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<title>
Entry
- #615830 - PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 4; PPNAD4
- OMIM
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<span class="h4">#615830</span>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="/clinicalSynopsis/615830"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS610489"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9660;</div>
&nbsp;
<div style="display: table-cell;">Clinical Resources</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
<div class="panel-body small mim-panel-body">
<div><a href="https://clinicaltrials.gov/search?cond=PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=18374&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=615830[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=189427" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0070549" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/615830" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0070549" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>ORPHA:</strong> 189427<br />
<strong>DO:</strong> 0070549<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>
615830
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 4; PPNAD4
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
CUSHING SYNDROME, ADRENAL, DUE TO PPNAD4<br />
CHROMOSOME 19p13 DUPLICATION SYNDROME
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
ACTH-INDEPENDENT ADRENAL CUSHING SYNDROME, SOMATIC, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="cytogeneticLocation" class="mim-anchor"></a>
<p>
<span class="mim-text-font">
<strong>
<em>
Cytogenetic location: <a href="/geneMap/19/9?start=-3&limit=10&highlight=9">19p13</a>
&nbsp;
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:1-19900000&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">19:1-19,900,000</a> </span>
</em>
</strong>
</span>
</p>
</div>
<div>
<br />
</div>
<div>
<a id="geneMap" class="mim-anchor"></a>
<div style="margin-bottom: 10px;">
<span class="h4 mim-font">
<strong>Gene-Phenotype Relationships</strong>
</span>
</div>
<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>
</tr>
</thead>
<tbody>
<tr>
<td rowspan="1">
<span class="mim-font">
<a href="/geneMap/19/9?start=-3&limit=10&highlight=9">
19p13
</a>
</span>
</td>
<td>
<span class="mim-font">
Pigmented nodular adrenocortical disease, primary, 4
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615830"> 615830 </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="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved">4</abbr>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/615830" 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/PS610489" 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')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/615830" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/615830" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Weight </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Weight gain <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/262286000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">262286000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/816159004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">816159004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/161831008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">161831008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3814804&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3814804</a>, <a href="https://bioportal.bioontology.org/search?q=C0043094&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0043094</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004324</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004324</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Moon facies <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/67967009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">67967009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0332601&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0332601</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0500011" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0500011</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0500011" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0500011</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> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypertension <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38341003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38341003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/401-405.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">401-405.99</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/997.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">997.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020538&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020538</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</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>
<span class="mim-font">
- Osteoporosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64859006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64859006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Z82.62" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Z82.62</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M81.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M81.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/733.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">733.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/V17.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">V17.81</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/733.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">733.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2911643&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2911643</a>, <a href="https://bioportal.bioontology.org/search?q=C0029456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029456</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000939" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000939</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000939" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000939</a>]</span><br /> -
Osteopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/312894000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">312894000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029453&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029453</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000938" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000938</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000938" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000938</a>]</span><br />
</span>
</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">
- Skin fragility <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/247427007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">247427007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241181&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241181</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001030" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001030</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001030" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001030</a>]</span><br /> -
Stria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/201067006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">201067006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/47212006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">47212006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/201066002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">201066002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L90.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L90.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/701.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">701.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0152459&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0152459</a>, <a href="https://bioportal.bioontology.org/search?q=C1253938&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1253938</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001065" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001065</a>]</span><br /> -
Easy bruising <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/425075004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">425075004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/424131007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">424131007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423798</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000978" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000978</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000978" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000978</a>]</span><br /> -
Acne <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/88616000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">88616000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11381005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11381005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L70.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L70.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/L70.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L70.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/L70" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L70</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0718217&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0718217</a>, <a href="https://bioportal.bioontology.org/search?q=C0702166&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0702166</a>, <a href="https://bioportal.bioontology.org/search?q=C0001144&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001144</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001061" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001061</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001061" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001061</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hair </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hirsutism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399939002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399939002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L68.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L68.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/704.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">704.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001007</a>]</span><br /> -
Alopecia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/278040002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">278040002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56317004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56317004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L65.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L65.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/704.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">704.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/704.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">704.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002170&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002170</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001596" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001596</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002293" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002293</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001596" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001596</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MUSCLE, SOFT TISSUES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Proximal muscle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249939004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249939004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221629&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221629</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003701" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003701</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003701" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003701</a>]</span><br /> -
