strong>Noonan syndrome: clinical aspects and molecular pathogenesis.</strong>
Molec. Syndromol. 1: 2-26, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20648242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20648242</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20648242[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=20648242" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1159/000276766" target="_blank">Full Text</a>]
</p>
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<a id="108" class="mim-anchor"></a>
<a id="Thiel2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Thiel, C., Wilken, M., Zenker, M., Sticht, H., Fahsold, R., Gusek-Schneider, G.-C., Rauch, A.
<strong>Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome.</strong>
Am. J. Med. Genet. 149A: 1263-1267, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19449407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19449407</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19449407" 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.32837" target="_blank">Full Text</a>]
</p>
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<a id="109" class="mim-anchor"></a>
<a id="Turner1938" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Turner, H. H.
<strong>A syndrome of infantilism, congenital webbed neck and cubitus valgus.</strong>
Endocrinology 23: 566-574, 1938.
</p>
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<li>
<a id="110" class="mim-anchor"></a>
<a id="Ucar1998" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ucar, B., Okten, A., Mocan, H., Ercin, C.
<strong>Noonan syndrome associated with central giant cell granuloma.</strong>
Clin. Genet. 53: 411-414, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660063</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9660063" 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.1399-0004.1998.tb02756.x" target="_blank">Full Text</a>]
</p>
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<a id="111" class="mim-anchor"></a>
<a id="van der Burgt1994" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
van der Burgt, I., Berends, E., Lommen, E., van Beersum, S., Hamel, B., Mariman, E.
<strong>Clinical and molecular studies in a large Dutch family with Noonan syndrome.</strong>
Am. J. Med. Genet. 53: 187-191, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7856646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7856646</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7856646" 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.1320530213" target="_blank">Full Text</a>]
</p>
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<a id="112" class="mim-anchor"></a>
<a id="Wagner1981" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wagner, M. L., Spjut, H. J., Dutton, R. V., Glassman, A. L., Askew, J. B.
<strong>Polyarticular pigmented villonodular synovitis.</strong>
Am. J. Roentgen. 136: 821-823, 1981.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6784483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6784483</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6784483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.2214/ajr.136.4.821" target="_blank">Full Text</a>]
</p>
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<a id="113" class="mim-anchor"></a>
<a id="Wendt1986" class="mim-anchor"></a>
<div class="">
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Wendt, R. G., Wolfe, F., McQueen, D., Murphy, P., Solomon, H., Housholder, M.
<strong>Polyarticular pigmented villonodular synovitis in children: evidence for a genetic contribution.</strong>
J. Rheum. 13: 921-926, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3820202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3820202</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3820202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="114" class="mim-anchor"></a>
<a id="Wiedemann1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wiedemann, H.-R., Glatzl, J.
<strong>Follow-up of Ullrich's original patient with 'Ullrich-Turner' syndrome.</strong>
Am. J. Med. Genet. 41: 134-136, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1951454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1951454</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1951454" 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.1320410132" target="_blank">Full Text</a>]
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<a id="115" class="mim-anchor"></a>
<a id="Wiedemann1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wiedemann, H.-R.
<strong>Otto Ullrich and his syndromes.</strong>
Am. J. Med. Genet. 41: 128-133, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1951453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1951453</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1951453" 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.1320410131" target="_blank">Full Text</a>]
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<a id="116" class="mim-anchor"></a>
<a id="Witt1985" class="mim-anchor"></a>
<div class="">
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Witt, D., Allanson, J., Wadsworth, L., Hall, J. G.
<strong>Bleeding disorders in 7 cases of Noonan syndrome; further evidence of heterogeneity. (Abstract)</strong>
Am. J. Hum. Genet. 37: A83 only, 1985.
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<a id="117" class="mim-anchor"></a>
<a id="Witt1987" class="mim-anchor"></a>
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Witt, D. R., Hoyme, E., Zonana, J., Manchester, D. K., Fryns, J. P., Stevenson, J. G., Curry, C. J. R., Hall, J. G.
<strong>Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature.</strong>
Am. J. Med. Genet. 27: 841-856, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3321992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3321992</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3321992" 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.1320270412" target="_blank">Full Text</a>]
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<a id="118" class="mim-anchor"></a>
<a id="Witt1988" class="mim-anchor"></a>
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Witt, D. R., McGillivray, B. C., Allanson, J. E., Hughes, H. E., Hathaway, W. E., Zipursky, A., Hall, J. G.
<strong>Bleeding diathesis in Noonan syndrome: a common association.</strong>
Am. J. Med. Genet. 31: 305-317, 1988.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3232698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3232698</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3232698" 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.1320310208" target="_blank">Full Text</a>]
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<a id="119" class="mim-anchor"></a>
<a id="Yoshida2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yoshida, R., Hasegawa, T., Hasegawa, Y., Nagai, T., Kinoshita, E., Tanaka, Y., Kanegane, H., Ohyama, K., Onishi, T., Hanew, K., Okuyama, T., Horikawa, R., Tanaka, T., Ogata, T.
<strong>Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.</strong>
J. Clin. Endocr. Metab. 89: 3359-3364, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15240615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15240615</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15240615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jc.2003-032091" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Marla J. F. O'Neill - updated : 10/13/2017
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Cassandra L. Kniffin - updated : 11/3/2015<br>Cassandra L. Kniffin - updated : 3/19/2012<br>Cassandra L. Kniffin - updated : 10/26/2010<br>Cassandra L. Kniffin - updated : 10/14/2010<br>Marla J. F. O'Neill - updated : 10/9/2009<br>Cassandra L. Kniffin - updated : 6/18/2009<br>Kelly A. Przylepa - updated : 2/2/2009<br>Marla J. F. O'Neill - updated : 4/24/2008<br>Marla J. F. O'Neill - updated : 2/1/2008<br>Marla J. F. O'Neill - updated : 12/21/2007<br>Marla J. F. O'Neill - updated : 10/24/2007<br>John A. Phillips, III - updated : 5/31/2007<br>John A. Phillips, III - updated : 4/18/2007<br>John A. Phillips, III - updated : 4/18/2007<br>Marla J. F. O'Neill - updated : 3/9/2007<br>Victor A. McKusick - updated : 1/30/2007<br>John A. Phillips, III - updated : 11/17/2006<br>Victor A. McKusick - updated : 5/4/2006<br>Victor A. McKusick - updated : 2/24/2006<br>Victor A. McKusick - updated : 4/14/2005<br>Marla J. F. O'Neill - updated : 1/4/2005<br>Jane Kelly - updated : 11/9/2004<br>Marla J. F. O'Neill - updated : 5/12/2004<br>Marla J. F. O'Neill - updated : 4/2/2004<br>Natalie E. Krasikov - updated : 3/29/2004<br>Siobhan M. Dolan - updated : 2/19/2004<br>Victor A. McKusick - updated : 1/14/2004<br>Victor A. McKusick - updated : 5/15/2003<br>Victor A. McKusick - updated : 5/13/2003<br>Cassandra L. Kniffin - updated : 1/9/2003<br>Victor A. McKusick - updated : 11/27/2002<br>Victor A. McKusick - updated : 11/12/2001<br>Victor A. McKusick - updated : 8/6/2001<br>John A. Phillips, III - updated : 7/10/2001<br>Michael J. Wright - updated : 5/21/2001<br>Sonja A. Rasmussen - updated : 10/12/2000<br>Paul Brennan - updated : 4/10/2000<br>Victor A. McKusick - updated : 4/30/1998<br>Victor A. McKusick - updated : 12/19/1997<br>Iosif W. Lurie - updated : 1/8/1997<br>Iosif W. Lurie - updated : 9/12/1996
