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<title>
Entry
- #616028 - ADAMS-OLIVER SYNDROME 5; AOS5
- OMIM
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<span class="h4">#616028</span>
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<a href="/clinicalSynopsis/616028"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS100300"> <strong>Phenotypic Series</strong> </a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<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>ORPHA:</strong> 974<br />
<strong>DO:</strong> 0060227<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>
616028
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
ADAMS-OLIVER SYNDROME 5; AOS5
</span>
</h3>
</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/9/656?start=-3&limit=10&highlight=656">
9q34.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Adams-Oliver syndrome 5
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616028"> 616028 </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">
NOTCH1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/190198"> 190198 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/616028" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS100300" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="sr-only">Toggle Dropdown</span>
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</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/616028" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/616028" 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">
- Aplasia cutis congenita of the scalp <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855698&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855698</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007385" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007385</a>]</span><br /> -
Prominent veins of the scalp <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1856542&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1856542</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001043" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001043</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Neck </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Aplasia cutis congenita (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254237003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254237003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35484002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35484002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q84.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q84.8</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0282160&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0282160</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001057" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001057</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001057" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001057</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Tricuspid valve incompetence <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111287006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111287006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0040961&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040961</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005180" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005180</a>]</span><br /> -
Pulmonary valve stenosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56786000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56786000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034089&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034089</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001642" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001642</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001642" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001642</a>]</span><br /> -
Mitral valve hypoplasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/93271008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">93271008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0344763&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344763</a>]</span><br /> -
Multiperforated patent foramen ovale <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014984&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014984</a>]</span><br /> -
Dilated right atrium <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253350005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253350005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0344709&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344709</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030718</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030718</a>]</span><br /> -
Right ventricular hypertrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/89792004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">89792004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162770&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162770</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001667" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001667</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001667" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001667</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pulmonary artery hypertension <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11399002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11399002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2973725&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2973725</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002092" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002092</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002092" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002092</a>]</span><br /> -
Portal vein thrombosis (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/17920008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">17920008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I81</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/452" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">452</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0155773&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0155773</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030242" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030242</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030242" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030242</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Features </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Umbilical hernia (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/396347007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">396347007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K42" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K42</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K42.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K42.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/553.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">553.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019322&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019322</a>, <a href="https://bioportal.bioontology.org/search?q=C0041636&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0041636</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001537" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001537</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001537" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001537</a>]</span><br /> -
Inguinal hernia (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/396232000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">396232000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K40</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K40.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K40.90</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/550" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">550</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019294&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019294</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000023" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000023</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000023" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000023</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spleen </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Splenomegaly (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16294009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16294009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038002&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038002</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</a>]</span><br /> -
