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<title>
Entry
- #610954 - PITT-HOPKINS SYNDROME; PTHS
- OMIM
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<span class="h4">#610954</span>
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<a href="/clinicalSynopsis/610954"><strong>Clinical Synopsis</strong></a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=PITT-HOPKINS SYNDROME" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0060488" 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/610954" 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:0060488" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 702344008<br />
<strong>ORPHA:</strong> 2896<br />
<strong>DO:</strong> 0060488<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>
610954
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
PITT-HOPKINS SYNDROME; PTHS
</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">
ENCEPHALOPATHY, SEVERE EPILEPTIC, WITH AUTONOMIC DYSFUNCTION<br />
MENTAL RETARDATION, SYNDROMAL, WITH INTERMITTENT HYPERVENTILATION
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/18/199?start=-3&limit=10&highlight=199">
18q21.2
</a>
</span>
</td>
<td>
<span class="mim-font">
Pitt-Hopkins syndrome
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610954"> 610954 </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">
TCF4
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602272"> 602272 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/610954" 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>
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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>
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<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/610954" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/610954" 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> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Head </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Microcephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1148757008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1148757008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/742.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">742.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551563&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551563</a>, <a href="https://bioportal.bioontology.org/search?q=C0025958&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025958</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Microcephaly-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Coarse face <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845847&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845847</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000280</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000280</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=cda94218d725bd8a9c75ca88c2113224" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Face,Coarse-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=cda94218d725bd8a9c75ca88c2113224&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Bitemporal narrowing <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000341" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000341</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000341" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000341</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=130363281c65526c396a969f71815381" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Forehead,Narrow-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=130363281c65526c396a969f71815381&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Square forehead <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2673741&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2673741</a>]</span><br /> -
Protruding lower face <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674469&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674469</a>]</span><br /> -
High cheekbones <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674470&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674470</a>]</span><br /> -
Full cheeks <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866231&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866231</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000293" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000293</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000293" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000293</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=85459d10e5df48479ec4a2ec6cfc0455" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Cheeks,Full-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=85459d10e5df48479ec4a2ec6cfc0455&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Short philtrum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861324&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861324</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000322</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000322</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=16ecf2e0f23dddf7b8b7cf447ceb827b" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Philtrum,Short-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=16ecf2e0f23dddf7b8b7cf447ceb827b&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">
- Cup-shaped ears <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845447&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845447</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000378" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000378</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000378" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000378</a>]</span><br /> -
Fleshy ears <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674471&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674471</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">
- Deep-set eyes <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246923005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246923005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423224&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423224</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000490" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000490</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000490" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000490</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=08eb099548b91270db09ad79e8e75da3" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Eye,Deeply_Set-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=08eb099548b91270db09ad79e8e75da3&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 /> -
Strabismus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22066006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22066006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.40</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038379&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038379</a>, <a href="https://bioportal.bioontology.org/search?q=C2020541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2020541</a>, <a href="https://bioportal.bioontology.org/search?q=C1423541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1423541</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000486" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000486</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000486" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000486</a>]</span><br /> -
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 /> -
Astigmatism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/82649003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">82649003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H52.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H52.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H52.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H52.20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/367.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">367.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/367.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">367.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004106&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004106</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000483" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000483</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000483" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000483</a>]</span><br /> -
Upslanting palpebral fissures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246799009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246799009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423109&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423109</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000582" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000582</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000582" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000582</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Nose </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Broad nasal bridge <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249321001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249321001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849367&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849367</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000431" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000431</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000431" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000431</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=3f6587f50506c9d70db0628b3fa5f2c5" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Nasal_Bridge,Wide-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=3f6587f50506c9d70db0628b3fa5f2c5&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 /> -
Beaked nasal bridge <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674472&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674472</a>]</span><br /> -
Downturned, pointed nasal tip <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674473&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674473</a>]</span><br /> -
Flaring nostrils <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248568003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248568003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/21558008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">21558008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0277873&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0277873</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030863" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030863</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000454" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000454</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">
- Wide open mouth <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674474&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674474</a>]</span><br /> -
Cupid's bow upper lip <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850629&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850629</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002263</a>]</span><br /> -
Thick, fleshy lips <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674475&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674475</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Teeth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Widely spaced teeth <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844813&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844813</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000687" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000687</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000687" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000687</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=5df0e44305e6ff6a9784b3b2408e902a" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Teeth,Widely_Spaced-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=5df0e44305e6ff6a9784b3b2408e902a&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Neck </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Short neck <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95427009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95427009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0521525&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0521525</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000470" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000470</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000470" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000470</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=5edf45ce6835f32360d28d26249e2531" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Neck,Short-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=5edf45ce6835f32360d28d26249e2531&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Abnormal breathing patterns <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806247&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806247</a>]</span><br /> -