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Victor A. McKusick : 6/2/1986
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carol : 10/07/2022
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alopez : 10/06/2022<br>alopez : 02/10/2022<br>alopez : 11/09/2020<br>alopez : 10/15/2019<br>alopez : 03/29/2019<br>alopez : 12/17/2018<br>carol : 07/16/2018<br>carol : 07/13/2018<br>carol : 10/17/2017<br>alopez : 10/13/2017<br>carol : 11/09/2015<br>ckniffin : 11/3/2015<br>carol : 9/23/2015<br>ckniffin : 9/21/2015<br>carol : 8/2/2013<br>ckniffin : 8/1/2013<br>carol : 6/20/2013<br>carol : 6/20/2013<br>carol : 6/7/2013<br>carol : 7/27/2012<br>alopez : 3/30/2012<br>terry : 3/28/2012<br>terry : 3/28/2012<br>ckniffin : 3/19/2012<br>carol : 12/8/2011<br>wwang : 6/2/2011<br>wwang : 2/7/2011<br>ckniffin : 1/21/2011<br>wwang : 1/10/2011<br>ckniffin : 12/23/2010<br>wwang : 11/12/2010<br>ckniffin : 11/8/2010<br>wwang : 11/5/2010<br>ckniffin : 10/26/2010<br>wwang : 10/19/2010<br>ckniffin : 10/14/2010<br>wwang : 10/6/2010<br>ckniffin : 9/28/2010<br>alopez : 1/28/2010<br>ckniffin : 1/19/2010<br>carol : 11/23/2009<br>wwang : 10/16/2009<br>terry : 10/9/2009<br>wwang : 7/21/2009<br>ckniffin : 6/18/2009<br>wwang : 6/3/2009<br>terry : 6/1/2009<br>terry : 4/29/2009<br>wwang : 3/10/2009<br>joanna : 2/9/2009<br>carol : 2/4/2009<br>terry : 2/2/2009<br>terry : 1/30/2009<br>carol : 5/22/2008<br>wwang : 4/24/2008<br>terry : 4/24/2008<br>wwang : 2/6/2008<br>terry : 2/1/2008<br>wwang : 1/8/2008<br>terry : 12/21/2007<br>wwang : 10/25/2007<br>terry : 10/24/2007<br>carol : 5/31/2007<br>carol : 5/30/2007<br>wwang : 4/19/2007<br>alopez : 4/18/2007<br>carol : 4/18/2007<br>wwang : 3/12/2007<br>terry : 3/9/2007<br>alopez : 2/19/2007<br>alopez : 1/31/2007<br>terry : 1/30/2007<br>carol : 11/27/2006<br>alopez : 11/17/2006<br>alopez : 5/4/2006<br>carol : 4/25/2006<br>alopez : 3/3/2006<br>terry : 2/24/2006<br>carol : 1/12/2006<br>terry : 12/21/2005<br>ckniffin : 6/30/2005<br>tkritzer : 4/27/2005<br>terry : 4/14/2005<br>carol : 1/5/2005<br>terry : 1/4/2005<br>tkritzer : 11/9/2004<br>tkritzer : 11/3/2004<br>carol : 5/13/2004<br>carol : 5/13/2004<br>terry : 5/12/2004<br>tkritzer : 4/5/2004<br>terry : 4/2/2004<br>tkritzer : 3/30/2004<br>terry : 3/29/2004<br>tkritzer : 2/19/2004<br>terry : 2/19/2004<br>tkritzer : 1/15/2004<br>terry : 1/14/2004<br>terry : 11/19/2003<br>carol : 11/13/2003<br>terry : 7/31/2003<br>alopez : 6/3/2003<br>tkritzer : 5/19/2003<br>terry : 5/15/2003<br>alopez : 5/14/2003<br>terry : 5/13/2003<br>cwells : 1/14/2003<br>ckniffin : 1/9/2003<br>mgross : 12/10/2002<br>carol : 12/4/2002<br>tkritzer : 12/3/2002<br>terry : 11/27/2002<br>alopez : 1/7/2002<br>alopez : 11/27/2001<br>alopez : 11/21/2001<br>alopez : 11/13/2001<br>terry : 11/12/2001<br>carol : 8/6/2001<br>mcapotos : 7/26/2001<br>cwells : 7/19/2001<br>cwells : 7/10/2001<br>alopez : 5/21/2001<br>mcapotos : 10/13/2000<br>mcapotos : 10/12/2000<br>alopez : 4/10/2000<br>dholmes : 5/12/1998<br>carol : 5/2/1998<br>terry : 4/30/1998<br>dholmes : 12/31/1997<br>terry : 12/19/1997<br>jenny : 11/19/1997<br>alopez : 6/27/1997<br>terry : 3/6/1997<br>terry : 3/6/1997<br>jenny : 3/4/1997<br>jenny : 1/21/1997<br>jenny : 1/8/1997<br>carol : 9/12/1996<br>terry : 8/19/1996<br>terry : 7/29/1996<br>carol : 6/25/1996<br>mark : 9/19/1995<br>carol : 1/31/1995<br>terry : 12/22/1994<br>mimadm : 12/2/1994<br>jason : 7/27/1994<br>davew : 7/14/1994
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<h3>
<span class="mim-font">
<strong>#</strong> 163950
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<h3>
<span class="mim-font">
NOONAN SYNDROME 1; NS1
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<span class="mim-font">
<em>Alternative titles; symbols</em>
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<h4>
<span class="mim-font">
NOONAN SYNDROME<br />
MALE TURNER SYNDROME<br />
FEMALE PSEUDO-TURNER SYNDROME<br />
TURNER PHENOTYPE WITH NORMAL KARYOTYPE
</span>
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Other entities represented in this entry:
</span>
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<span class="h3 mim-font">
PTERYGIUM COLLI SYNDROME, INCLUDED
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<strong>SNOMEDCT:</strong> 205684007, 205824006; &nbsp;
<strong>ICD10CM:</strong> Q87.19; &nbsp;
<strong>ORPHA:</strong> 648; &nbsp;
<strong>DO:</strong> 0060578; &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">
12q24.13
</span>
</td>
<td>
<span class="mim-font">
Noonan syndrome 1
</span>
</td>
<td>
<span class="mim-font">
163950
</span>
</td>
<td>
<span class="mim-font">
Autosomal dominant
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
PTPN11
</span>
</td>
<td>
<span class="mim-font">
176876
</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 Noonan syndrome-1 (NS1) is caused by heterozygous mutation in the PTPN11 gene (176876) on chromosome 12q24.</p><p>Mutation in the PTPN11 gene also causes LEOPARD syndrome-1 (LPRD1; 151100), a disorder with features overlapping those of Noonan syndrome.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, facial dysmorphism, and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, downslanting palpebral fissures, a high-arched palate, and low-set, posteriorly rotated ears. Cardiac involvement is present in up to 90% of patients. Pulmonic stenosis and hypertrophic cardiomyopathy are the most common forms of cardiac disease, but a variety of other lesions are also observed. Additional relatively frequent features include multiple skeletal defects (chest and spine deformities), webbed neck, mental retardation, cryptorchidism, and bleeding diathesis (summary by Tartaglia et al., 2002). </p><p><strong><em>Genetic Heterogeneity of Noonan Syndrome</em></strong></p><p>
See also NS3 (609942), caused by mutation in the KRAS gene (190070); NS4 (610733), caused by mutation in the SOS1 gene (182530); NS5 (611553), caused by mutation in the RAF1 gene (164760); NS6 (613224), caused by mutation in the NRAS gene (164790); NS7 (613706), caused by mutation in the BRAF gene (164757); NS8 (615355), caused by mutation in the RIT1 gene (609591); NS9 (616559), caused by mutation in the SOS2 gene (601247); NS10 (616564), caused by mutation in the LZTR1 gene (600574); NS11 (618499), caused by mutation in the MRAS gene (608435); NS12 (618624), caused by mutation in the RRAS2 gene (600098); and NS13 (619087), caused by mutation in the MAPK1 gene (176948).</p><p>Autosomal recessive forms of Noonan syndrome include NS2 (605275), caused by mutation in the LZTR1 gene (600574), and NS14 (619745), caused by mutation in the SPRED2 gene (609292).</p><p>See also Noonan syndrome-like disorder with loose anagen hair-1 (NSLH1; 607721), caused by mutation in the SHOC2 gene (602775); Noonan syndrome-like disorder with loose anagen hair-2 (NSLH2; 617506), caused by mutation in the PPP1CB gene (600590); and Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL; 613563), caused by mutation in the CBL gene (165360).</p><p>Mutations in the neurofibromin gene (NF1; 613113), which is the site of mutations causing classic neurofibromatosis type I (NF1; 162200), have been found in neurofibromatosis-Noonan syndrome (NFNS; 601321).</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The disorder now known as Noonan syndrome bears similarities to the disorder described by Turner (1938) and shown by Ford et al. (1959) to have its basis in a 45,X chromosomal aberration called Turner syndrome, Ullrich-Turner syndrome (Wiedemann and Glatzl, 1991), or monosomy X. </p><p>Migeon and Whitehouse (1967) described 2 families, each with 2 sibs with somatic features of the Turner phenotype. In 1 family, 2 brothers had webbing of the neck, coarctation of the aorta, and cryptorchidism. In the second, a brother and sister were affected. </p><p>Diekmann et al. (1967) described 2 brothers and a sister, with normal and unrelated parents, who had somatic characteristics of the Turner syndrome, particularly pterygium colli and deformed sternum, and had myocardiopathy leading to death at ages 12 and 10 years in 2 of them. </p><p>Noonan (1968) reported 19 patients of whom 17 had pulmonary stenosis and 2 had patent ductus arteriosus (see 607411). Twelve were males and 7 were females. Deformity of the sternum with precocious closure of sutures was a frequent feature. </p><p>Among 95 male patients with pulmonary stenosis, Celermajer et al. (1968) found the Turner phenotype in 8. In 5 of these, karyotyping was performed. In 4 the chromosomes were normal; in 1, an extra acrocentric chromosome was present. </p><p>Kaplan et al. (1968) described 2 brothers with Noonan syndrome and elevated alkaline phosphatase levels, one of whom also had malignant schwannoma of the forearm. </p><p>Nora and Sinha (1968) observed mother-to-offspring transmission in 3 families; in 1 family, transmission was through 3 generations. </p><p>Baird and De Jong (1972) described 7 cases in 3 generations. One affected woman had 5 affected children (out of 6) with 2 different husbands. Seizures and anomalous upper lateral incisors may have been coincidental. </p><p>Simpson