Hypersplenism (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/58381000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">58381000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D73.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D73.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/289.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">289.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020532&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020532</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001971" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001971</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001971" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001971</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Esophageal varices (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28670008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28670008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I85.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I85.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I85" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I85</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I85.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I85.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0014867&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014867</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002040" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002040</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002040" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002040</a>]</span><br /> -
Hypertensive gastropathy (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014979&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014979</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> Skull </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Absent bone in areas of aplasia cutis congenita <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014981&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014981</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hands </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Brachydactyly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43476002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43476002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221357&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221357</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001156" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001156</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001156" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001156</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Feet </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Brachydactyly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43476002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43476002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221357&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221357</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001156" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001156</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001156" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001156</a>]</span><br /> -
Syndactyly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/373413006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">373413006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q70.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q70.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q70" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q70</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/755.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">755.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2117411&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2117411</a>, <a href="https://bioportal.bioontology.org/search?q=C0039075&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0039075</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001159" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001159</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001159" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001159</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=bcc47de729f2f227ecf8427f5adf6d12" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Foot,Osseous_Syndactyly_of-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=bcc47de729f2f227ecf8427f5adf6d12&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> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cutis marmorata telangiectatica congenita <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254778000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254778000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0345419&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0345419</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025107</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025107</a>]</span><br /> -
Strawberry nevi <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/402867006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">402867006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/83343001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">83343001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56975005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56975005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/195382003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">195382003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254206003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254206003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q82.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q82.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0206733&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0206733</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005306" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005306</a>]</span><br /> -
Macular hemangioma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014982&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014982</a>]</span><br /> -
Cavernous hemangioma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/416824008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">416824008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56975005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56975005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/33377007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">33377007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D18.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D18.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018920&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018920</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001048" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001048</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001048" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001048</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Nails </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypoplastic or absent toenails <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014983&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014983</a>]</span><br /> -
Dystrophic toenails <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833225&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833225</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001810" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001810</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001810" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001810</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Ischemic infarct of brain <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014971&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014971</a>]</span><br /> -
Sagittal sinus thrombosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/192760003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">192760003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/70607008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">70607008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0338575&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0338575</a>]</span><br /> -
Cortical venous thromboses <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014972&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014972</a>]</span><br /> -