Intermittent breathing <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3808077&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3808077</a>]</span><br /> -
Hyperventilation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/68978004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">68978004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R06.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R06.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/786.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">786.01</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020578&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020578</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002883" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002883</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002883" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002883</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Constipation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14760008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14760008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/564.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/564.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009806&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009806</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span><br /> -
Gastroesophageal reflux <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/235595009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">235595009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/722884003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">722884003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/698065002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">698065002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K21</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K21.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K21.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/530.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">530.81</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3813607&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3813607</a>, <a href="https://bioportal.bioontology.org/search?q=C4317146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4317146</a>, <a href="https://bioportal.bioontology.org/search?q=C0017168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017168</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002020</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002020</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> External Genitalia (Male) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Small penis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/34911001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">34911001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/276333003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">276333003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q55.62" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q55.62</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/752.64" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">752.64</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240701&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240701</a>, <a href="https://bioportal.bioontology.org/search?q=C4551492&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551492</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030260</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000054" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000054</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000054" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000054</a>]</span><br />
</span>
</div>
</div>
<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 />
</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> Hands </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Small, slender palms <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277783&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277783</a>]</span><br /> -
Clubbing of the fingers <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30760008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30760008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R68.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R68.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009080&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009080</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100759" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100759</a>]</span><br /> -
Tapered fingers <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249768009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249768009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0426886&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0426886</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001182" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001182</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001182" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001182</a>]</span><br /> -
Simian crease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248409006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248409006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424731&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424731</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000954" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000954</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000954" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000954</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 /> -
Fetal pads <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277784&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277784</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Feet </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Slender feet <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/299464006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">299464006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0576227&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0576227</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001786" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001786</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001786" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001786</a>]</span><br /> -
Pes planus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/23407003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">23407003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/203534009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">203534009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/53226007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">53226007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q66.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q66.5</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M21.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M21.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/754.61" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.61</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/734" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">734</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0016202&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0016202</a>, <a href="https://bioportal.bioontology.org/search?q=C0392477&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0392477</a>, <a href="https://bioportal.bioontology.org/search?q=C0264133&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0264133</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001763</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001763</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=1f893093d35c2d1df583eed57a47b6cb" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Pes_Planus-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=1f893093d35c2d1df583eed57a47b6cb&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 /> -
Pes valgus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249803006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249803006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1578482&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1578482</a>, <a href="https://bioportal.bioontology.org/search?q=C0016202&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0016202</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001763</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0008081" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008081</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008081" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008081</a>]</span><br /> -
Fetal pads <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277784&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277784</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MUSCLE, SOFT TISSUES </strong>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br />
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<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
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<em> Central Nervous System </em>
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<div style="margin-left: 2em;">
<span class="mim-font">
- Mental retardation, severe <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40700009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40700009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F72" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F72</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/318.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">318.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036857&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036857</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010864" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010864</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010864" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010864</a>]</span><br /> -
Poor or absent speech development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674458&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674458</a>]</span><br /> -
Delayed motor development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854301&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854301</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001270" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001270</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001270" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001270</a>]</span><br /> -
Limited walking abilities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674459&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674459</a>]</span><br /> -
Unstable, ataxic gait <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674460&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674460</a>]</span><br /> -
Incoordination <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/281016006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">281016006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302289002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302289002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0520966&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0520966</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002311</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002311</a>]</span><br /> -
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Bulging of the caudate nuclei <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674461&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674461</a>]</span><br /> -
Ventricular asymmetry <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674462&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674462</a>]</span><br /> -
Agenesis or hypoplasia of the corpus callosum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674463&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674463</a>]</span><br /> -
Atrophy of the frontal and parietal cortex <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674464&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674464</a>]</span><br /> -