et al. (1969) reported experiences suggesting that rubella embryopathy may result in the Turner phenotype, thereby accounting for either the male Turner syndrome or the female pseudo-Turner syndrome. A particularly convincing pedigree for autosomal dominant inheritance was reported by Bolton et al. (1974), who found the condition in a man and 4 sons (in a sibship of 10). Four of the 5 affected persons had pulmonic stenosis. Father-to-son transmission was reported by Qazi et al. (1974). </p><p>Koretzky et al. (1969) described an unusual type of pulmonary valvular dysplasia which showed a familial tendency with either affected parent and offspring or affected sibs. Although some relatives had pulmonary valvular stenosis of the standard dome-shaped variety, the valvular dysplasia in others was characterized by the presence of three distinct cusps and no commissural fusion. The obstructive mechanism was related to markedly thickened, immobile cusps, with disorganized myxomatous tissue. Other features were retarded growth, abnormal facies (triangular face, hypertelorism, low-set ears and ptosis of the eyelids), absence of ejection click, and unusually marked right axis deviation by electrocardiogram. It now seems clear that the patients of Koretzky et al. (1969) had Noonan syndrome. </p><p>Mendez and Opitz (1985) stated that the Watson syndrome (193520) and the LEOPARD syndrome (151100) 'are essentially indistinguishable from the Noonan syndrome.' Witt et al. (1987) reviewed the occurrence of lymphedema in Noonan syndrome. When it does occur, it opens the possibility of prenatal diagnosis by imaging methods or by AFP level. Noonan syndrome was one of the causes found for posterior cervical hygroma in a series of previable fetuses studied by Kalousek and Seller (1987). The authors found, furthermore, that 45,X Turner syndrome lethal in the fetal period showed a constant association of 3 defects, posterior cervical cystic hygroma, generalized subcutaneous edema, and preductal aortic coarctation. </p><p>Evans et al. (1991) found a large cutaneous lymphangioma of the right cheek and amegakaryocytic thrombocytopenia in a male infant with Noonan syndrome. </p><p>Donnenfeld et al. (1991) presented a case of Noonan syndrome in which posterior nuchal cystic hygroma was diagnosed at 13 to 14 weeks of gestation by ultrasonography. The hygroma had regressed by the time of birth leaving nuchal skin fold redundancy and pterygium colli. </p><p>On the basis of studies of genital tract function in 11 adult males with Noonan syndrome, Elsawi et al. (1994) concluded that bilateral testicular maldescent was a main factor in contributing to impairment of fertility. Four of the 11 men had fathered children. </p><p>Lee et al. (1992) reviewed the ophthalmologic and orthoptic findings in 58 patients with Noonan syndrome. External features were hypertelorism (74%), downward sloping palpebral apertures (38%), epicanthal folds (39%), and ptosis (48%). Orthoptic examination revealed strabismus in 48%, refractive errors in 61%, amblyopia in 33%, and nystagmus in 9% of cases. Anterior segment changes, found in 63% of patients, included prominent corneal nerves (46%), anterior stromal dystrophy (4%), cataracts (8%), and panuveitis (2%). Fundal changes occurred in 20% of patients and included optic nerve head drusen, optic disc hypoplasia, colobomas, and myelinated nerve fiber layer. Lee et al. (1992) recommended early ophthalmic examination of children with Noonan syndrome. </p><p>Allanson et al. (1985) studied the changes in facial appearance with age. They pointed out that the manifestations may be subtle in adults. Ranke et al. (1988) analyzed the clinical features of 144 patients from 2 West German centers. The size at birth was normal in both sexes. In both males and females, the mean height followed along the 3rd percentile until puberty, but decreased transiently due to an approximately 2-year delay in onset of puberty. Final height approaches the lower limits of normal at the end of the second decade of life. The mean adult height was 162.5 cm in males and 152.7 cm in females, respectively. Allanson (1987) provided a useful review. The fetal primidone syndrome, occurring in the offspring of mothers taking this anticonvulsant, closely simulates the Noonan syndrome. </p><p>Baraitser and Patton (1986) reported 4 unrelated children (2 boys, 2 girls) with a Noonan-like syndrome associated with sparse hair as a conspicuous feature. See 115150. </p><p>Leichtman (1996) reported a family suggesting that cardiofaciocutaneous syndrome (CFC; 115150) is a variable expression of Noonan syndrome. He described a 4-year-old girl who had all of the manifestations of CFC syndrome (characteristic facial and cardiac anomalies, developmental delay, hypotrichosis, eczematic eruption with resistance to treatment), whose mother had typical characteristics of Noonan syndrome. Lorenzetti and Fryns (1996) reported a 13-year-old boy with Noonan syndrome and retinitis pigmentosa. Because similar eye defects are found in CFC syndrome, the authors suggested that CFC and Noonan syndromes might be variable manifestations of the same entity. However, Neri and Zollino (1996) noted distinctions between the patient reported by Lorenzetti and Fryns (1996) and CFC syndrome, and stated that similarity of eye defects is not enough to conclude that CFC and Noonan syndromes are the same condition. </p><p>Early feeding difficulties are common in Noonan syndrome but often go unrecognized. Shah et al. (1999) studied a consecutive series of children with Noonan syndrome whose diagnosis had been confirmed by a clinical geneticist. Sixteen had poor feeding (poor suck or refusal to take solids or liquids) and symptoms of gastrointestinal dysfunction (vomiting, constipation, abdominal pain, and bloating). All 16 had required nasogastric tube feeding. Seven of the 25 had foregut dysmotility and gastroesophageal reflux. In 4 of these, electrogastrography and antroduodenal manometry demonstrated immature gastric motility reminiscent of that of a preterm infant of 32 to 35 weeks' gestation. Other children had less severe forms of gastric dysmotility. The authors highlighted the importance of recognizing this common, treatable feature of Noonan syndrome. </p><p>Lemire (2002) described a father, son, and daughter with an apparently autosomal dominant disorder characterized by craniofacial anomalies, coarctation of the aorta, hypertrophic cardiomyopathy, and other structural heart defects with normal psychomotor development. Some clinical features such as webbed neck, low-set ears, low posterior hairline, and widely spaced nipples suggested Noonan syndrome. Alternatively, a previously unrecognized disorder was considered. The paternal age at the father's birth was 50 years. The father presented at age 13 years when postductal coarctation of the aorta was discovered during routine physical examination. Preoperative evaluation showed hypertrophied interventricular septum with pulmonic stenosis and bicuspid aortic valve in addition to the aortic coarctation. At age 22 years, echocardiogram showed marked systolic thickening of interventricular septum and posterior wall of the left ventricle and concentric left ventricular hypertrophy. He later developed atrial flutter and congestive heart failure. His son was recognized at birth to have 2 small ventricular septal defects, mildly hypoplastic aortic arch, and coarctation of the aorta. The coarctation was repaired at age 14 days and bilateral inguinal hernias at age 5 weeks. At age 9 months, he was found to have congestive heart failure due to a restrictive cardiomyopathy. At age 10 months, studies confirmed the presence of spongy myocardium with much impaired diastolic function. He died of early acute graft failure at age 14 months after heart transplantation. Autopsy showed restrictive cardiomyopathy with generalized myocardium hypertrophy. The daughter was found at birth to have a small ventricular septal defect, small patent ductus arteriosus, aneurysm of the atrial septum, and coarctation of the aorta. Cardiomyopathy was suspected on the basis of excessive thickening of the lower two-thirds of the interventricular septum and of the free wall of the right ventricle. Coarctation of the aorta was repaired surgically at age 19 days. At age 10.5 months, she was noted to have plagiocephaly, facial asymmetry with left side smaller than the right, webbed neck, asymmetric chest with widely spaced nipples, and edema of the dorsum of the feet. At age 2 years, bicuspid aortic valve and diffuse concentric hypertrophy of the left ventricle were noted. </p><p>Holder-Espinasse and Winter (2003) described a 6-year-old girl with clinical features of Noonan syndrome, short stature, and headache who was noted to have Arnold-Chiari malformation (207950) on MRI. They cited 3 previous reports of Noonan syndrome and Chiari malformation and/or syringomelia (Ball and Peiris, 1982; Gabrielli et al., 1990; Colli et al., 2001). Holder-Espinasse and Winter (2003) concluded that Chiari malformation should be considered part of the Noonan syndrome spectrum and that brain and cervical spine MRI should be required in patients with Noonan