Structural abnormalities of cerebellum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014973&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014973</a>]</span><br /> -
Hypoplasia of dentate nucleus <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014974&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014974</a>]</span><br /> -
High signal intensities in periventricular white matter <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014975&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014975</a>]</span><br /> -
High signal intensities at gray/white matter junction <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014976&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014976</a>]</span><br /> -
Seizures (rare) <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 />
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<strong> MISCELLANEOUS </strong>
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- Variable phenotype <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837514&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837514</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span><br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the notch receptor 1 gene (NOTCH1, <a href="/entry/190198#0003">190198.0003</a>)<br />
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<h5>
Adams-Oliver syndrome
- <a href="/phenotypicSeries/PS100300">PS100300</a>
- 6 Entries
</h5>
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<strong>Location</strong>
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<strong>Phenotype</strong>
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<strong>Inheritance</strong>
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<strong>Phenotype<br />mapping key</strong>
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<strong>Phenotype<br />MIM number</strong>
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<strong>Gene/Locus</strong>
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<strong>Gene/Locus<br />MIM number</strong>
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<span class="mim-font">
<a href="/geneMap/3/448?start=-3&limit=10&highlight=448"> 3p14.1 </a>
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<span class="mim-font">
<a href="/entry/615297"> Adams-Oliver syndrome 4 </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/615297"> 615297 </a>
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<a href="/entry/614789"> EOGT </a>
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<span class="mim-font">
<a href="/entry/614789"> 614789 </a>
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<span class="mim-font">
<a href="/geneMap/3/571?start=-3&limit=10&highlight=571"> 3q13.32-q13.33 </a>
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<span class="mim-font">
<a href="/entry/100300"> Adams-Oliver syndrome 1 </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/100300"> 100300 </a>
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<a href="/entry/610911"> ARHGAP31 </a>
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<span class="mim-font">
<a href="/entry/610911"> 610911 </a>
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<span class="mim-font">
<a href="/geneMap/4/139?start=-3&limit=10&highlight=139"> 4p15.2 </a>
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<span class="mim-font">
<a href="/entry/614814"> Adams-Oliver syndrome 3 </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/614814"> 614814 </a>
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<span class="mim-font">
<a href="/entry/147183"> RBPJ </a>
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<span class="mim-font">
<a href="/entry/147183"> 147183 </a>
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<span class="mim-font">
<a href="/geneMap/9/656?start=-3&limit=10&highlight=656"> 9q34.3 </a>
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<span class="mim-font">
<a href="/entry/616028"> Adams-Oliver syndrome 5 </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/616028"> 616028 </a>
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<a href="/entry/190198"> NOTCH1 </a>
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<span class="mim-font">
<a href="/entry/190198"> 190198 </a>
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<span class="mim-font">
<a href="/geneMap/15/112?start=-3&limit=10&highlight=112"> 15q15.1 </a>
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<span class="mim-font">
<a href="/entry/616589"> Adams-Oliver syndrome 6 </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/616589"> 616589 </a>
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<a href="/entry/605185"> DLL4 </a>
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<span class="mim-font">
<a href="/entry/605185"> 605185 </a>
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<span class="mim-font">
<a href="/geneMap/19/291?start=-3&limit=10&highlight=291"> 19p13.2 </a>
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<span class="mim-font">
<a href="/entry/614219"> Adams-Oliver syndrome 2 </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/614219"> 614219 </a>
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<span class="mim-font">
<a href="/entry/614194"> DOCK6 </a>
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<span class="mim-font">
<a href="/entry/614194"> 614194 </a>
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</table>
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that Adams-Oliver syndrome-5 (AOS5) is caused by heterozygous mutation in the NOTCH1 gene (<a href="/entry/190198">190198</a>) on chromosome 9q34.</p>
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<a id="description" class="mim-anchor"></a>
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<strong>Description</strong>
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<p>Adams-Oliver syndrome (AOS) is a rare developmental disorder defined by the combination of aplasia cutis congenita of the scalp vertex and terminal transverse limb defects (e.g., amputations, syndactyly, brachydactyly, or oligodactyly). In addition, vascular anomalies such as cutis marmorata telangiectatica congenita, pulmonary hypertension, portal hypertension, and retinal hypervascularization are recurrently seen. Congenital heart defects have been estimated to be present in 20% of AOS patients; reported malformations include ventricular septal defects, anomalies of the great arteries and their valves, and tetralogy of Fallot (summary by <a href="#4" class="mim-tip-reference" title="Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. &lt;strong&gt;Mutations in NOTCH1 cause Adams-Oliver syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 95: 275-284, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25132448/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25132448&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[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/10.1016/j.ajhg.2014.07.011&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25132448">Stittrich et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25132448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of Adams-Oliver syndrome, see AOS1 (<a href="/entry/100300">100300</a>).</p>
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<strong>Clinical Features</strong>
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<p><a href="#1" class="mim-tip-reference" title="Dallapiccola, B., Giannotti, A., Marino, B., Digilio, C., Obregon, G. &lt;strong&gt;Familial aplasia cutis congenita and coarctation of the aorta.&lt;/strong&gt; Am. J. Med. Genet. 43: 762-763, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1621771/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1621771&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320430423&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1621771">Dallapiccola et al. (1992)</a> observed aplasia cutis congenita and coarctation of the aorta in a mother and son. Both had coarctectomy, at age 14 years and 5 months, respectively. The aortic valve was bicuspid in the son. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1621771" 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="Vandersteen, A. M., Dixon, J. W. &lt;strong&gt;Adams-Oliver syndrome, a family with dominant inheritance and a severe phenotype.&lt;/strong&gt; Clin. Dysmorph. 