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br />
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<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Happy personality <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674465&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674465</a>]</span><br /> -
Aggression <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/61372001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">61372001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001807&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001807</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006919" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006919</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000718</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000718</a>]</span><br /> -
Stereotypic movements <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853236&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853236</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000733</a>]</span><br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the transcription factor-4 gene (TCF4, <a href="/entry/602272#0001">602272.0001</a>)<br />
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<p>A number sign (#) is used with this entry because of evidence that Pitt-Hopkins syndrome (PTHS) is caused by heterozygous mutation in the TCF4 gene (<a href="/entry/602272">602272</a>) on chromosome 18q21.</p>
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<p>Pitt-Hopkins syndrome (PTHS) is characterized by impaired intellectual development, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea (<a href="#14" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. &lt;strong&gt;Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).&lt;/strong&gt; Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436255/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436255&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[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/10.1086/515583&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17436255">Zweier et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17436255" 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>See also Pitt-Hopkins-like syndrome-1 (<a href="/entry/610042">610042</a>), caused by mutation in the CNTNAP2 gene (<a href="/entry/604569">604569</a>) on chromosome 7q35, and Pitt-Hopkins-like syndrome-2 (<a href="/entry/600565">600565</a>), caused by mutation in the NRXN1 gene (<a href="/entry/600565">600565</a>) on chromosome 2p16.</p>
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<p><a href="#9" class="mim-tip-reference" title="Pitt, D., Hopkins, I. &lt;strong&gt;A syndrome of mental retardation, wide mouth and intermittent overbreathing.&lt;/strong&gt; Aust. Paediat. J. 14: 182-184, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/728011/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;728011&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/jpc.1978.14.3.182&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="728011">Pitt and Hopkins (1978)</a> described 2 unrelated patients with a sporadic disorder comprising mental retardation, wide mouth, and intermittent overbreathing. The first patient, a male born of unrelated Greek parents, was profoundly retarded with poor muscular development. Head circumference and body measurements were normal. The mouth was wide with thick fleshy lips and a broad palate; the nose was beaked with broad nasal bridge, and the nostrils flared. There was bilateral pes cavus. Mild clubbing of the fingers and toes was present, and he had a left simian crease. An abnormal respiratory cycle was present every day, and showed extreme fluctuations. He overbreathed at up to 120 breaths per minute for 1 to 2 minutes and then had a period of apnea for up to 2 minutes, during the latter part of which he became cyanosed until a new episode of overbreathing terminated the cyanosis. The rhythm was absent at times during wakefulness and regularly during sleep, and increased with emotional stimuli. He died of pneumonia at the age of 20 years. The second patient, a female of unrelated Sicilian parents, was also retarded and had similar facial features. She was dwarfed and microcephalic, with everted feet and clubbing of fingers and toes. She also had an abnormal pattern of breathing with periodicity similar to that of the first patient. Electroencephalograms of both patients showed an excess of slow components. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=728011" 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="#11" class="mim-tip-reference" title="Singh, H. A. &lt;strong&gt;Mental retardation, macrostomia and hyperpnoea syndrome.&lt;/strong&gt; J. Paediat. Child Health 29: 156-157, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8489799/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8489799&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1440-1754.1993.tb00472.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="8489799">Singh (1993)</a> described a male patient with features similar to those of the patients reported by <a href="#9" class="mim-tip-reference" title="Pitt, D., Hopkins, I. &lt;strong&gt;A syndrome of mental retardation, wide mouth and intermittent overbreathing.&lt;/strong&gt; Aust. Paediat. J. 14: 182-184, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/728011/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;728011&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/jpc.1978.14.3.182&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="728011">Pitt and Hopkins (1978)</a>, notably, wide mouth, thick lips, prominent nose, clubbing of fingers and toes, pes cavus, mental retardation, abnormal breathing pattern, and a history of epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8489799+728011" 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="Van Balkom, I. D. C., Quartel, S., Hennekam, R. C. M. &lt;strong&gt;Mental retardation, &#x27;coarse&#x27; face, and hyperbreathing: confirmation of the Pitt-Hopkins syndrome.&lt;/strong&gt; Am. J. Med. Genet. 75: 273-276, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9475596/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9475596&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19980123)75:3&lt;273::aid-ajmg9&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="9475596">Van Balkom et al. (1998)</a> described a similar female patient. Mental retardation and poor motor development were present. Daily episodic hyperbreathing, which caused massive swallowing of air and necessitated changing to clothes of a larger size during the daytime because of abdominal distention, was noted. Height and head circumference were below the 3rd centile. She had coarse hair, heavy eyebrows, a broad nasal bridge, large nose, flared nares, wide mouth with thick, fleshy lips, a broad palate, and an abnormal ear with a dysplastic helix on the right side. At the age of 40 years, all fingers as well as the great toes were clubbed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9475596" 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="#8" class="mim-tip-reference" title="Peippo, M. M., Simola, K. O. J., Valanne, L. K., Larsen, A. T., Kahkonen, M., Auranen, M. P., Ignatius, J. &lt;strong&gt;Pitt-Hopkins syndrome in two patients and further definition of the phenotype.&lt;/strong&gt; Clin. Dysmorph. 15: 47-54, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16531728/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16531728&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/01.mcd.0000184973.14775.32&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16531728">Peippo et al. (2006)</a> noted that of the 4 reported patients with PTHS, all showed dysmorphism consisting of large beaked nose, cup-shaped ears with broad helices, a wide mouth, cupid-bow upper lip, wide and shallow palate, and broad or clubbed fingertips. They further defined the Pitt-Hopkins syndrome phenotype with a description of 2 new patients. In addition to severe developmental retardation, hypotonia, postnatal growth retardation, microcephaly, abnormal breathing, and characteristic dysmorphic features, both had epilepsy and intestinal problems with severe constipation in one and Hirschsprung disease (see <a href="/entry/142623">142623</a>) in the other. Other abnormalities were hypopigmented skin macules in one and high-grade myopia in the other. Both had unusual frontal slow-and-sharp wave discharges on electroencephalography. MRI in both showed a similar hypoplastic corpus callosum with missing rostrum and posterior part of the splenium and bulbous caudate nuclei bulging towards the frontal horns. <a href="#1" class="mim-tip-reference" title="Amiel, J., Rio, M., de Pontual, L., Redon, R., Malan, V., Boddaert, N., Plouin, P., Carter, N. P., Lyonnet, S., Munnich, A., Colleaux, L. &lt;strong&gt;Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.&lt;/strong&gt; Am. J. Hum. Genet. 80: 988-993, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436254/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436254&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17436254[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/10.1086/515582&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17436254">Amiel et al. (2007)</a> ascertained 4 cases of PTHS. They noted that the abnormal ventilatory pattern characterized by daily bouts of diurnal hyperventilation that is the hallmark of PTHS was not reported in patients younger than 3 years of age. Epilepsy generally occurred later in the course of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16531728+17436254" 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="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. &lt;strong&gt;Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).&lt;/strong&gt; Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436255/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436255&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[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/10.1086/515583&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17436255">Zweier et al. (2007)</a> studied the 2 sporadic cases reported by <a href="#8" class="mim-tip-reference" title="Peippo, M. M., Simola, K. O. J., Valanne, L. K., Larsen, A. T., Kahkonen, M., Auranen, M. P., Ignatius, J. &lt;strong&gt;Pitt-Hopkins syndrome in two patients and further definition of the phenotype.&lt;/strong&gt; Clin. Dysmorph. 15: 47-54, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16531728/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16531728&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/01.mcd.0000184973.14775.32&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16531728">Peippo et al. (2006)</a> and 29 additional patients with severe mental retardation, breathing anomalies, and PTHS-like facial dysmorphism. These patients included the sib pair described by <a href="#7" class="mim-tip-reference" title="Orrico, A., Galli, L., Zappella, M., Lam, C.-W., Bonifacio, S., Torricelli, F., Hayek, G. &lt;strong&gt;Possible case of Pitt-Hopkins syndrome in sibs.&lt;/strong&gt; Am. J. Med. Genet. 103: 157-159, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11568923/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11568923&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1523&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11568923">Orrico et al. (2001)</a> and the patient of <a href="#12" class="mim-tip-reference" title="Van Balkom, I. D. C., Quartel, S., Hennekam, R. C. M. &lt;strong&gt;Mental retardation, &#x27;coarse&#x27; face, and hyperbreathing: confirmation of the Pitt-Hopkins syndrome.&lt;/strong&gt; Am. J. Med. Genet. 75: 273-276, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9475596/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9475596&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19980123)75:3&lt;273::aid-ajmg9&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="9475596">Van Balkom et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17436255+11568923+16531728+9475596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Brockschmidt, A., Todt, U., Ryu, S., Hoischen, A., Landwehr, C., Birnbaum, S., Frenck, W., Radlwimmer, B., Lichter, P., Engels, H., Driever, W., Kubisch, C., Weber, R. G. &lt;strong&gt;Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4.&lt;/strong&gt; Hum. Molec. Genet. 