syndrome, particularly if headaches or neurologic symptoms are present. </p><p>For a comprehensive review of Turner syndrome, including clinical management, see Ranke and Saenger (2001). </p><p>Kondoh et al. (2003) described a transient leukemoid reaction and an apparently spontaneously regressing neuroblastoma in a 3-month-old Japanese patient with Noonan syndrome and a de novo missense mutation in the PTPN11 gene (176876.0007). </p><p>Noonan et al. (2003) reported their findings in 73 adults over 21 years of age with Noonan syndrome. In 30%, adult height was in the normal range between the 10th and 90th percentiles. More than half of the females and nearly 40% of males had an adult height below the third percentile. The presence or severity of heart disease was not a factor, and none of the adults with normal height had been treated with growth hormone. Serial measurements of height over many years through childhood to adulthood were available in only a few patients, but their pattern of growth suggested that catch up may occur in late adolescence. The possible benefit of growth hormone therapy could not be evaluated. </p><p>Croonen et al. (2008) evaluated ECG findings and cardiographic abnormalities in 84 patients with Noonan syndrome, 54 (67%) of whom were positive for a mutation in the PTPN11 gene. As reported previously, pulmonary stenosis was the most common cardiac abnormality, followed by atrial septal defect and hypertrophic cardiomyopathy. ECG showed at least 1 characteristic finding in 50% of cases, including left axis deviation in 38 (45%), small R waves in the left precordial leads in 20 (24%), and an abnormal Q wave in 5 (6%) Noonan patients; however, these ECG findings were not associated with a PTPN11 mutation or with a specific cardiac anomaly. </p><p>Among 40 Italian patients with Noonan syndrome, Ferrero et al. (2008) found short stature in 92%, congenital heart defect in 82.5%, isolated pulmonic stenosis in 60.6%, and hypertrophic obstructive cardiomyopathy in 12.2%. Prenatal anomalies were observed in 25% of cases, with polyhydramnios being the most common. PTPN11 mutations were detected in 11 sporadic patients and 1 family, totaling 12 (31.5%) of 38 cases. One patient without a detectable mutation had a Chiari I malformation with seizures. Another of the remaining patients had a mutation in the SOS1 gene. </p><p>Kruszka et al. (2017) reviewed clinical data and images of 125 patients diagnosed with Noonan syndrome, 37 of whom were clinically diagnosed (mutation not known) and 88 of whom carried mutations in Noonan-associated genes: 61 in PTPN11, 8 in RIT1, 7 in SOS1, 4 in RAF1, 2 in BRAF, and 1 in KRAS; in addition, 3 patients carried mutations in MAP2K1 (176872), 1 patient in MAP2K2 (601263), and 1 patient in the SHOC2 gene. The authors stated that NS was phenotypically similar across the different population groups, which were from 20 countries, with widely spaced eyes and low-set ears present in more than 80% of patients, short stature in more than 70%, and pulmonary stenosis in roughly 50% of patients. Only 2 features, ptosis and webbed neck, were statistically different between the groups, with ptosis being present in 63% of African patients versus 72% of Asian patients and 94% of Latin American patients, and webbed neck being present in 36% of Asian patients versus 57% of African patients and 69% of Latin American patients. Kruszka et al. (2017) also analyzed the usefulness of facial analysis technology in diagnosing NS, comparing 161 Caucasian, African, Asian, and Latin American NS patients with 161 gender- and age-matched controls. The sensitivity and specificity to discriminate between NS and controls was 0.88 and 0.89, respectively, when the entire cohort was evaluated concurrently. Test accuracy increased significantly when the cohort was analyzed by specific ethnic population, with sensitivities ranging from 0.94 to 0.96, and specificities from 0.90 to 0.98. However, the authors emphasized that facial analysis technology is a tool and not a substitute for clinical evaluation, since it does not consider other important features of NS such as webbed neck, chest deformities, and congenital heart disease. </p><p>Croonen et al. (2017) provided a detailed analysis of motor performance in daily life of 19 children with a phenotypic and genotypic diagnosis of Noonan syndrome (genetic diagnosis was not reported). The children ranged in age from 6 years to nearly 12 years old, with a mean age of 9.3 years. More than 60% of the parents reported that their children experienced pain, decreased muscle strength, reduced endurance, and/or clumsiness in daily functioning. Norm-referenced test results confirmed that motor performance, strength, and endurance were significantly impaired in the children, and decreased functional motor performance appeared to be related to decreased visual perception and reduced muscle strength. The authors noted the possibility of selection bias in the study, since of 29 patients invited to participate, 5 did not respond and 4 declined (1 had incomplete address data); the authors suggested that children without clinical complaints might be less likely to participate in research. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Other Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Giant Cell Lesions</em></strong></p><p>
Some patients with Noonan syndrome develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villonodular synovitis (PVNS) when occurring in the jaw or joints. Early reports described this as a separate disorder (Leszczynski et al., 1975; Lindenbaum and Hunt, 1977; Wagner et al., 1981); however, it is now considered part of the phenotypic spectrum of Noonan syndrome (Tartaglia et al., 2010). </p><p>Cohen et al. (1974) described a patient with short stature, ocular hypertelorism, prominent posteriorly angulated ears, short webbed neck, cubitus valgus, pulmonic stenosis, multiple lentigines, and giant cell lesions of both bone and soft tissue. Cohen (1982) presented a photographic montage of the patient. Cohen and Gorlin (1991) reviewed further known cases to a total of 14. Chuong et al. (1986) studied central giant cell lesions of the jaw in 17 patients and noted that 2 of these occurred in patients with Noonan syndrome. </p><p>Ucar et al. (1998) described a patient with Noonan syndrome and PVNS. As indicated by the photographs provided, the patient showed facies and sternal configuration typical of Noonan syndrome. Cubitus valgus, pulmonary valve stenosis, and patent foramen ovale, as well as cryptorchidism, were also present. A central giant cell granuloma was found originating from the lateral wall of the right maxillary sinus and caused the presenting complaint of proptosis of the right eye. (Giant cell granulomas in the head and neck region are called central when they occur in bone and peripheral when they occur in gingiva or alveolar mucosa.) In this family the patient's father also had the phenotype of Noonan syndrome, suggesting autosomal dominant inheritance. </p><p>Bertola et al. (2001) described a family with typical clinical findings of Noonan syndrome associated with giant cell lesions in maxilla and mandible. The authors raised the possibility that Noonan syndrome and Noonan syndrome-like disorder with multiple giant cell lesions might be allelic disorders. This was indeed demonstrated to be the case by Tartaglia et al. (2002), who found a mutation in the PTPN11 gene (176876.0004), which is the site of mutation in about half of unrelated individuals with sporadic or familial Noonan syndrome. </p><p><strong><em>Hematologic Abnormalities And Leukemia</em></strong></p><p>
Thrombocytopenia occurs in some cases of the Noonan syndrome (Goldstein, 1979). Partial deficiency of factor XI was described by Kitchens and Alexander (1983). Out of 9 patients with Noonan syndrome, de Haan et al. (1988) found 4 with partial deficiency of factor XI (30-65% of normal). They reviewed the other reports of bleeding tendency associated with thrombocytopenia or with abnormal platelet function. </p><p>Witt et al. (1988) described bleeding diathesis in 19 patients with Noonan syndrome. Several different defects were identified in the coagulation and platelet systems, occurring singly or in combination; for example, 2 patients had factor XI deficiency, 3 had presumptive von Willebrand disease, and 1 had thrombocytopenia. In 5 of the patients an unusually pungent odor of urine and sweat was noted by parents. One of these patients was reported by Humbert et al. (1970) as a case of trimethylaminuria (136131) and another patient was suspected of having this condition. Sharland et al. (1990) also described a variety of coagulation factor deficiencies. The most common abnormality was a partial factor XI deficiency in the heterozygote range, found in 21 of 31 patients. Of 72 patients studied (37 male, 35 female, mean age 11.4 years) by Sharland et al. (1992), 47 (65%) had a history of abnormal bruising or bleeding. In 29 patients (40%), prolonged activated partial thromboplastin time was found. In 36 patients (50%) specific abnormalities were found in the intrinsic pathway of coagulation, i.e., partial deficiency of factor XI:C, XII:C, and