20: 210-213, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21785343/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21785343&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/MCD.0b013e32834964d1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21785343">Vandersteen and Dixon (2011)</a> described a father and 2 daughters from New Zealand with Adams-Oliver syndrome. The proband was a 24-year-old woman with congenital prominent scalp veins, cutis marmorata telangiectatica congenita (CMTC; <a href="/entry/219250">219250</a>), and brachydactyly. She had mild motor delay with an in-toeing gait, and radiographs showed bilateral hip dysplasia. Brain MRI at age 7 years showed white matter abnormalities, with multiple high-signal intensities in the periventricular white matter and larger lesions at the gray/white matter junction. At age 24 years, she had short stature, no visible cutaneous vascular malformation of the scalp, and normal hair growth. Her more severely affected sister had cutis aplasia and prominent veins on the scalp, brachydactyly of all digits, and nail aplasia of all toes except the left hallux. She also exhibited extensive generalized CMTC and was diagnosed with pulmonary hypertension; she died of complications of right-sided heart failure at 3.5 years of age. Autopsy showed exudative crusted scalp lesions with a venous hemangiomatous border, right ventricular hypertrophy, dilated right atrium, and tricuspid valve incompetence. The cerebellum showed structural abnormalities with absent inferior medullary velum and tela choroidea. Histologic examination showed hypoplasia of the folia with loss of myelin and cells from Purkinje, granular, and molecular layers. There was also hypoplasia of the dentate nucleus. Lung pathology was consistent with grade 4 pulmonary hypertension. The girls' father had a congenital scalp defect, prominent scalp veins, and CMTC noted at birth. Skull x-ray was reported to show thin bone in the left parietal region. No limb abnormalities were reported, and there was no history of developmental delay or learning difficulties. He developed epilepsy at age 15 years, and insulin-dependent diabetes in his 20s. At age 34, he developed progressive proximal muscle weakness of the upper and lower limb girdles, with no sensory component and normal creatine phosphokinase level. Electromyography suggested a myopathic process, and he died of complications of myopathy at age 44 years. No autopsy was performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21785343" 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="Silva, G., Braga, A., Leitao, B., Mesquita, A., Reis, A., Duarte, C., Barbot, J., Silva, E. S. &lt;strong&gt;Adams-Oliver syndrome and portal hypertension: fortuitous association or common mechanism?&lt;/strong&gt; Am. J. Med. Genet. 158A: 648-651, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22307742/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22307742&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.34435&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22307742">Silva et al. (2012)</a> reported a boy of Portuguese origin who at birth was noted to have extensive cutis aplasia of the scalp, cutis marmorata, bilateral brachydactyly and syndactyly of the toes with hypoplastic nails, and umbilical and right scrotal hernias. Evaluation of a systolic ejection murmur revealed mild pulmonary stenosis. Head CT showed partial agenesis of the wall with exposure of the dura mater and a necrotic area along the sagittal sinus and biparietal areas. MRI at 1.5 months of age showed absence of the middle portion of the parietal bones; however, by 6 years of age, the parietal bones had grown to cover the cranium completely. The patient also developed progressive splenomegaly and at 5 months of age had portal vein obstruction with esophageal varices and hypertensive gastropathy. After thrombosis of a mesenteric-portal shunt, a splenorenal shunt was inserted, which closed spontaneously by 3 years of age. He had an ischemic stroke at placement of the first shunt. He also had spastic diplegia, left frontal lobe epilepsy, hyperactivity and attention deficit disorder, and severe psychomotor retardation. At 11 years of age, he had chronic liver failure with hyperammonemia and coagulopathy, with multiple hospitalizations for decompensated ascites and/or encephalopathy. <a href="#2" class="mim-tip-reference" title="Silva, G., Braga, A., Leitao, B., Mesquita, A., Reis, A., Duarte, C., Barbot, J., Silva, E. S. &lt;strong&gt;Adams-Oliver syndrome and portal hypertension: fortuitous association or common mechanism?&lt;/strong&gt; Am. J. Med. Genet. 158A: 648-651, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22307742/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22307742&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.34435&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22307742">Silva et al. (2012)</a> suggested that early embryonic vascular disruption might explain the vascular phenomena. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22307742" 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="Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. &lt;strong&gt;Mutations in NOTCH1 cause Adams-Oliver syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 95: 275-284, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25132448/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25132448&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[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/10.1016/j.ajhg.2014.07.011&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25132448">Stittrich et al. (2014)</a> restudied the 2 families with AOS reported by <a href="#5" class="mim-tip-reference" title="Vandersteen, A. M., Dixon, J. W. &lt;strong&gt;Adams-Oliver syndrome, a family with dominant inheritance and a severe phenotype.&lt;/strong&gt; Clin. Dysmorph. 20: 210-213, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21785343/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21785343&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/MCD.0b013e32834964d1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21785343">Vandersteen and Dixon (2011)</a> and <a href="#2" class="mim-tip-reference" title="Silva, G., Braga, A., Leitao, B., Mesquita, A., Reis, A., Duarte, C., Barbot, J., Silva, E. S. &lt;strong&gt;Adams-Oliver syndrome and portal hypertension: fortuitous association or common mechanism?&lt;/strong&gt; Am. J. Med. Genet. 158A: 648-651, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22307742/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22307742&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.34435&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22307742">Silva et al. (2012)</a>, and described affected individuals from 3 more unrelated families. Patients had aplasia cutis congenita of the scalp, with or without an underlying bony defect, as well as variable transverse distal upper or lower extremity reduction deficits or hypoplasia, including isolated toenail hypoplasia without other findings. One patient exhibited distal vesicles of calcinosis cutis. Intracranial vascular lesions were present in 3 patients. Cardiovascular findings included narrow pulmonary arteries, pulmonary valve stenosis, hypoplastic portal venous tree, distal aortic arch narrowing, mitral annulus hypoplasia, dilated main pulmonary artery, and vascular thromboses. Cutis marmorata was present in 4 of the families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22307742+21785343+25132448" 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="Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C. &lt;strong&gt;Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.&lt;/strong&gt; Circ. Cardiovasc. Genet. 8: 572-581, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25963545/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25963545&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25963545[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/10.1161/CIRCGENETICS.115.001086&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25963545">Southgate et al. (2015)</a> studied 17 patients from 11 families with molecularly proven AOS5, including the family originally reported by <a href="#1" class="mim-tip-reference" title="Dallapiccola, B., Giannotti, A., Marino, B., Digilio, C., Obregon, G. &lt;strong&gt;Familial aplasia cutis congenita and coarctation of the aorta.&lt;/strong&gt; Am. J. Med. Genet. 