16: 1488-1494, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17478476/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17478476&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddm099&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17478476">Brockschmidt et al. (2007)</a> reported a girl with PTHS resulting from a 0.5-Mb microdeletion on chromosome 18q21.2. She had severely delayed psychomotor development, only achieving assisted walking at age 5 years. At age 7 years, she had no speech, hypotonia, and truncal ataxia. Dysmorphic features included coarse face with a broad and slightly depressed nasal bridge, wide mouth with a bow-shaped upper lip, short philtrum, dysplastic ears with anteverted earlobes, short neck, and low frontal and nuchal hairlines. Other features included widely spaced nipples, long tapering fingers, simian creases, proximally-inserted thumbs, and flat feet with superimposed toes. She had a happy disposition and began to have hyperventilation attacks at age 7.5 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17478476" 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="Rosenfeld, J. A., Leppig, K., Ballif, B. C., Thiese, H., Erdie-Lalena, C., Bawle, E., Sastry, S., Spence, J. E., Bandholz, A., Surti, U., Zonana, J., Keller, K., Meschino, W., Bejjani, B. A., Torchia, B. S., Shaffer, L. G. &lt;strong&gt;Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations.&lt;/strong&gt; Genet. Med. 11: 797-805, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19938247/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19938247&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/GIM.0b013e3181bd38a9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19938247">Rosenfeld et al. (2009)</a> identified 7 new cases of Pitt-Hopkins syndrome due to deletions of TCF4 and reviewed the 59 previously reported cases in the literature. Among their newly identified patients, all had features consistent with Pitt-Hopkins syndrome, although only 3 had breathing anomalies and none had seizures. Review of the literature indicated that although all reported patients had severe psychomotor retardation, the onset of seizures and hyperventilation episodes were limited to the first decade in most patients. Hyperventilation episodes were more common than seizures and were seen in the oldest patients, and individuals with missense TCF4 mutations were more likely to develop seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19938247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Marangi, G., Ricciardi, S., Orteschi, D., Lattante, S., Murdolo, M., Dallapiccola, B., Biscione, C., Lecce, R., Chiurazzi, P., Romano, C., Greco, D., Pettinato, R., and 14 others. &lt;strong&gt;The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.&lt;/strong&gt; Am. J. Med. Genet. 155A: 1536-1545, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21671391/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21671391&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.34070&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21671391">Marangi et al. (2011)</a> identified haploinsufficiency for the TCF4 gene in 14 of 63 Italian patients referred for suspicion of Pitt-Hopkins syndrome. One patient with the full syndrome had a balanced translocation involving the TCF4 gene. The patients ranged in age between 2 and 12 years, and all had severe intellectual disability with nearly absent language development. Eleven patients had a distinctive facial appearance, with bitemporal narrowing, square forehead, deep-set eyes, upslanted palpebral fissures, broad nasal bridge with pointed tip and flaring nostrils, full cheeks, protruding lower jaw and lip, and cup-shaped ears. Most (86%) had breathing abnormalities. Variable additional features included myopia, constipation, epilepsy, and uncoordinated movements. <a href="#6" class="mim-tip-reference" title="Marangi, G., Ricciardi, S., Orteschi, D., Lattante, S., Murdolo, M., Dallapiccola, B., Biscione, C., Lecce, R., Chiurazzi, P., Romano, C., Greco, D., Pettinato, R., and 14 others. &lt;strong&gt;The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.&lt;/strong&gt; Am. J. Med. Genet. 155A: 1536-1545, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21671391/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21671391&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.34070&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21671391">Marangi et al. (2011)</a> noted the phenotypic overlap with Angelman (<a href="/entry/105830">105830</a>) and Rett (<a href="/entry/312750">312750</a>) syndromes, but concluded that the facial gestalt of PTHS combined with additional features can lead to the correct clinical diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21671391" 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="Lehalle, D., Williams, C., Siu, V. M., Clayton-Smith, J. &lt;strong&gt;Fetal pads as a clue to the diagnosis of Pitt-Hopkins syndrome.&lt;/strong&gt; Am. J. Med. Genet. 155A: 1685-1689, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21671383/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21671383&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.34055&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21671383">Lehalle et al. (2011)</a> reported 4 unrelated patients with genetically confirmed PTHS who had fetal pads on the fingers and toes. They suggested that the presence of fetal pads can be a useful feature in the diagnosis of Pitt-Hopkins syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21671383" 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>Clinical Variability</em></strong></p><p>
<a href="#14" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. &lt;strong&gt;Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).&lt;/strong&gt; Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436255/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436255&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[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/10.1086/515583&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17436255">Zweier et al. (2007)</a> failed to find a mutation in the TCF4 gene in 2 sibs described by <a href="#7" class="mim-tip-reference" title="Orrico, A., Galli, L., Zappella, M., Lam, C.-W., Bonifacio, S., Torricelli, F., Hayek, G. &lt;strong&gt;Possible case of Pitt-Hopkins syndrome in sibs.&lt;/strong&gt; Am. J. Med. Genet. 103: 157-159, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11568923/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11568923&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1523&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11568923">Orrico et al. (2001)</a>, or in the patient reported by <a href="#12" class="mim-tip-reference" title="Van Balkom, I. D. C., Quartel, S., Hennekam, R. C. M. &lt;strong&gt;Mental retardation, &#x27;coarse&#x27; face, and hyperbreathing: confirmation of the Pitt-Hopkins syndrome.&lt;/strong&gt; Am. J. Med. Genet. 75: 273-276, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9475596/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9475596&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19980123)75:3&lt;273::aid-ajmg9&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="9475596">Van Balkom et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17436255+11568923+9475596" 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="#4" class="mim-tip-reference" title="Kalscheuer, V. M., Feenstra, I., Van Ravenswaaij-Arts, C. M. A., Smeets, D. F. C. M., Menzel, C., Ullmann, R., Musante, L., Ropers, H.-H. &lt;strong&gt;Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome.&lt;/strong&gt; Am. J. Med. Genet. 146A: 2053-2059, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18627065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18627065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32419&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18627065">Kalscheuer et al. (2008)</a> reported a girl with a de novo heterozygous balanced translocation t(18;20)(q21.1;q11.2) that disrupted the TCF4 gene and CHD6 gene on chromosome 20. She had mild to moderate mental retardation and minor facial anomalies, including a broad, square face, hypertelorism, flat nasal bridge, prominent ears, and a short neck. She also had mild hearing loss. However, she did not have features of the classic Pitt-Hopkins phenotype, such as breathing problems, hyperventilation, or epilepsy. PCR analysis showed that the breakpoints in TCF4 and CHD6 were in intron 3 and intron 1, respectively. Fusion transcripts were produced, with CHD6 exon 1 spliced to TCF4 exon 4. The findings indicated that not all mutations in TCF4 cause the severe PTHS phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18627065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="diagnosis" class="mim-anchor"></a>
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<strong>Diagnosis</strong>
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<p><a href="#13" class="mim-tip-reference" title="Whalen, S., Heron, D., Gaillon, T., Moldovan, O., Rossi, M., Devillard, F., Giuliano, F., Soares, G., Mathieu-Dramard, M., Afenjar, A., Charles, P., Mignot, C., and 25 others. &lt;strong&gt;Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.&lt;/strong&gt; Hum. Mutat. 33: 64-72, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22045651/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22045651&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.21639&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22045651">Whalen et al. (2012)</a> evaluated the clinical features of 112 patients with PTHS, 79 of whom had previously been reported, to better define the phenotype and allow for a more accurate clinical diagnosis. The most recognizable feature was the facial gestalt, including deep-set eyes, strabismus, myopia, marked nasal root, broad and/or beaked nasal bridge, large mouth, everted lower lip, tented upper lip, and/or prominent Cupid's bow, and ears with thick and overfolded helix. Of the 33 new patients, 63% had a single palmar crease, 65% had long, slender fingers, and 57% had flat feet. Intellectual disability was severe in all cases, and language was always absent or limited to only a few words. All had delayed walking, most had hypotonia (73%), and most had an ataxic or unsteady gait. Hyperventilation was present in over half of the patients, occurring spontaneously or triggered by emotional situations. Most (94%) also had stereotypic movements, particularly of the arms, wrists, and fingers. Most (89%) had a smiling appearance, as well as anxiety (81%). Variable features included constipation (77%) and cryptorchidism (33%). Less common features included microcephaly (7%), seizures (20%), and abnormalities on brain imaging (about 50%). <a href="#13" class="mim-tip-reference" title="Whalen, S., Heron, D., Gaillon, T., Moldovan, O., Rossi, M., Devillard, F., Giuliano, F., Soares, G., Mathieu-Dramard, M., Afenjar, A., Charles, P., Mignot, C., and 25 others. &lt;strong&gt;Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.&lt;/strong&gt; Hum. Mutat. 33: 64-72, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22045651/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22045651&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.21639&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22045651">Whalen et al. (2012)</a> suggested and outlined a clinical diagnostic score for PTHS. The TCF4 mutational spectrum included 40% point mutations, 30% small deletions/insertions, and 30% deletions. Most of these were private mutations and generated premature stop codons. Almost all cases occurred de novo; 1 resulted from somatic mosaicism in the mother, and there was 1 pair of monozygotic twins. Missense mutations were localized in the bHLH domain, which is a mutational hotspot. There were no apparent genotype/phenotype correlations. The findings confirmed that TCF4 haploinsufficiency is the molecular mechanism underlying PTHS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22045651" 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>
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<strong>Inheritance</strong>
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<p>In all PTHS patients with heterozygous mutation in the TCF4 gene whose parents were available for analysis, the mutation was shown to occur de novo (<a href="#1" class="mim-tip-reference" title="Amiel, J., Rio, M., de Pontual, L., Redon, R., Malan, V., Boddaert, N., Plouin, P., Carter, N. P., Lyonnet, S., Munnich, A., Colleaux, L. &lt;strong&gt;Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.&lt;/strong&gt; Am. J. Hum. Genet. 80: 988-993, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436254/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436254&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17436254[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/10.1086/515582&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17436254">Amiel et al., 2007</a>; <a href="#14" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. &lt;strong&gt;Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).&lt;/strong&gt; Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436255/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436255&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[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/10.1086/515583&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17436255">Zweier et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17436255+17436254" 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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<strong>Molecular Genetics</strong>