VIII:C. Multiple abnormalities among these 36 patients included combined deficiencies of factors XI and XII (4 patients), of factors XI and VIII (4 patients), and of factors VIII, XI, and XII (1 patient). In 5 families, similar coagulation-factor deficiencies were present in first-degree relatives. Sharland et al. (1992) suggested that because of the involvement of several factors, either singly or in combination, there are likely to be regulatory factors that control the intrinsic (contact activation) system; that these factors are under chromosomal genetic control; and that abnormalities of this regulation occur in Noonan syndrome. </p><p>Derbent et al. (2010) examined the hematologic profile of 30 patients with Noonan syndrome, of whom 11 (36.7%) had proven PTPN11 mutations. There were no statistically significant differences between the mutation-positive and mutation-negative groups with respect to any of the hematology results or the presence of moderate mental retardation, pulmonic stenosis, chest deformity, genitourinary anomalies, or sensorineural hearing loss. However, short stature and mild mental retardation were more common in PTPN11 carriers. Only 1 of the patients had a history of easy bruising; however, his hematologic and coagulation tests were normal. None of the other patients had clinical coagulation problems. Noonan syndrome patients had significantly lower values for platelet count, activity of factors XI, XII, and protein C (612283) compared to controls. Patient values for PT, aPTT, INR, and bleeding time were also statistically different from the corresponding control findings, but the absence of clinical problems rendered the tests diagnostically inconclusive. Two patients had low protein C activity (about 50% of normal), but neither had a thrombotic event or any complication during about 3 years of follow-up. Derbent et al. (2010) concluded that patients with Noonan syndrome should have a thorough coagulation evaluation, but complications related to coagulation are unlikely and extensive testing is unnecessary. </p><p>Juvenile myelomonocytic leukemia (JMML; 607785) has been observed in some cases of Noonan syndrome (Bader-Meunier et al., 1997; Fukuda et al., 1997; Choong et al., 1999). </p><p>Strullu et al. (2014) found that 36 (5.6%) of 641 NS1 patients with a confirmed germline PTPN11 mutation developed a myeloproliferative disorder (MPD in 16) or juvenile myelomonocytic leukemia (JMML in 20). Hematologic abnormalities most often appeared in the neonatal period, earlier than in patients with sporadic JMML. None of the MPD patients required chemotherapy, and all were alive at a median follow-up of 3 years. In contrast, 12 (60%) of those with JMML had life-threatening complications, and 10 of the 12 died soon after diagnosis. Almost all (11 of 12) patients with severe neonatal JMML were males. Some PTPN11 mutations were preferentially associated with myeloproliferation, particularly mutations in codon Asp61 or a T73I mutation (176876.0011). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Noonan syndrome is inherited in an autosomal dominant pattern (Tartaglia et al., 2010). </p><p>Wendt et al. (1986) reported a man with polyarticular pigmented villonodular synovitis who had an affected son and daughter. Dunlap et al. (1989) made reference to the fact that the father of one of his cases was affected with Noonan syndrome and PVNS. </p><p>Elalaoui et al. (2010) reported 2 sibs, born of unrelated Moroccan parents, with Noonan syndrome resulting from the same heterozygous mutation in the PTPN11 gene (176876.0003). Both had characteristic features of Noonan syndrome, including pulmonic stenosis and facial anomalies, but neither parent showed any signs of the disorder. Molecular analysis did not detect the mutation in multiple tissues of either parent, excluding somatic mosaicism. Both affected children inherited the same haplotypes from their mother and father, whereas their unaffected brother inherited distinct haplotypes. This suggested that a common somatic germ cell event in 1 of the parents was responsible for the mutation, likely the father as he was 45 years of age, but the parental origin could not be definitively determined. Elalaoui et al. (2010) suggested an empirical recurrence rate of less than 1% in this family. </p>
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<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Noonan syndrome has an estimated incidence of 1 in 1,000 to 2,500 live births (Tartaglia et al., 2001). </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>By means of a genomewide linkage analysis in a large Dutch kindred with autosomal dominant Noonan syndrome, Jamieson et al. (1994) localized the gene to chromosome 12; maximum lod = 4.04 at theta = 0.0. Linkage analysis using chromosome 12 markers in 20 smaller, 2-generation families gave a maximum lod of 2.89 at theta = 0.07, but haplotype analysis showed nonlinkage in 1 family. These data suggested that a gene for Noonan syndrome is located in the 12q22-qter region between markers D12S84 and D12S366. Clinical studies in this kindred were reported by van der Burgt et al. (1994). </p><p>Brady et al. (1997) further analyzed the 3-generation Dutch family studied by Jamieson et al. (1994) using newly isolated CA-repeat markers derived from the interval between D12S84 and D12S366. In this way they were able to reduce the localization to an interval bounded by markers D12S105 and NOS1 (163731), which has been mapped to 12q24.2-q24.31. </p><p>Legius et al. (1998) performed linkage analysis in a 4-generation Belgian family with Noonan syndrome in some individuals and CFC syndrome in others. Clinical and linkage data in this family indicated that the 2 syndromes result from variable expression of the same genetic defect. They found a maximum lod score of 4.43 at zero recombination for marker D12S84 in 12q24. A crossover in this pedigree narrowed the candidate gene region to a 5-cM interval between D12S84 and D12S1341. A remarkable feature of the family studied by Legius et al. (1998) was the presence of 3 dizygotic twins in the offspring of 2 affected females. A dizygotic twin pair was observed in the offspring of an affected female in the family in which linkage was studied by Jamieson et al. (1994). It is possible that an increased frequency of dizygotic twinning is associated with NS1/CFC linked to 12q24. The fragile X syndrome (300624) is another mendelian disorder with a possibly increased frequency of dizygotic twinning (Partington et al., 1996; Schwartz et al., 1994). </p><p><strong><em>Exclusion Studies</em></strong></p><p>
Using a number of probes at the neurofibromatosis type I locus in the study of 11 families with Noonan syndrome in 2 or 3 generations, Sharland et al. (1992) excluded proximal 17q as the location of the gene. Studying six 2-generation families with classic Noonan syndrome, Flintoff et al. (1993) could find no evidence of linkage of this disorder to NF1 on 17q or to NF2 (101000) on 22q. </p><p>In a study of candidate genes, Ion et al. (2000) excluded the genes EPS8 (600206) and DCN (125255) from the critical region by FISH analysis. They also excluded the MYL2 (160781) and RPL6 (603703) genes by mutation analysis. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Cytogenetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Robin et al. (1995) described 6 patients with Noonan syndrome who underwent molecular evaluation for submicroscopic deletion of chromosome 22q11. None of these patients presented with conotruncal heart defects. Evidence for 22q11 hemizygosity was demonstrated in only 1 patient. This patient had Noonan-like manifestations without clinical manifestations of DiGeorge (188400) or velocardiofacial (192430) syndromes. Digilio et al. (1996) studied 4 patients with Noonan syndrome and tetralogy of Fallot. Chromosome analysis was normal in all 4 patients. DNA analysis showed no hemizygosity for the 22q11 region in any of the patients. </p><p><strong><em>Duplication of Chromosome 12q24.13</em></strong></p><p>