43: 762-763, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1621771/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1621771&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320430423&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1621771">Dallapiccola et al. (1992)</a>. The authors noted that the proportion of AOS probands with congenital heart abnormalities (5 of 11; 45%) was significantly higher than in previous reports of AOS cases (13-20%). Cardiovascular anomalies were identified in 8 (47%) of 17 affected mutation carriers, suggesting that NOTCH1 variants may represent a distinct subtype of AOS associated with cardiac malformations. Many vascular complications, including cutis marmorata telangiectatica congenita and portal vein abnormalities, were also seen in NOTCH1-positive cases. In addition, these patients predominantly exhibited mild terminal transverse limb defects, in contrast to reports of other AOS-associated genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1621771+25963545" 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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<p>The transmission pattern of AOS5 in the families reported by <a href="#1" class="mim-tip-reference" title="Dallapiccola, B., Giannotti, A., Marino, B., Digilio, C., Obregon, G. &lt;strong&gt;Familial aplasia cutis congenita and coarctation of the aorta.&lt;/strong&gt; Am. J. Med. Genet. 43: 762-763, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1621771/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1621771&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320430423&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1621771">Dallapiccola et al. (1992)</a> and <a href="#5" class="mim-tip-reference" title="Vandersteen, A. M., Dixon, J. W. &lt;strong&gt;Adams-Oliver syndrome, a family with dominant inheritance and a severe phenotype.&lt;/strong&gt; Clin. Dysmorph. 20: 210-213, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21785343/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21785343&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/MCD.0b013e32834964d1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21785343">Vandersteen and Dixon (2011)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1621771+21785343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The heterozygous mutations in the probands of families 1, 3, and 4 of <a href="#4" class="mim-tip-reference" title="Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. &lt;strong&gt;Mutations in NOTCH1 cause Adams-Oliver syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 95: 275-284, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25132448/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25132448&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[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/10.1016/j.ajhg.2014.07.011&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25132448">Stittrich et al. (2014)</a> occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25132448" 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><a href="#4" class="mim-tip-reference" title="Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S. &lt;strong&gt;Mutations in NOTCH1 cause Adams-Oliver syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 95: 275-284, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25132448/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25132448&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[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/10.1016/j.ajhg.2014.07.011&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25132448">Stittrich et al. (2014)</a> performed whole-exome sequencing in affected individuals from 11 families with Adams-Oliver syndrome who were negative for mutations in known AOS-associated genes. The authors identified heterozygous mutations in the NOTCH1 gene in 5 families, including the 2 families originally reported by <a href="#5" class="mim-tip-reference" title="Vandersteen, A. M., Dixon, J. W. &lt;strong&gt;Adams-Oliver syndrome, a family with dominant inheritance and a severe phenotype.&lt;/strong&gt; Clin. Dysmorph. 20: 210-213, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21785343/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21785343&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/MCD.0b013e32834964d1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21785343">Vandersteen and Dixon (2011)</a> and <a href="#2" class="mim-tip-reference" title="Silva, G., Braga, A., Leitao, B., Mesquita, A., Reis, A., Duarte, C., Barbot, J., Silva, E. S. &lt;strong&gt;Adams-Oliver syndrome and portal hypertension: fortuitous association or common mechanism?&lt;/strong&gt; Am. J. Med. Genet. 158A: 648-651, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22307742/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22307742&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.34435&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22307742">Silva et al. (2012)</a>; the mutations included an 85-kb deletion spanning the NOTCH1 5-prime region (<a href="/entry/190198#0003">190198.0003</a>), a splice site mutation (<a href="/entry/190198#0004">190198.0004</a>), and 3 missense mutations (C429R, <a href="/entry/190198#0005">190198.0005</a>; C1496Y, <a href="/entry/190198#0006">190198.0006</a>; D1989N, <a href="/entry/190198#0007">190198.0007</a>). The mutations were confirmed to have occurred de novo in 3 probands, and none of the variants was found in more 10,000 control genomes or exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22307742+21785343+25132448" 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>By exome sequencing in 12 unrelated AOS probands who were negative for mutation in the ARHGAP31 (<a href="/entry/610911">610911</a>) and RBPJ (<a href="/entry/147183">147183</a>) genes, <a href="#3" class="mim-tip-reference" title="Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C. &lt;strong&gt;Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.&lt;/strong&gt; Circ. Cardiovasc. Genet. 8: 572-581, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25963545/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25963545&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25963545[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/10.1161/CIRCGENETICS.115.001086&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25963545">Southgate et al. (2015)</a> identified 2 probands with heterozygous mutations in the NOTCH1 gene: a nonsense mutation (Y550X; <a href="/entry/190198#0008">190198.0008</a>) in the proband of a 3-generation family segregating autosomal dominant AOS, and a 2-bp deletion (<a href="/entry/190198#0009">190198.0009</a>) in the male proband originally reported by <a href="#1" class="mim-tip-reference" title="Dallapiccola, B., Giannotti, A., Marino, B., Digilio, C., Obregon, G. &lt;strong&gt;Familial aplasia cutis congenita and coarctation of the aorta.&lt;/strong&gt; Am. J. Med. Genet. 43: 762-763, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1621771/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1621771&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320430423&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1621771">Dallapiccola et al. (1992)</a>. <a href="#3" class="mim-tip-reference" title="Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C. &lt;strong&gt;Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.&lt;/strong&gt; Circ. Cardiovasc. Genet. 8: 572-581, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25963545/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25963545&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25963545[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/10.1161/CIRCGENETICS.115.001086&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25963545">Southgate et al. (2015)</a> performed mutation screening of NOTCH1 coding regions in 52 additional probands with a clear clinical diagnosis of AOS and identified 9 more patients with heterozygous mutations in NOTCH1. Cardiovascular evaluation of 2 apparently unaffected mutation carriers from 2 of the families did not reveal any cardiac abnormality (see, e.g., <a href="/entry/190198#0010">190198.0010</a>), demonstrating incomplete penetrance for mutations in NOTCH1. Noting that NOTCH1 mutations accounted for 17% of cases in their cohort, <a href="#3" class="mim-tip-reference" title="Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C. &lt;strong&gt;Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.&lt;/strong&gt; Circ. Cardiovasc. Genet. 8: 572-581, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25963545/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25963545&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25963545[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/10.1161/CIRCGENETICS.115.001086&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25963545">Southgate et al. (2015)</a> concluded that NOTCH1 is the primary cause of Adams-Oliver syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1621771+25963545" 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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<a id="1" class="mim-anchor"></a>
<a id="Dallapiccola1992" class="mim-anchor"></a>
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Dallapiccola, B., Giannotti, A., Marino, B., Digilio, C., Obregon, G.