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<p>By array-comparative genomic hybridization in a patient with PTHS, <a href="#1" class="mim-tip-reference" title="Amiel, J., Rio, M., de Pontual, L., Redon, R., Malan, V., Boddaert, N., Plouin, P., Carter, N. P., Lyonnet, S., Munnich, A., Colleaux, L. &lt;strong&gt;Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.&lt;/strong&gt; Am. J. Hum. Genet. 80: 988-993, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436254/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436254&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17436254[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/10.1086/515582&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17436254">Amiel et al. (2007)</a> demonstrated a 1.8-Mb de novo microdeletion on 18q21.1; by molecular karyotyping with SNP arrays, <a href="#14" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. &lt;strong&gt;Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).&lt;/strong&gt; Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436255/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436255&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[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/10.1086/515583&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17436255">Zweier et al. (2007)</a> detected a 1.2-Mb deletion on 18q21.2 in another patient with this syndrome. In studies of patients with phenotypic features consistent with Pitt-Hopkins syndrome, both <a href="#1" class="mim-tip-reference" title="Amiel, J., Rio, M., de Pontual, L., Redon, R., Malan, V., Boddaert, N., Plouin, P., Carter, N. P., Lyonnet, S., Munnich, A., Colleaux, L. &lt;strong&gt;Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.&lt;/strong&gt; Am. J. Hum. Genet. 80: 988-993, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436254/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436254&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17436254[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/10.1086/515582&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17436254">Amiel et al. (2007)</a> and <a href="#14" class="mim-tip-reference" title="Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. &lt;strong&gt;Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).&lt;/strong&gt; Am. J. Hum. Genet. 80: 994-1001, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17436255/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17436255&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[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/10.1086/515583&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17436255">Zweier et al. (2007)</a> demonstrated de novo heterozygous mutations in the TCF4 gene (see <a href="/entry/602272#0001">602272.0001</a>-<a href="/entry/602272#0004">602272.0004</a>), which is located within the region of the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17436255+17436254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Brockschmidt, A., Todt, U., Ryu, S., Hoischen, A., Landwehr, C., Birnbaum, S., Frenck, W., Radlwimmer, B., Lichter, P., Engels, H., Driever, W., Kubisch, C., Weber, R. G. &lt;strong&gt;Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4.&lt;/strong&gt; Hum. Molec. Genet. 16: 1488-1494, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17478476/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17478476&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddm099&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17478476">Brockschmidt et al. (2007)</a> identified a de novo 0.5-Mb microdeletion of 18q21.2 encompassing the TCF4 gene in a girl with PTHS. RT-PCR analysis showed that the deletion resulted in functional TCF4 haploinsufficiency. The deletion occurred on the paternal chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17478476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Zweier, C., Sticht, H., Bijlsma, E. K., Clayton-Smith, J., Boonen, S. E., Fryer, A., Greally, M. T., Hoffmann, L., den Hollander, N. S., Jongmans, M., Kant, S. G., King, M. D., and 9 others. &lt;strong&gt;Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.&lt;/strong&gt; J. Med. Genet. 45: 738-744, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18728071/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18728071&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2008.060129&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18728071">Zweier et al. (2008)</a> identified 16 different TCF4 mutations (see, e.g., <a href="/entry/602272#0005">602272.0005</a>-<a href="/entry/602272#0006">602272.0006</a>) in 16 (14%) of 117 patients with a phenotype similar to PTHS. Thirteen of the mutations were frameshift, nonsense, or splice-site mutations, consistent with haploinsufficiency as the disease-causing mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18728071" 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="#3" class="mim-tip-reference" title="de Pontual, L., Mathieu, Y., Golzio, C., Rio, M., Malan, V., Boddaert, N., Soufflet, C., Picard, C., Durandy, A., Dobbie, A., Heron, D., Isidor B., and 12 others. &lt;strong&gt;Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.&lt;/strong&gt; Hum. Mutat. 30: 669-676, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19235238/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19235238&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20935&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19235238">De Pontual et al. (2009)</a> identified 12 different mutations in the TCF4 gene among 13 patients with Pitt-Hopkins syndrome. A clustering of mutations in the basic domain of the E-protein indicated a mutation hotspot. In vitro studies demonstrated that wildtype TCF4 only activated the reporter construct when cotransfected with ASCL1 (<a href="/entry/100790">100790</a>) and ASCL1/TCF4 mutant heterodimers had decreased transcriptional activity compared to ASCL1/TCF4 wildtype heterodimers, consistent with a loss of TCF4 function. All mutations occurred de novo, except for 1 that was inherited from a mother who had chronic depression and epilepsy from age 20 years and was somatic mosaic for the mutation. In addition to severe mental retardation and characteristic facial features, all patients had low levels of IgM, but none showed features of an immunodeficiency. <a href="#3" class="mim-tip-reference" title="de Pontual, L., Mathieu, Y., Golzio, C., Rio, M., Malan, V., Boddaert, N., Soufflet, C., Picard, C., Durandy, A., Dobbie, A., Heron, D., Isidor B., and 12 others. &lt;strong&gt;Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.&lt;/strong&gt; Hum. Mutat. 30: 669-676, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19235238/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19235238&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20935&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19235238">De Pontual et al. (2009)</a> noted that the patients had been diagnosed over a 12-month period, suggesting that the disorder may be more common than originally thought. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19235238" 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>REFERENCES</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436254[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=17436254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Brockschmidt2007" class="mim-anchor"></a>
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Brockschmidt, A., Todt, U., Ryu, S., Hoischen, A., Landwehr, C., Birnbaum, S., Frenck, W., Radlwimmer, B., Lichter, P., Engels, H., Driever, W., Kubisch, C., Weber, R. G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17478476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17478476</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17478476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="de Pontual2009" class="mim-anchor"></a>
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de Pontual, L., Mathieu, Y., Golzio, C., Rio, M., Malan, V., Boddaert, N., Soufflet, C., Picard, C., Durandy, A., Dobbie, A., Heron, D., Isidor B., and 12 others.
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Hum. Mutat. 30: 669-676, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19235238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19235238</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19235238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/humu.20935" target="_blank">Full Text</a>]
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Kalscheuer, V. M., Feenstra, I., Van Ravenswaaij-Arts, C. M. A., Smeets, D. F. C. M., Menzel, C., Ullmann, R., Musante, L., Ropers, H.-H.
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Am. J. Med. Genet. 146A: 2053-2059, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18627065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18627065</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18627065" 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.32419" target="_blank">Full Text</a>]
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<a id="Lehalle2011" class="mim-anchor"></a>
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Lehalle, D., Williams, C., Siu, V. M., Clayton-Smith, J.
<strong>Fetal pads as a clue to the diagnosis of Pitt-Hopkins syndrome.</strong>
Am. J. Med. Genet. 155A: 1685-1689, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21671383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21671383</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21671383" 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.34055" target="_blank">Full Text</a>]
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<a id="Marangi2011" class="mim-anchor"></a>
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Marangi, G., Ricciardi, S., Orteschi, D., Lattante, S., Murdolo, M., Dallapiccola, B., Biscione, C., Lecce, R., Chiurazzi, P., Romano, C., Greco, D., Pettinato, R., and 14 others.
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Am. J. Med. Genet. 155A: 1536-1545, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21671391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21671391</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21671391" 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.34070" target="_blank">Full Text</a>]
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<a id="Orrico2001" class="mim-anchor"></a>
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Orrico, A., Galli, L., Zappella, M., Lam, C.-W., Bonifacio, S., Torricelli, F., Hayek, G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11568923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11568923</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11568923" 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.1523" target="_blank">Full Text</a>]
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Peippo, M. M., Simola, K. O. J., Valanne, L. K., Larsen, A. T., Kahkonen, M., Auranen, M. P., Ignatius, J.
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[<a href="https://doi.org/10.1097/01.mcd.0000184973.14775.32" target="_blank">Full Text</a>]
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Pitt, D., Hopkins, I.
<strong>A syndrome of mental retardation, wide mouth and intermittent overbreathing.</strong>
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[<a href="https://doi.org/10.1111/jpc.1978.14.3.182" target="_blank">Full Text</a>]
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Rosenfeld, J. A., Leppig, K., Ballif, B. C., Thiese, H., Erdie-Lalena, C., Bawle, E., Sastry, S., Spence, J. E., Bandholz, A., Surti, U., Zonana, J., Keller, K., Meschino, W., Bejjani, B. A., Torchia, B. S., Shaffer, L. G.
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[<a href="https://doi.org/10.1097/GIM.0b013e3181bd38a9" target="_blank">Full Text</a>]
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Singh, H. A.
<strong>Mental retardation, macrostomia and hyperpnoea syndrome.</strong>
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[<a href="https://doi.org/10.1111/j.1440-1754.1993.tb00472.x" target="_blank">Full Text</a>]
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Van Balkom, I. D. C., Quartel, S., Hennekam, R. C. M.