Shchelochkov et al. (2008) described a 3-year-old girl with clinical features consistent with Noonan syndrome. She presented with postnatal-onset failure to thrive, microcephaly, velopalatal incompetence, pectus excavatum, aortic coarctation, and atrial and ventricular septal defects. Facial features included ptosis, hypertelorism, epicanthal folds, cupped simple ears, and wide mouth with downturned corners. Speech and fine and gross motor development were at the level of a 12- to 18-month-old child, atypical for a child with Noonan syndrome. Array CGH showed an interstitial 10-Mb duplication, 12q24.11-q24.23, that includes the genes PTPN11 (176876), TBX5 (601620), and TBX3 (601621). This was confirmed by FISH analysis and chromosome analysis. Sequencing of PTPN11, KRAS (190070), SOS1 (182530), and the coding region of RAF1 (164760) did not reveal any pathogenic mutations. Shchelochkov et al. (2008) proposed that duplications of the region containing PTPN11 may result in a Noonan syndrome phenotype and may account for the basis of Noonan syndrome in some of the 15 to 30% of patients for whom no mutations can be detected by sequencing of components of the RAS/MAPK signaling pathway. </p><p>Graham et al. (2009) reported another patient with Noonan syndrome caused by an 8.98-Mb duplication on chromosome 12q24.13 encompassing the PTPN11 gene, which was confirmed by FISH analysis. However, duplications were not observed in a screening of more than 250 Noonan syndrome cases without mutations in known disease-causing genes. Changes affecting the 3-prime untranslated region of the PTPN11 transcript were also not found in 36 patients without disease-causing mutations. In contrast to Shchelochkov et al. (2008), Graham et al. (2009) concluded that duplication of PTPN11 represents an uncommon cause of Noonan syndrome. However, the rare observation of NS in individuals with duplications involving the PTPN11 locus suggested that increased dosage of this gene may have dysregulating effects on intracellular signaling. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Butler et al. (2000) used metacarpophalangeal pattern profile (MCPP) analysis to evaluate 15 individuals with Noonan syndrome. Discriminant analysis resulted in the correct classification of 93% of Noonan syndrome patients based on 2 MCPP variables (metacarpal 1 and middle phalanx 3). The authors suggested that MCPP analysis may be useful as a diagnostic tool in screening subjects for Noonan syndrome. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>MacFarlane et al. (2001) reported growth data from the first 3 years of a multicenter study examining the efficacy and safety of recombinant human GH in 23 children with Noonan syndrome. Sixteen male and 7 female patients (aged 9.3 +/- 2.6 years at onset of GH therapy, mean +/- SD; range 4.8-13.7) were each assessed at 1, 2, and 3 years after starting treatment. Comparisons were made with a group of 8 subjects (6 males and 2 females, aged 9.0 +/- 4.1 years; range 4.1-14.8) with Noonan syndrome and not treated with recombinant GH, and measured over the same period. All treated subjects underwent annual cardiac assessment. Height SD score increased from -2.7 +/- 0.4 at the start of GH therapy to -1.9 +/- 0.9 three years later. This corresponded to an increase in height from 116.1 +/- 13.2 to 137.3 +/- 14.0 cm. Height velocity increased from 4.4 +/- 1.7 cm/year in the year before treatment to 8.4 +/- 1.7, 6.2 +/- 1.7, and 5.8 +/- 1.8 during the first, second, and third years of GH treatment, respectively. Height acceleration was not significant during the second or third years when pubertal subjects were excluded. The authors concluded that the increase in growth rate in Noonan syndrome resulting from 1 year of GH therapy seems to be maintained during the second year, although height velocity shows a less significant increase over pretherapy values. Possible abnormal anabolic effects of recombinant GH on myocardial thickness were not confirmed, and no treated patient developed features of hypertrophic cardiomyopathy. </p><p>Kirk et al. (2001) presented data on 66 Noonan syndrome patients (54 males) treated with growth hormone. Treatment improved height velocity in the short term, but longer-term therapy resulted in a waning of effect. The study indicated that final height is not substantially improved in most patients. </p><p>From a study of 14 children with Noonan syndrome who were treated with human growth hormone, half of whom had a missense mutation in the PTPN11 gene, Ferreira et al. (2005) found that those with a PTPN11 mutation had a lower increase in IGF-I (147440) levels during treatment and a significantly lower gain in height SD score after 3 years of treatment compared with those without mutations. </p><p>Binder et al. (2005) compared GH secretion and IGF-I/IGFBP3 (146732) levels of the PTPN11 mutation-positive (mut+ group) versus the mutation-negative individuals (mut- group). IGF-I and IGFBP3 levels were significantly lower in the mut+ group. In contrast, GH levels showed a tendency to be higher in the mut+ group during spontaneous secretion at night and arginine stimulation. The mean change in height SDS after 1 year of rhGH therapy was +0.66 + 0.21 in the mut+ group (8 individuals), but +1.26 + 0.36 in the mut- group (3 individuals; p = 0.007). The authors concluded that PTPN11 mutations in Noonan syndrome cause mild GH resistance by a post-receptor signaling defect, which seems to be partially compensated for by elevated GH secretion. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In more than 50% of patients with Noonan syndrome, Tartaglia et al. (2001) identified mutations in the PTPN11 gene (see, e.g., 176876.0001-176876.0003). All the PTPN11 missense mutations were clustered in the interacting portions of the amino N-SH2 (Src homology 2) domain and the phosphotyrosine phosphatase (PTP) domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of 2 N-SH2 mutants indicated that in these cases there may be a significant shift of the equilibrium favoring the active conformation. The findings suggested that gain-of-function changes resulting in excessive SHP2 activity underlie the pathogenesis of Noonan syndrome. </p><p>After germline mutations in PTPN11 (176876) were demonstrated in the Noonan syndrome, Tartaglia et al. (2003) investigated defects in PTPN11 in myeloid disorders including cases of juvenile myelomonocytic leukemia (JMML; 607785) in children with Noonan syndrome. Specific mutations in PTPN11 associated with isolated JMML occurred as somatic changes and had never been observed as germline defects, leading Tartaglia et al. (2003) to speculate that these molecular defects are stronger and associated with embryonic lethality. Conversely, most mutations in PTPN11 associated with Noonan syndrome, which were sufficient to perturb developmental processes, were not fully leukemogenic, suggesting a milder gain-of-function effect. </p><p>In 10 affected members from a large 4-generation Belgian family with Noonan syndrome and some features suggestive of CFC syndrome, Schollen et al. (2003) identified a missense mutation in the PTPN11 gene (176876.0018). The mutation was not found in 7 unaffected relatives or 3 spouses. </p><p>Musante et al. (2003) screened the PTPN11 gene for mutations in 96 familial or sporadic Noonan syndrome patients and identified 15 missense mutations in 32 patients (33%). No obvious clinical differences were detected between subgroups of patients with mutations in different PTPN11 domains. Analysis of the clinical features of their patients revealed that several patients with facial abnormalities thought to be pathognomonic for NS did not have a mutation in the PTPN11 gene. Widely varying phenotypes among the 64 patients without PTPN11 mutations indicated further genetic heterogeneity. Musante et al. (2003) also screened 5 sporadic patients with CFC syndrome and found no mutations in the PTPN11 gene. </p><p>Bertola et al. (2004) described a young woman with clinical features of Noonan syndrome but with some characteristics of CFC as well, including prominent ectodermal involvement (sparse and very coarse hair, and sparse eyebrows and eyelashes), developmental delay, and mental retardation. They identified a T411M mutation in the PTPN11 gene (176876.0019); the same mutation was found in her mother and older sister, not initially considered to be affected but who had subtle clinical findings compatible with the diagnosis of Noonan syndrome. The mother had 5 miscarriages, 2 of them twinning pregnancies. Bertola et al. (2004) suggested that all first-degree relatives of patients with confirmed Noonan syndrome, even those with no signs of the disorder, be screened for PTPN11 mutations in order to provide accurate assessments of recurrence risk. </p><p>Yoshida et al. (2004) reported PTPN11 mutation analysis and clinical assessment in 45 Japanese patients with Noonan syndrome. Sequence analysis of the coding exons 1 through 15 of PTPN11 revealed a novel 3-bp deletion (176876.0024) and 10 recurrent missense mutations in 18 patients. The authors estimated that PTPN11 mutations account for approximately 40% of Japanese Noonan syndrome patients. </p><p>Jongmans et al. (2005) performed mutation analysis of the PTPN11 gene in 170 Noonan syndrome patients and identified a mutation in 76 (45%) of them. They described the distribution of these mutations, as well as genotype-phenotype relationships. The usefulness of the Noonan syndrome scoring system developed by van der Burgt et al. (1994) was demonstrated; when physicians based their diagnosis on the scoring system, the percentage of mutation-positive patients was higher. </p><p>Mutations in the KRAS gene (190070) can also cause Noonan syndrome (NS3; 609942). One patient with a T58I mutation (190070.0011) also had a myeloproliferative disorder resembling juvenile myelomonocytic leukemia (JMML) (Schubbert et al., 2006). </p><p>Tartaglia et al. (2006) proposed a model that splits NS- and leukemia-associated PTPN11 mutations in the 2 major classes of activating lesions with differential perturbing effects on development and hematopoiesis. The results documented a strict correlation between the identity of the lesion and disease, and demonstrated that NS-causative mutations have less potency for promoting SHP2 gain of function than do