<strong>Familial aplasia cutis congenita and coarctation of the aorta.</strong>
Am. J. Med. Genet. 43: 762-763, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1621771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1621771</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1621771" 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.1320430423" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
<a id="Silva2012" class="mim-anchor"></a>
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<p class="mim-text-font">
Silva, G., Braga, A., Leitao, B., Mesquita, A., Reis, A., Duarte, C., Barbot, J., Silva, E. S.
<strong>Adams-Oliver syndrome and portal hypertension: fortuitous association or common mechanism?</strong>
Am. J. Med. Genet. 158A: 648-651, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22307742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22307742</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22307742" 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.34435" target="_blank">Full Text</a>]
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<a id="Southgate2015" class="mim-anchor"></a>
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Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C.
<strong>Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.</strong>
Circ. Cardiovasc. Genet. 8: 572-581, 2015.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25963545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25963545</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25963545[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=25963545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1161/CIRCGENETICS.115.001086" target="_blank">Full Text</a>]
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<a id="Stittrich2014" class="mim-anchor"></a>
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Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S.
<strong>Mutations in NOTCH1 cause Adams-Oliver syndrome.</strong>
Am. J. Hum. Genet. 95: 275-284, 2014.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25132448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25132448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25132448[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=25132448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ajhg.2014.07.011" target="_blank">Full Text</a>]
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<a id="Vandersteen2011" class="mim-anchor"></a>
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Vandersteen, A. M., Dixon, J. W.
<strong>Adams-Oliver syndrome, a family with dominant inheritance and a severe phenotype.</strong>
Clin. Dysmorph. 20: 210-213, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21785343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21785343</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21785343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/MCD.0b013e32834964d1" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 01/30/2016
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Marla J. F. O&#x27;Neill : 9/23/2014
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carol : 01/30/2016<br>carol : 9/25/2014<br>mcolton : 9/23/2014
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<strong>#</strong> 616028
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ADAMS-OLIVER SYNDROME 5; AOS5
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<strong>ORPHA:</strong> 974; &nbsp;
<strong>DO:</strong> 0060227; &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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9q34.3
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Adams-Oliver syndrome 5
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616028
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Autosomal dominant
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3
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NOTCH1
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190198
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<p>A number sign (#) is used with this entry because of evidence that Adams-Oliver syndrome-5 (AOS5) is caused by heterozygous mutation in the NOTCH1 gene (190198) on chromosome 9q34.</p>
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<strong>Description</strong>
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<p>Adams-Oliver syndrome (AOS) is a rare developmental disorder defined by the combination of aplasia cutis congenita of the scalp vertex and terminal transverse limb defects (e.g., amputations, syndactyly, brachydactyly, or oligodactyly). In addition, vascular anomalies such as cutis marmorata telangiectatica congenita, pulmonary hypertension, portal hypertension, and retinal hypervascularization are recurrently seen. Congenital heart defects have been estimated to be present in 20% of AOS patients; reported malformations include ventricular septal defects, anomalies of the great arteries and their valves, and tetralogy of Fallot (summary by Stittrich et al., 2014). </p><p>For a discussion of genetic heterogeneity of Adams-Oliver syndrome, see AOS1 (100300).</p>