<strong>Mental retardation, 'coarse' face, and hyperbreathing: confirmation of the Pitt-Hopkins syndrome.</strong>
Am. J. Med. Genet. 75: 273-276, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9475596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9475596</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9475596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/(sici)1096-8628(19980123)75:3&lt;273::aid-ajmg9&gt;3.0.co;2-r" target="_blank">Full Text</a>]
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<a id="Whalen2012" class="mim-anchor"></a>
<div class="">
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Whalen, S., Heron, D., Gaillon, T., Moldovan, O., Rossi, M., Devillard, F., Giuliano, F., Soares, G., Mathieu-Dramard, M., Afenjar, A., Charles, P., Mignot, C., and 25 others.
<strong>Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.</strong>
Hum. Mutat. 33: 64-72, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22045651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22045651</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22045651" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/humu.21639" target="_blank">Full Text</a>]
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<a id="Zweier2007" class="mim-anchor"></a>
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Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A.
<strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong>
Am. J. Hum. Genet. 80: 994-1001, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17436255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17436255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17436255[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=17436255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/515583" target="_blank">Full Text</a>]
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<a id="Zweier2008" class="mim-anchor"></a>
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Zweier, C., Sticht, H., Bijlsma, E. K., Clayton-Smith, J., Boonen, S. E., Fryer, A., Greally, M. T., Hoffmann, L., den Hollander, N. S., Jongmans, M., Kant, S. G., King, M. D., and 9 others.
<strong>Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.</strong>
J. Med. Genet. 45: 738-744, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18728071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18728071</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18728071" 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.2008.060129" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 1/10/2012
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Cassandra L. Kniffin - updated : 10/13/2011<br>Cassandra L. Kniffin - updated : 1/20/2011<br>Ada Hamosh - updated : 5/24/2010<br>Cassandra L. Kniffin - updated : 3/9/2010<br>Cassandra L. Kniffin - updated : 10/20/2008
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Victor A. McKusick : 4/20/2007
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carol : 07/29/2024
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carol : 11/22/2022<br>carol : 11/21/2022<br>carol : 05/23/2019<br>alopez : 07/13/2018<br>carol : 05/25/2016<br>carol : 1/19/2012<br>ckniffin : 1/10/2012<br>carol : 10/14/2011<br>terry : 10/13/2011<br>ckniffin : 10/13/2011<br>wwang : 2/4/2011<br>ckniffin : 1/20/2011<br>alopez : 5/24/2010<br>wwang : 3/25/2010<br>ckniffin : 3/9/2010<br>wwang : 1/11/2010<br>ckniffin : 12/16/2009<br>carol : 12/30/2008<br>ckniffin : 12/16/2008<br>wwang : 10/21/2008<br>ckniffin : 10/20/2008<br>wwang : 5/29/2008<br>carol : 5/29/2007<br>carol : 5/4/2007<br>joanna : 4/23/2007<br>alopez : 4/23/2007
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<strong>#</strong> 610954
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PITT-HOPKINS SYNDROME; PTHS
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<em>Alternative titles; symbols</em>
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ENCEPHALOPATHY, SEVERE EPILEPTIC, WITH AUTONOMIC DYSFUNCTION<br />
MENTAL RETARDATION, SYNDROMAL, WITH INTERMITTENT HYPERVENTILATION
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<strong>SNOMEDCT:</strong> 702344008; &nbsp;
<strong>ORPHA:</strong> 2896; &nbsp;
<strong>DO:</strong> 0060488; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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18q21.2
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Pitt-Hopkins syndrome
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610954
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Autosomal dominant
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3
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TCF4
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602272
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that Pitt-Hopkins syndrome (PTHS) is caused by heterozygous mutation in the TCF4 gene (602272) on chromosome 18q21.</p>
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<strong>Description</strong>
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<p>Pitt-Hopkins syndrome (PTHS) is characterized by impaired intellectual development, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea (Zweier et al., 2007). </p><p>See also Pitt-Hopkins-like syndrome-1 (610042), caused by mutation in the CNTNAP2 gene (604569) on chromosome 7q35, and Pitt-Hopkins-like syndrome-2 (600565), caused by mutation in the NRXN1 gene (600565) on chromosome 2p16.</p>
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<strong>Clinical Features</strong>
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<p>Pitt and Hopkins (1978) described 2 unrelated patients with a sporadic disorder comprising mental retardation, wide mouth, and intermittent overbreathing. The first patient, a male born of unrelated Greek parents, was profoundly retarded with poor muscular development. Head circumference and body measurements were normal. The mouth was wide with thick fleshy lips and a broad palate; the nose was beaked with broad nasal bridge, and the nostrils flared. There was bilateral pes cavus. Mild clubbing of the fingers and toes was present, and he had a left simian crease. An abnormal respiratory cycle was present every day, and showed extreme fluctuations. He overbreathed at up to 120 breaths per minute for 1 to 2 minutes and then had a period of apnea for up to 2 minutes, during the latter part of which he became cyanosed until a new episode of overbreathing terminated the cyanosis. The rhythm was absent at times during wakefulness and regularly during sleep, and increased with emotional stimuli. He died of pneumonia at the age of 20 years. The second patient, a female of unrelated Sicilian parents, was also retarded and had similar facial features. She was dwarfed and microcephalic, with everted feet and clubbing of fingers and toes. She also had an abnormal pattern of breathing with periodicity similar to that of the first patient. Electroencephalograms of both patients showed an excess of slow components. </p><p>Singh (1993) described a male patient with features similar to those of the patients reported by Pitt and Hopkins (1978), notably, wide mouth, thick lips, prominent nose, clubbing of fingers and toes, pes cavus, mental retardation, abnormal breathing pattern, and a history of epilepsy. </p><p>Van Balkom et al. (1998) described a similar female patient. Mental retardation and poor motor development were present. Daily episodic hyperbreathing, which caused massive swallowing of air and necessitated changing to clothes of a larger size during the daytime because of abdominal distention, was noted. Height and head circumference were below the 3rd centile. She had coarse hair, heavy eyebrows, a broad nasal bridge, large nose, flared nares, wide mouth with thick, fleshy lips, a broad palate, and an abnormal ear with a dysplastic helix on the right side. At the age of 40 years, all fingers as well as the great toes were clubbed. </p><p>Peippo et al. (2006) noted that of the 4 reported patients with PTHS, all showed dysmorphism consisting of large beaked nose, cup-shaped ears with broad helices, a wide mouth, cupid-bow upper lip, wide and shallow palate, and broad or clubbed fingertips. They further defined the Pitt-Hopkins syndrome phenotype with a description of 2 new patients. In addition to severe developmental retardation, hypotonia, postnatal growth retardation, microcephaly, abnormal breathing, and characteristic dysmorphic features, both had epilepsy and intestinal problems with severe constipation in one and Hirschsprung disease (see 142623) in the other. Other abnormalities were hypopigmented skin macules in one and high-grade myopia in the other. Both had unusual frontal slow-and-sharp wave discharges on electroencephalography. MRI in both showed a similar hypoplastic corpus callosum with missing rostrum and posterior part of the splenium and bulbous caudate nuclei bulging towards the frontal horns. Amiel et al. (2007) ascertained 4 cases of PTHS. They noted that the abnormal ventilatory pattern characterized by daily bouts of diurnal hyperventilation that is the hallmark of