leukemia-associated ones. </p><p>Roberts et al. (2007) and Tartaglia et al. (2007) investigated sizable groups of patients with Noonan syndrome but no mutation in PTPN11, which accounts for approximately 50% of such cases. They found that many had missense mutations in the SOS1 gene (182530) and that the SOS1-positive case patients represented approximately 20% of cases of Noonan syndrome. The phenotype of Noonan syndrome caused by SOS1 mutation, while within the Noonan syndrome spectrum, appears to be distinctive (see NS4, 610733). </p><p>Kontaridis et al. (2006) examined the enzymatic properties of mutations in PTPN11 causing LEOPARD syndrome and found that, in contrast to the activating mutations that cause Noonan syndrome and neoplasia, LEOPARD syndrome mutants are catalytically defective and act as dominant-negative mutations that interfere with growth factor/ERK-MAPK (see 176948)-mediated signaling. Kontaridis et al. (2006) concluded that the pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation. </p><p>In a prospective multicenter study in 35 Noonan syndrome patients with growth retardation, Limal et al. (2006) compared growth and hormonal growth factors before and during recombinant human GH therapy in patients with and without PTPN11 mutations. Sequencing of the PTPN11 coding sequence revealed 12 different heterozygous missense mutations in 20 of the 35 patients (57%). The results showed that among NS1 patients with short stature, some neonates had birth length less than -2 SDS. Growth of patients with mutations was reduced and responded less efficiently to GH than that of patients without mutations. Limal et al. (2006) concluded that the association of low IGF1 (147440) and insulin-like growth factor-binding protein, acid-labile subunit (IGFALS; 601489) with normal IGFBP3 (146732) levels could explain growth impairment of children with mutations and could suggest a GH resistance by a late postreceptor signaling defect. </p><p>In a case of fetal demise at 12 weeks' gestation, Becker et al. (2007) identified compound heterozygosity for the N308S (176876.0004) and Y63C (176876.0008) mutations in the PTPN11 gene. The mother and father, who exhibited facial features of Noonan syndrome and had both undergone surgical correction of pulmonary valve stenosis, were heterozygous for N308S and Y63C, respectively. A second pregnancy resulted in the birth of a boy with Noonan syndrome carrying the paternal Y63C mutation. </p><p>Ferrero et al. (2008) identified PTPN11 mutations in 31.5% of 37 sporadic patients and 1 family with a clinical diagnosis of Noonan syndrome. One of the remaining patients had a mutation in the SOS1 gene. </p><p><strong><em>Cooccurrence of NF1 and PTPN11 Mutations</em></strong></p><p>
Bertola et al. (2005) provided molecular evidence of the concurrence of neurofibromatosis and Noonan syndrome in a patient with a de novo missense mutation in the NF1 gene (613113.0043) and a mutation in the PTPN11 gene (176876.0023) inherited from her father. The proposita was noted to have cafe-au-lait spots at birth. Valvar and infundibular pulmonary stenosis and aortic coarctation were diagnosed at 20 months of age and surgically corrected at 3 years of age. As illustrated, the patient had marked hypertelorism and proptosis as well as freckling and cafe-au-lait spots. Lisch nodules were present. At the age of 8 years, a pilocytic astrocytoma in the suprasellar region involving the optic chiasm (first presenting symptomatically at 2 years of age), was partially resected. The father, who was diagnosed with Noonan syndrome, had downslanting palpebral fissures and prominent nasal labial folds. He was of short stature (159 cm) and had pectus excavatum. Electrocardiogram showed left-anterior hemiblock and complete right bundle branch block. </p><p>Thiel et al. (2009) reported a patient with features of both neurofibromatosis I and Noonan syndrome who was compound heterozygous for mutations in both the NF1 (162200.0044) and PTPN11 (176876.0027) genes. The PTPN11 mutation occurred de novo, and the NF1 mutation was inherited from the patient's mother, who had mild features of neurofibromatosis I, including the absence of optic gliomas. The proband developed bilateral optic gliomas before age 2 years, suggesting an additive effect of the 2 mutations on the Ras pathway. The proband also had short stature, delayed development, sternal abnormalities, and valvular pulmonary stenosis. </p><p><strong><em>Reviews</em></strong></p><p>
Tartaglia et al. (2010) provided a detailed review of the clinical and molecular features of Noonan syndrome. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Nomenclature</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Dunlap et al. (1989) referred to Noonan syndrome with multiple giant cells lesions as the Noonan syndrome-cherubism association. Cohen and Gorlin (1991) recommended that it not be called Noonan syndrome, pigmented villonodular synovitis, central giant cell granuloma, or cherubism, because each of these is a specific diagnostic entity sui generis and the use of such terms results in nosologic blinders that tend to limit the workup of patients. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In a mouse model of Noonan syndrome in which transgenic mice carried a cardiomyocyte-specific gain-of-function Q79R mutation in the PTPN11 gene (176876.0018), Nakamura et al. (2007) demonstrated that the developmental effects of Q79R cardiac expression are stage-specific and that ablation of subsequent ERK1/2 (see 176948) activation prevented the development of cardiac abnormalities. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Cole (1980) pointed out that the blacksmith in the famous painting 'Among Those Left' by Ivan Le Lorraine Albright appears to have had Noonan syndrome. The contour of the sternum, the low-set ears, and the short stature are suggestive. Genetic confirmation was provided by studies of a great-grandson with general features of the Noonan syndrome and cardiac abnormalities consistent with that diagnosis (pulmonic stenosis and regurgitation, abnormal architecture of the left ventricular musculature). Opitz and Pallister (1979) reproduced the first published illustration of the Noonan syndrome by Kobylinski (1883), and Opitz (1985) republished the photograph of Rickey E., the first patient with 'her' syndrome studied at the State University of Iowa by Jacqueline A. Noonan. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Alslev and Reinwein (1958); Char et al. (1972); Duncan et al. (1981);
Fisher et al. (1982); Golabi et al. (1985); Hall et al. (1982); Levy
et al. (1970); Linde et al. (1973); Miller and Motulsky (1978); Nora
et al. (1974); Pierini and Pierini (1979); Sharland et al. (1992);
Wiedemann (1991); Witt et al. (1985)
</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">
Allanson, J. E., Hall, J. G., Hughes, H. E., Preus, M., Witt, R. D.
<strong>Noonan syndrome: the changing phenotype.</strong>
Am. J. Med. Genet. 21: 507-514, 1985.
[PubMed: 4025385]
[Full Text: https://doi.org/10.1002/ajmg.1320210313]
</p>
</li>
<li>
<p class="mim-text-font">
Allanson, J. E.
<strong>Noonan syndrome.</strong>
J. Med. Genet. 24: 9-13, 1987.
[PubMed: 3543368]
[Full Text: https://doi.org/10.1136/jmg.24.1.9]
</p>
</li>
<li>
<p class="mim-text-font">
Alslev, J., Reinwein, H.
<strong>Ueber das familiaere Vorkommen des sogenannten Ullrich-Turner-Syndromes und das Vorhandensein eines pterygium colli, eines Kryptorchismus und des Meige-Syndromes bei zwei Bruedern mit kongenitalen Vitien.</strong>
Dtsch. Med. Wschr. 83: 601-604, 1958.
[PubMed: 13537698]
[Full Text: https://doi.org/10.1055/s-0028-1114324]
</p>
</li>
<li>
<p class="mim-text-font">
Bader-Meunier, B., Tchernia, G., Mielot, F., Fontaine, J. L., Thomas, C., Lyonnet, S., Lavergne, J. M., Dommergues, J. P.
<strong>Occurrence of myeloproliferative disorder in patients with Noonan syndrome.</strong>
J. Pediat. 130: 885-889, 1997.
[PubMed: 9202609]
[Full Text: https://doi.org/10.1016/s0022-3476(97)70273-7]
</p>
</li>
<li>
<p class="mim-text-font">
Baird, P. A., De Jong, B. P.
<strong>Noonan&#x27;s syndrome (XX and XY Turner phenotype) in three generations of a family.</strong>
J. Pediat. 80: 110-114, 1972.
[PubMed: 5016336]
[Full Text: https://doi.org/10.1016/s0022-3476(72)80466-9]
</p>
</li>
<li>
<p class="mim-text-font">
Ball, M. J., Peiris, A.
<strong>Chiari (type 1) malformation and syringomelia in a patient with Noonan&#x27;s syndrome. (Letter)</strong>
J. Neurol. Neurosurg. Psychiat. 45: 753-754, 1982.
[PubMed: 7131003]
[Full Text: https://doi.org/10.1136/jnnp.45.8.753]
</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">
Becker, K., Hughes, H., Howard, K., Armstrong, M., Roberts, D., Lazda, E. J., Short, J. P., Shaw, A., Patton, M. A., Tartaglia, M.
<strong>Early fetal death associated with compound heterozygosity for Noonan syndrome-causative PTPN11 mutations.</strong>
Am. J. Med. Genet. 143A: 1249-1252, 2007.
[PubMed: 17497712]
[Full Text: https://doi.org/10.1002/ajmg.a.31738]
</p>
</li>
<li>
<p class="mim-text-font">
Bertola, D. R., Kim, C. A., Pereira, A. C., Mota, G. F. A., Krieger, J. E., Vieira, I. C., Valente, M., Loreto, M. R., Magalhaes, R. P., Gonzalez, C. H.