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<strong>Clinical Features</strong>
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<p>Dallapiccola et al. (1992) observed aplasia cutis congenita and coarctation of the aorta in a mother and son. Both had coarctectomy, at age 14 years and 5 months, respectively. The aortic valve was bicuspid in the son. </p><p>Vandersteen and Dixon (2011) described a father and 2 daughters from New Zealand with Adams-Oliver syndrome. The proband was a 24-year-old woman with congenital prominent scalp veins, cutis marmorata telangiectatica congenita (CMTC; 219250), and brachydactyly. She had mild motor delay with an in-toeing gait, and radiographs showed bilateral hip dysplasia. Brain MRI at age 7 years showed white matter abnormalities, with multiple high-signal intensities in the periventricular white matter and larger lesions at the gray/white matter junction. At age 24 years, she had short stature, no visible cutaneous vascular malformation of the scalp, and normal hair growth. Her more severely affected sister had cutis aplasia and prominent veins on the scalp, brachydactyly of all digits, and nail aplasia of all toes except the left hallux. She also exhibited extensive generalized CMTC and was diagnosed with pulmonary hypertension; she died of complications of right-sided heart failure at 3.5 years of age. Autopsy showed exudative crusted scalp lesions with a venous hemangiomatous border, right ventricular hypertrophy, dilated right atrium, and tricuspid valve incompetence. The cerebellum showed structural abnormalities with absent inferior medullary velum and tela choroidea. Histologic examination showed hypoplasia of the folia with loss of myelin and cells from Purkinje, granular, and molecular layers. There was also hypoplasia of the dentate nucleus. Lung pathology was consistent with grade 4 pulmonary hypertension. The girls' father had a congenital scalp defect, prominent scalp veins, and CMTC noted at birth. Skull x-ray was reported to show thin bone in the left parietal region. No limb abnormalities were reported, and there was no history of developmental delay or learning difficulties. He developed epilepsy at age 15 years, and insulin-dependent diabetes in his 20s. At age 34, he developed progressive proximal muscle weakness of the upper and lower limb girdles, with no sensory component and normal creatine phosphokinase level. Electromyography suggested a myopathic process, and he died of complications of myopathy at age 44 years. No autopsy was performed. </p><p>Silva et al. (2012) reported a boy of Portuguese origin who at birth was noted to have extensive cutis aplasia of the scalp, cutis marmorata, bilateral brachydactyly and syndactyly of the toes with hypoplastic nails, and umbilical and right scrotal hernias. Evaluation of a systolic ejection murmur revealed mild pulmonary stenosis. Head CT showed partial agenesis of the wall with exposure of the dura mater and a necrotic area along the sagittal sinus and biparietal areas. MRI at 1.5 months of age showed absence of the middle portion of the parietal bones; however, by 6 years of age, the parietal bones had grown to cover the cranium completely. The patient also developed progressive splenomegaly and at 5 months of age had portal vein obstruction with esophageal varices and hypertensive gastropathy. After thrombosis of a mesenteric-portal shunt, a splenorenal shunt was inserted, which closed spontaneously by 3 years of age. He had an ischemic stroke at placement of the first shunt. He also had spastic diplegia, left frontal lobe epilepsy, hyperactivity and attention deficit disorder, and severe psychomotor retardation. At 11 years of age, he had chronic liver failure with hyperammonemia and coagulopathy, with multiple hospitalizations for decompensated ascites and/or encephalopathy. Silva et al. (2012) suggested that early embryonic vascular disruption might explain the vascular phenomena. </p><p>Stittrich et al. (2014) restudied the 2 families with AOS reported by Vandersteen and Dixon (2011) and Silva et al. (2012), and described affected individuals from 3 more unrelated families. Patients had aplasia cutis congenita of the scalp, with or without an underlying bony defect, as well as variable transverse distal upper or lower extremity reduction deficits or hypoplasia, including isolated toenail hypoplasia without other findings. One patient exhibited distal vesicles of calcinosis cutis. Intracranial vascular lesions were present in 3 patients. Cardiovascular findings included narrow pulmonary arteries, pulmonary valve stenosis, hypoplastic portal venous tree, distal aortic arch narrowing, mitral annulus hypoplasia, dilated main pulmonary artery, and vascular thromboses. Cutis marmorata was present in 4 of the families. </p><p>Southgate et al. (2015) studied 17 patients from 11 families with molecularly proven AOS5, including the family originally reported by Dallapiccola et al. (1992). The authors noted that the proportion of AOS probands with congenital heart abnormalities (5 of 11; 45%) was significantly higher than in previous reports of AOS cases (13-20%). Cardiovascular anomalies were identified in 8 (47%) of 17 affected mutation carriers, suggesting that NOTCH1 variants may represent a distinct subtype of AOS associated with cardiac malformations. Many vascular complications, including cutis marmorata telangiectatica congenita and portal vein abnormalities, were also seen in NOTCH1-positive cases. In addition, these patients predominantly exhibited mild terminal transverse limb defects, in contrast to reports of other AOS-associated genes. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of AOS5 in the families reported by Dallapiccola et al. (1992) and Vandersteen and Dixon (2011) was consistent with autosomal dominant inheritance. </p><p>The heterozygous mutations in the probands of families 1, 3, and 4 of Stittrich et al. (2014) occurred de novo. </p>
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<strong>Molecular Genetics</strong>
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<p>Stittrich et al. (2014) performed whole-exome sequencing in affected individuals from 11 families with Adams-Oliver syndrome who were negative for mutations in known AOS-associated genes. The authors identified heterozygous mutations in the NOTCH1 gene in 5 families, including the 2 families originally reported by Vandersteen and Dixon (2011) and Silva et al. (2012); the mutations included an 85-kb deletion spanning the NOTCH1 5-prime region (190198.0003), a splice site mutation (190198.0004), and 3 missense mutations (C429R, 190198.0005; C1496Y, 190198.0006; D1989N, 190198.0007). The mutations were confirmed to have occurred de novo in 3 probands, and none of the variants was found in more 10,000 control genomes or exomes. </p><p>By exome sequencing in 12 unrelated AOS probands who were negative for mutation in the ARHGAP31 (610911) and RBPJ (147183) genes, Southgate et al. (2015) identified 2 probands with heterozygous mutations in the NOTCH1 gene: a nonsense mutation (Y550X; 190198.0008) in the proband of a 3-generation family segregating autosomal dominant AOS, and a 2-bp deletion (190198.0009) in the male proband originally reported by Dallapiccola et al. (1992). Southgate et al. (2015) performed mutation screening of NOTCH1 coding regions in 52 additional probands with a clear clinical diagnosis of AOS and identified 9 more patients with heterozygous mutations in NOTCH1. Cardiovascular evaluation of 2 apparently unaffected mutation carriers from 2 of the families did not reveal any cardiac abnormality (see, e.g., 190198.0010), demonstrating incomplete penetrance for mutations in NOTCH1. Noting that NOTCH1 mutations accounted for 17% of cases in their cohort, Southgate et al. (2015) concluded that NOTCH1 is the primary cause of Adams-Oliver syndrome. </p>
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<strong>REFERENCES</strong>
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Dallapiccola, B., Giannotti, A., Marino, B., Digilio, C., Obregon, G.
<strong>Familial aplasia cutis congenita and coarctation of the aorta.</strong>
Am. J. Med. Genet. 43: 762-763, 1992.
[PubMed: 1621771]
[Full Text: https://doi.org/10.1002/ajmg.1320430423]
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Silva, G., Braga, A., Leitao, B., Mesquita, A., Reis, A., Duarte, C., Barbot, J., Silva, E. S.
<strong>Adams-Oliver syndrome and portal hypertension: fortuitous association or common mechanism?</strong>
Am. J. Med. Genet. 158A: 648-651, 2012.
[PubMed: 22307742]
[Full Text: https://doi.org/10.1002/ajmg.a.34435]
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Southgate, L., Sukalo, M., Karountzos, A. S. V., Taylor, E. J., Collinson, C. S., Ruddy, D., Snape, K. M., Dallapiccola, B., Tolmie, J. L., Joss, S., Brancati, F., Digilio, M. C., Graul-Neumann, L. M., Salviati, L., Coerdt, W., Jacquemin, E., Wuyts, W., Zenker, M., Machado, R. D., Trembath, R. C.
<strong>Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies.</strong>
Circ. Cardiovasc. Genet. 8: 572-581, 2015.
[PubMed: 25963545]
[Full Text: https://doi.org/10.1161/CIRCGENETICS.115.001086]
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Stittrich, A.-B., Lehman, A., Bodian, D. L., Ashworth, J., Zong, Z., Li, H., Lam, P., Khromykh, A., Iyer, R. K., Vockley, J. G., Baveja, R., Silva, E. S., Dixon, J., Leon, E. L., Solomon, B. D., Glusman, G., Niederhuber, J. E., Roach, J. C., Patel, M. S.
<strong>Mutations in NOTCH1 cause Adams-Oliver syndrome.</strong>
Am. J. Hum. Genet. 95: 275-284, 2014.
[PubMed: 25132448]
[Full Text: https://doi.org/10.1016/j.ajhg.2014.07.011]
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Vandersteen, A. M., Dixon, J. W.
<strong>Adams-Oliver syndrome, a family with dominant inheritance and a severe phenotype.</strong>
Clin. Dysmorph. 20: 210-213, 2011.
[PubMed: 21785343]
[Full Text: https://doi.org/10.1097/MCD.0b013e32834964d1]
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