PTHS was not reported in patients younger than 3 years of age. Epilepsy generally occurred later in the course of the disease. </p><p>Zweier et al. (2007) studied the 2 sporadic cases reported by Peippo et al. (2006) and 29 additional patients with severe mental retardation, breathing anomalies, and PTHS-like facial dysmorphism. These patients included the sib pair described by Orrico et al. (2001) and the patient of Van Balkom et al. (1998). </p><p>Brockschmidt et al. (2007) reported a girl with PTHS resulting from a 0.5-Mb microdeletion on chromosome 18q21.2. She had severely delayed psychomotor development, only achieving assisted walking at age 5 years. At age 7 years, she had no speech, hypotonia, and truncal ataxia. Dysmorphic features included coarse face with a broad and slightly depressed nasal bridge, wide mouth with a bow-shaped upper lip, short philtrum, dysplastic ears with anteverted earlobes, short neck, and low frontal and nuchal hairlines. Other features included widely spaced nipples, long tapering fingers, simian creases, proximally-inserted thumbs, and flat feet with superimposed toes. She had a happy disposition and began to have hyperventilation attacks at age 7.5 years. </p><p>Rosenfeld et al. (2009) identified 7 new cases of Pitt-Hopkins syndrome due to deletions of TCF4 and reviewed the 59 previously reported cases in the literature. Among their newly identified patients, all had features consistent with Pitt-Hopkins syndrome, although only 3 had breathing anomalies and none had seizures. Review of the literature indicated that although all reported patients had severe psychomotor retardation, the onset of seizures and hyperventilation episodes were limited to the first decade in most patients. Hyperventilation episodes were more common than seizures and were seen in the oldest patients, and individuals with missense TCF4 mutations were more likely to develop seizures. </p><p>Marangi et al. (2011) identified haploinsufficiency for the TCF4 gene in 14 of 63 Italian patients referred for suspicion of Pitt-Hopkins syndrome. One patient with the full syndrome had a balanced translocation involving the TCF4 gene. The patients ranged in age between 2 and 12 years, and all had severe intellectual disability with nearly absent language development. Eleven patients had a distinctive facial appearance, with bitemporal narrowing, square forehead, deep-set eyes, upslanted palpebral fissures, broad nasal bridge with pointed tip and flaring nostrils, full cheeks, protruding lower jaw and lip, and cup-shaped ears. Most (86%) had breathing abnormalities. Variable additional features included myopia, constipation, epilepsy, and uncoordinated movements. Marangi et al. (2011) noted the phenotypic overlap with Angelman (105830) and Rett (312750) syndromes, but concluded that the facial gestalt of PTHS combined with additional features can lead to the correct clinical diagnosis. </p><p>Lehalle et al. (2011) reported 4 unrelated patients with genetically confirmed PTHS who had fetal pads on the fingers and toes. They suggested that the presence of fetal pads can be a useful feature in the diagnosis of Pitt-Hopkins syndrome. </p><p><strong><em>Clinical Variability</em></strong></p><p>
Zweier et al. (2007) failed to find a mutation in the TCF4 gene in 2 sibs described by Orrico et al. (2001), or in the patient reported by Van Balkom et al. (1998). </p><p>Kalscheuer et al. (2008) reported a girl with a de novo heterozygous balanced translocation t(18;20)(q21.1;q11.2) that disrupted the TCF4 gene and CHD6 gene on chromosome 20. She had mild to moderate mental retardation and minor facial anomalies, including a broad, square face, hypertelorism, flat nasal bridge, prominent ears, and a short neck. She also had mild hearing loss. However, she did not have features of the classic Pitt-Hopkins phenotype, such as breathing problems, hyperventilation, or epilepsy. PCR analysis showed that the breakpoints in TCF4 and CHD6 were in intron 3 and intron 1, respectively. Fusion transcripts were produced, with CHD6 exon 1 spliced to TCF4 exon 4. The findings indicated that not all mutations in TCF4 cause the severe PTHS phenotype. </p>
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<strong>Diagnosis</strong>
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<p>Whalen et al. (2012) evaluated the clinical features of 112 patients with PTHS, 79 of whom had previously been reported, to better define the phenotype and allow for a more accurate clinical diagnosis. The most recognizable feature was the facial gestalt, including deep-set eyes, strabismus, myopia, marked nasal root, broad and/or beaked nasal bridge, large mouth, everted lower lip, tented upper lip, and/or prominent Cupid's bow, and ears with thick and overfolded helix. Of the 33 new patients, 63% had a single palmar crease, 65% had long, slender fingers, and 57% had flat feet. Intellectual disability was severe in all cases, and language was always absent or limited to only a few words. All had delayed walking, most had hypotonia (73%), and most had an ataxic or unsteady gait. Hyperventilation was present in over half of the patients, occurring spontaneously or triggered by emotional situations. Most (94%) also had stereotypic movements, particularly of the arms, wrists, and fingers. Most (89%) had a smiling appearance, as well as anxiety (81%). Variable features included constipation (77%) and cryptorchidism (33%). Less common features included microcephaly (7%), seizures (20%), and abnormalities on brain imaging (about 50%). Whalen et al. (2012) suggested and outlined a clinical diagnostic score for PTHS. The TCF4 mutational spectrum included 40% point mutations, 30% small deletions/insertions, and 30% deletions. Most of these were private mutations and generated premature stop codons. Almost all cases occurred de novo; 1 resulted from somatic mosaicism in the mother, and there was 1 pair of monozygotic twins. Missense mutations were localized in the bHLH domain, which is a mutational hotspot. There were no apparent genotype/phenotype correlations. The findings confirmed that TCF4 haploinsufficiency is the molecular mechanism underlying PTHS. </p>
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<strong>Inheritance</strong>
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<p>In all PTHS patients with heterozygous mutation in the TCF4 gene whose parents were available for analysis, the mutation was shown to occur de novo (Amiel et al., 2007; Zweier et al., 2007). </p>
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<strong>Molecular Genetics</strong>
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<p>By array-comparative genomic hybridization in a patient with PTHS, Amiel et al. (2007) demonstrated a 1.8-Mb de novo microdeletion on 18q21.1; by molecular karyotyping with SNP arrays, Zweier et al. (2007) detected a 1.2-Mb deletion on 18q21.2 in another patient with this syndrome. In studies of patients with phenotypic features consistent with Pitt-Hopkins syndrome, both Amiel et al. (2007) and Zweier et al. (2007) demonstrated de novo heterozygous mutations in the TCF4 gene (see 602272.0001-602272.0004), which is located within the region of the deletion. </p><p>Brockschmidt et al. (2007) identified a de novo 0.5-Mb microdeletion of 18q21.2 encompassing the TCF4 gene in a girl with PTHS. RT-PCR analysis showed that the deletion resulted in functional TCF4 haploinsufficiency. The deletion occurred on the paternal chromosome. </p><p>Zweier et al. (2008) identified 16 different TCF4 mutations (see, e.g., 602272.0005-602272.0006) in 16 (14%) of 117 patients with a phenotype similar to PTHS. Thirteen of the mutations were frameshift, nonsense, or splice-site mutations, consistent with haploinsufficiency as the disease-causing mechanism. </p><p>De Pontual et al. (2009) identified 12 different mutations in the TCF4 gene among 13 patients with Pitt-Hopkins syndrome. A clustering of mutations in the basic domain of the E-protein indicated a mutation hotspot. In vitro studies demonstrated that wildtype TCF4 only activated the reporter construct when cotransfected with ASCL1 (100790) and ASCL1/TCF4 mutant heterodimers had decreased transcriptional activity compared to ASCL1/TCF4 wildtype heterodimers, consistent with a loss of TCF4 function. All mutations occurred de novo, except for 1 that was inherited from a mother who had chronic depression and epilepsy from age 20 years and was somatic mosaic for the mutation. In addition to severe mental retardation and characteristic facial features, all patients had low levels of IgM, but none showed features of an immunodeficiency. De Pontual et al. (2009) noted that the patients had been diagnosed over a 12-month period, suggesting that the disorder may be more common than originally thought. </p>
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<strong>REFERENCES</strong>
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Amiel, J., Rio, M., de Pontual, L., Redon, R., Malan, V., Boddaert, N., Plouin, P., Carter, N. P., Lyonnet, S., Munnich, A., Colleaux, L.