<strong>Are Noonan syndrome and Noonan-like/multiple giant cell lesion syndrome distinct entities?</strong>
Am. J. Med. Genet. 98: 230-234, 2001.
[PubMed: 11169560]
[Full Text: https://doi.org/10.1002/1096-8628(20010122)98:3&lt;230::aid-ajmg1080&gt;3.0.co;2-k]
</p>
</li>
<li>
<p class="mim-text-font">
Bertola, D. R., Pereira, A. C., de Oliveira, P. S. L., Kim, C. A., Krieger, J. E.
<strong>Clinical variability in a Noonan syndrome family with a new PTPN11 gene mutation.</strong>
Am. J. Med. Genet. 130A: 378-383, 2004.
[PubMed: 15384080]
[Full Text: https://doi.org/10.1002/ajmg.a.30270]
</p>
</li>
<li>
<p class="mim-text-font">
Bertola, D. R., Pereira, A. C., Passetti, F., de Oliveira, P. S. L., Messiaen, L., Gelb, B. D., Kim, C. A., Krieger, J. E.
<strong>Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient.</strong>
Am. J. Med. Genet. 136A: 242-245, 2005.
[PubMed: 15948193]
[Full Text: https://doi.org/10.1002/ajmg.a.30813]
</p>
</li>
<li>
<p class="mim-text-font">
Binder, G., Neuer, K., Ranke, M. B., Wittekindt, N. E.
<strong>PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome.</strong>
J. Clin. Endocr. Metab. 90: 5377-5381, 2005.
[PubMed: 15985475]
[Full Text: https://doi.org/10.1210/jc.2005-0995]
</p>
</li>
<li>
<p class="mim-text-font">
Bolton, M. R., Pugh, D. M., Mattioli, L. F., Dunn, M. I., Schimke, R. N.
<strong>The Noonan syndrome: a family study.</strong>
Ann. Intern. Med. 80: 626-629, 1974.
[PubMed: 4823815]
[Full Text: https://doi.org/10.7326/0003-4819-80-5-626]
</p>
</li>
<li>
<p class="mim-text-font">
Brady, A. F., Jamieson, C. R., van der Burgt, I., Crosby, A., van Reen, M., Kremer, H., Mariman, E., Patton, M. A., Jeffery, S.
<strong>Further delineation of the critical region for Noonan syndrome on the long arm of chromosome 12.</strong>
Europ. J. Hum. Genet. 5: 336-337, 1997.
[PubMed: 9412792]
</p>
</li>
<li>
<p class="mim-text-font">
Butler, M. G., Kumar, R., Davis, M. F., Gale, D. D., Dahir, G. A., Meaney, F. J.
<strong>Metacarpophalangeal pattern profile analysis in Noonan syndrome.</strong>
Am. J. Med. Genet. 92: 128-131, 2000.
[PubMed: 10797437]
</p>
</li>
<li>
<p class="mim-text-font">
Celermajer, J. M., Bowdler, J. D., Cohen, D. H.
<strong>Pulmonary stenosis in patients with the Turner phenotype in the male.</strong>
Am. J. Dis. Child. 116: 351-358, 1968.
[PubMed: 4301561]
[Full Text: https://doi.org/10.1001/archpedi.1968.02100020355002]
</p>
</li>
<li>
<p class="mim-text-font">
Char, F., Rodriquez-Fernandez, H. L., Scott, C. I., Jr., Borgaonkar, D. S., Bell, B. B., Rowe, R. D.
<strong>The Noonan syndrome--a clinical study of forty-five cases.</strong>
Birth Defects Orig. Art. Ser. VIII(5): 110-118, 1972.
</p>
</li>
<li>
<p class="mim-text-font">
Choong, K., Freedman, M. H., Chitayat, D., Kelly, E. N., Taylor, G., Zipursky, A.
<strong>Juvenile myelomonocytic leukemia and Noonan syndrome.</strong>
J. Pediat. Hemat. Oncol. 21: 523-527, 1999.
[PubMed: 10598665]
</p>
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<li>
<p class="mim-text-font">
Chuong, R., Kaban, L. B., Kozakewich, H., Perez-Atayde, A.
<strong>Central giant cell lesions of the jaws: a clinicopathologic study.</strong>
J. Oral Maxillofac. Surg. 44: 708-713, 1986.
[PubMed: 3462363]
[Full Text: https://doi.org/10.1016/0278-2391(86)90040-6]
</p>
</li>
<li>
<p class="mim-text-font">
Cohen, M. M., Jr., Gorlin, R. J.
<strong>Noonan-like/multiple giant cell lesion syndrome.</strong>
Am. J. Med. Genet. 40: 159-166, 1991.
[PubMed: 1897569]
[Full Text: https://doi.org/10.1002/ajmg.1320400208]
</p>
</li>
<li>
<p class="mim-text-font">
Cohen, M. M., Jr., Ruvalcaba, R. H. A., Graham, C. B., Harrison, M. T., Morgan, A. F.
<strong>A new syndrome, and hyperparathyroidism.</strong>
Synd. Ident. 2: 14-17, 1974.
</p>
</li>
<li>
<p class="mim-text-font">
Cohen, M. M., Jr.
<strong>The Child with Multiple Birth Defects.</strong>
New York: Raven Press (pub.) 1982. Pp. 78-85.
</p>
</li>
<li>
<p class="mim-text-font">
Cole, R. B.
<strong>Noonan&#x27;s syndrome: a historical perspective.</strong>
Pediatrics 66: 468-469, 1980.
[PubMed: 6999448]
</p>
</li>
<li>
<p class="mim-text-font">
Colli, R., Colombo, P., Russo, F., Sterpa, A.
<strong>Malformazione di Arnold Chiari tipo 1 in soggetto con sindrome di Noonan.</strong>
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[PubMed: 11486425]
</p>
</li>
<li>
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Contributors:
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<span class="mim-text-font">
Marla J. F. O&#x27;Neill - updated : 10/13/2017<br>Cassandra L. Kniffin - updated : 11/3/2015<br>Cassandra L. Kniffin - updated : 3/19/2012<br>Cassandra L. Kniffin - updated : 10/26/2010<br>Cassandra L. Kniffin - updated : 10/14/2010<br>Marla J. F. O&#x27;Neill - updated : 10/9/2009<br>Cassandra L. Kniffin - updated : 6/18/2009<br>Kelly A. Przylepa - updated : 2/2/2009<br>Marla J. F. O&#x27;Neill - updated : 4/24/2008<br>Marla J. F. O&#x27;Neill - updated : 2/1/2008<br>Marla J. F. O&#x27;Neill - updated : 12/21/2007<br>Marla J. F. O&#x27;Neill - updated : 10/24/2007<br>John A. Phillips, III - updated : 5/31/2007<br>John A. Phillips, III - updated : 4/18/2007<br>John A. Phillips, III - updated : 4/18/2007<br>Marla J. F. O&#x27;Neill - updated : 3/9/2007<br>Victor A. McKusick - updated : 1/30/2007<br>John A. Phillips, III - updated : 11/17/2006<br>Victor A. McKusick - updated : 5/4/2006<br>Victor A. McKusick - updated : 2/24/2006<br>Victor A. McKusick - updated : 4/14/2005<br>Marla J. F. O&#x27;Neill - updated : 1/4/2005<br>Jane Kelly - updated : 11/9/2004<br>Marla J. F. O&#x27;Neill - updated : 5/12/2004<br>Marla J. F. O&#x27;Neill - updated : 4/2/2004<br>Natalie E. Krasikov - updated : 3/29/2004<br>Siobhan M. Dolan - updated : 2/19/2004<br>Victor A. McKusick - updated : 1/14/2004<br>Victor A. McKusick - updated : 5/15/2003<br>Victor A. McKusick - updated : 5/13/2003<br>Cassandra L. Kniffin - updated : 1/9/2003<br>Victor A. McKusick - updated : 11/27/2002<br>Victor A. McKusick - updated : 11/12/2001<br>Victor A. McKusick - updated : 8/6/2001<br>John A. Phillips, III - updated : 7/10/2001<br>Michael J. Wright - updated : 5/21/2001<br>Sonja A. Rasmussen - updated : 10/12/2000<br>Paul Brennan - updated : 4/10/2000<br>Victor A. McKusick - updated : 4/30/1998<br>Victor A. McKusick - updated : 12/19/1997<br>Iosif W. Lurie - updated : 1/8/1997<br>Iosif W. Lurie - updated : 9/12/1996
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Creation Date:
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<span class="mim-text-font">
Victor A. McKusick : 6/2/1986
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Edit History:
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