<strong>Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.</strong>
Am. J. Hum. Genet. 80: 988-993, 2007.
[PubMed: 17436254]
[Full Text: https://doi.org/10.1086/515582]
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<p class="mim-text-font">
Brockschmidt, A., Todt, U., Ryu, S., Hoischen, A., Landwehr, C., Birnbaum, S., Frenck, W., Radlwimmer, B., Lichter, P., Engels, H., Driever, W., Kubisch, C., Weber, R. G.
<strong>Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4.</strong>
Hum. Molec. Genet. 16: 1488-1494, 2007.
[PubMed: 17478476]
[Full Text: https://doi.org/10.1093/hmg/ddm099]
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de Pontual, L., Mathieu, Y., Golzio, C., Rio, M., Malan, V., Boddaert, N., Soufflet, C., Picard, C., Durandy, A., Dobbie, A., Heron, D., Isidor B., and 12 others.
<strong>Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.</strong>
Hum. Mutat. 30: 669-676, 2009.
[PubMed: 19235238]
[Full Text: https://doi.org/10.1002/humu.20935]
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Kalscheuer, V. M., Feenstra, I., Van Ravenswaaij-Arts, C. M. A., Smeets, D. F. C. M., Menzel, C., Ullmann, R., Musante, L., Ropers, H.-H.
<strong>Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome.</strong>
Am. J. Med. Genet. 146A: 2053-2059, 2008.
[PubMed: 18627065]
[Full Text: https://doi.org/10.1002/ajmg.a.32419]
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<p class="mim-text-font">
Lehalle, D., Williams, C., Siu, V. M., Clayton-Smith, J.
<strong>Fetal pads as a clue to the diagnosis of Pitt-Hopkins syndrome.</strong>
Am. J. Med. Genet. 155A: 1685-1689, 2011.
[PubMed: 21671383]
[Full Text: https://doi.org/10.1002/ajmg.a.34055]
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Marangi, G., Ricciardi, S., Orteschi, D., Lattante, S., Murdolo, M., Dallapiccola, B., Biscione, C., Lecce, R., Chiurazzi, P., Romano, C., Greco, D., Pettinato, R., and 14 others.
<strong>The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.</strong>
Am. J. Med. Genet. 155A: 1536-1545, 2011.
[PubMed: 21671391]
[Full Text: https://doi.org/10.1002/ajmg.a.34070]
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<p class="mim-text-font">
Orrico, A., Galli, L., Zappella, M., Lam, C.-W., Bonifacio, S., Torricelli, F., Hayek, G.
<strong>Possible case of Pitt-Hopkins syndrome in sibs.</strong>
Am. J. Med. Genet. 103: 157-159, 2001.
[PubMed: 11568923]
[Full Text: https://doi.org/10.1002/ajmg.1523]
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Peippo, M. M., Simola, K. O. J., Valanne, L. K., Larsen, A. T., Kahkonen, M., Auranen, M. P., Ignatius, J.
<strong>Pitt-Hopkins syndrome in two patients and further definition of the phenotype.</strong>
Clin. Dysmorph. 15: 47-54, 2006.
[PubMed: 16531728]
[Full Text: https://doi.org/10.1097/01.mcd.0000184973.14775.32]
</p>
</li>
<li>
<p class="mim-text-font">
Pitt, D., Hopkins, I.
<strong>A syndrome of mental retardation, wide mouth and intermittent overbreathing.</strong>
Aust. Paediat. J. 14: 182-184, 1978.
[PubMed: 728011]
[Full Text: https://doi.org/10.1111/jpc.1978.14.3.182]
</p>
</li>
<li>
<p class="mim-text-font">
Rosenfeld, J. A., Leppig, K., Ballif, B. C., Thiese, H., Erdie-Lalena, C., Bawle, E., Sastry, S., Spence, J. E., Bandholz, A., Surti, U., Zonana, J., Keller, K., Meschino, W., Bejjani, B. A., Torchia, B. S., Shaffer, L. G.
<strong>Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations.</strong>
Genet. Med. 11: 797-805, 2009.
[PubMed: 19938247]
[Full Text: https://doi.org/10.1097/GIM.0b013e3181bd38a9]
</p>
</li>
<li>
<p class="mim-text-font">
Singh, H. A.
<strong>Mental retardation, macrostomia and hyperpnoea syndrome.</strong>
J. Paediat. Child Health 29: 156-157, 1993.
[PubMed: 8489799]
[Full Text: https://doi.org/10.1111/j.1440-1754.1993.tb00472.x]
</p>
</li>
<li>
<p class="mim-text-font">
Van Balkom, I. D. C., Quartel, S., Hennekam, R. C. M.
<strong>Mental retardation, &#x27;coarse&#x27; face, and hyperbreathing: confirmation of the Pitt-Hopkins syndrome.</strong>
Am. J. Med. Genet. 75: 273-276, 1998.
[PubMed: 9475596]
[Full Text: https://doi.org/10.1002/(sici)1096-8628(19980123)75:3&lt;273::aid-ajmg9&gt;3.0.co;2-r]
</p>
</li>
<li>
<p class="mim-text-font">
Whalen, S., Heron, D., Gaillon, T., Moldovan, O., Rossi, M., Devillard, F., Giuliano, F., Soares, G., Mathieu-Dramard, M., Afenjar, A., Charles, P., Mignot, C., and 25 others.
<strong>Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.</strong>
Hum. Mutat. 33: 64-72, 2012.
[PubMed: 22045651]
[Full Text: https://doi.org/10.1002/humu.21639]
</p>
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<li>
<p class="mim-text-font">
Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A.
<strong>Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).</strong>
Am. J. Hum. Genet. 80: 994-1001, 2007.
[PubMed: 17436255]
[Full Text: https://doi.org/10.1086/515583]
</p>
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<li>
<p class="mim-text-font">
Zweier, C., Sticht, H., Bijlsma, E. K., Clayton-Smith, J., Boonen, S. E., Fryer, A., Greally, M. T., Hoffmann, L., den Hollander, N. S., Jongmans, M., Kant, S. G., King, M. D., and 9 others.
<strong>Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.</strong>
J. Med. Genet. 45: 738-744, 2008.
[PubMed: 18728071]
[Full Text: https://doi.org/10.1136/jmg.2008.060129]
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Cassandra L. Kniffin - updated : 1/10/2012<br>Cassandra L. Kniffin - updated : 10/13/2011<br>Cassandra L. Kniffin - updated : 1/20/2011<br>Ada Hamosh - updated : 5/24/2010<br>Cassandra L. Kniffin - updated : 3/9/2010<br>Cassandra L. Kniffin - updated : 10/20/2008
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