Buffalo hump <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/10867005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">10867005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0520573&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0520573</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025383" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025383</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025383" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025383</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Emotional lability <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18963009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18963009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R45.86" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R45.86</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085633&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085633</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000712</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000712" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000712</a>]</span><br /> -
Depression <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78667006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78667006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35489007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35489007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/366979004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">366979004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/255339005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">255339005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F34.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F34.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F32.A" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F32.A</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F33.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F33.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0812393&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0812393</a>, <a href="https://bioportal.bioontology.org/search?q=C0011581&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011581</a>, <a href="https://bioportal.bioontology.org/search?q=C0460137&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0460137</a>, <a href="https://bioportal.bioontology.org/search?q=C1579931&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1579931</a>, <a href="https://bioportal.bioontology.org/search?q=C0344315&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344315</a>, <a href="https://bioportal.bioontology.org/search?q=C4085311&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4085311</a>, <a href="https://bioportal.bioontology.org/search?q=C0011570&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011570</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000716</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000716</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ENDOCRINE FEATURES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Cushing syndrome <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237735008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237735008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/47270006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">47270006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/E24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E24</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/255.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">255.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0342443&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0342443</a>, <a href="https://bioportal.bioontology.org/search?q=C0010481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010481</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003118" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003118</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003118" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003118</a>]</span><br /> -
ACTH-independent hypercortisolemia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1968852&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1968852</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001579" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001579</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001579" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001579</a>]</span><br /> -
Adrenal adenomas, bilateral <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014426&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014426</a>]</span><br /> -
Adrenal hyperplasia, bilateral <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2062372&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2062372</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237751000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237751000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/419920004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">419920004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E25.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E25.0</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008221" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008221</a>]</span><br /> -
Diabetes mellitus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/73211009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">73211009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E08-E13" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E08-E13</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">250</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011849&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011849</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000819" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000819</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000819" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000819</a>]</span><br />
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<strong> LABORATORY ABNORMALITIES </strong>
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<span class="mim-font">
- Increased serum cortisol <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241003&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241003</a>]</span><br />
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<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
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- Variable age at onset<br /> -
Somatic mutations occur in adrenal tumor tissue (<a href="/entry/601639#0001">601639.0001</a>)<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by duplication of 294 kb to 2.7 Mb including the PRKACA gene on chromosome 19p13<br />
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<h5>
Pigmented nodular adrenocortical disease, primary
- <a href="/phenotypicSeries/PS610489">PS610489</a>
- 5 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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<td>
<span class="mim-font">
<a href="/geneMap/2/815?start=-3&limit=10&highlight=815"> 2q31.2 </a>
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<td>
<span class="mim-font">
<a href="/entry/610475"> Pigmented nodular adrenocortical disease, primary, 2 </a>
</span>
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<td>
<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/610475"> 610475 </a>
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<span class="mim-font">
<a href="/entry/604961"> PDE11A </a>
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<span class="mim-font">
<a href="/entry/604961"> 604961 </a>
</span>
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<span class="mim-font">
<a href="/geneMap/5/273?start=-3&limit=10&highlight=273"> 5q13.3 </a>
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<td>
<span class="mim-font">
<a href="/entry/614190"> Pigmented nodular adrenocortical disease, primary, 3 </a>
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<td>
<span class="mim-font">
</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>
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<span class="mim-font">
<a href="/entry/614190"> 614190 </a>
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<span class="mim-font">
<a href="/entry/603390"> PDE8B </a>
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<span class="mim-font">
<a href="/entry/603390"> 603390 </a>
</span>
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<td>
<span class="mim-font">
<a href="/geneMap/17/881?start=-3&limit=10&highlight=881"> 17q24.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610489"> Pigmented nodular adrenocortical disease, primary, 1 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610489"> 610489 </a>
</span>
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<span class="mim-font">
<a href="/entry/188830"> PRKAR1A </a>
</span>
</td>
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<span class="mim-font">
<a href="/entry/188830"> 188830 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/9?start=-3&limit=10&highlight=9"> 19p13 </a>
</span>
</td>
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<span class="mim-font">
<a href="/entry/615830"> Pigmented nodular adrenocortical disease, primary, 4 </a>
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</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
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<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved"> 4 </abbr>
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<td>
<span class="mim-font">
<a href="/entry/615830"> 615830 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615830"> PPNAD4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615830"> 615830 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/373?start=-3&limit=10&highlight=373"> 19p13.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615830"> Cushing syndrome, ACTH-independent adrenal, somatic </a>
</span>
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<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615830"> 615830 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601639"> PRKACA </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601639"> 601639 </a>
</span>
</td>
</tr>
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because primary pigmented nodular adrenocortical disease-4 (PPNAD4) is caused by a duplication on chromosome 19p13 that includes the PRKACA gene (<a href="/entry/601639">601639</a>). A recurrent somatic mutation in the PRKACA gene has been found in up to 70% of cortisol-secreting adrenocortical adenomas.</p><p>For a general phenotypic description and a discussion of genetic heterogeneity of primary pigmented nodular adrenocortical disease, see PPNAD1 (<a href="/entry/610489">610489</a>).</p>
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<strong>Description</strong>
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<p>Cushing syndrome is a clinical designation for the systemic signs and symptoms arising from excess cortisol production. Affected individuals typically show hypertension, impaired glucose tolerance, central obesity, osteoporosis, and sometimes depression. Corticotropin-independent Cushing syndrome results from autonomous cortisol production by the adrenal glands, often associated with adrenocortical tumors. Adrenocortical tumors are most common in adult females (summary by <a href="#2" class="mim-tip-reference" title="Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others. &lt;strong&gt;Activating hotspot L205R mutation in PRKACA and adrenal Cushing&#x27;s syndrome.&lt;/strong&gt; Science 344: 913-917, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24700472/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24700472&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1249480&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24700472">Cao et al., 2014</a>; <a href="#5" class="mim-tip-reference" title="Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others. &lt;strong&gt;Recurrent somatic mutations underlie corticotropin-independent Cushing&#x27;s syndrome.&lt;/strong&gt; Science 344: 917-920, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24855271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24855271&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1252328&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24855271">Sato et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24855271+24700472" 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="clinicalFeatures" class="mim-anchor"></a>
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<strong>Clinical Features</strong>
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<p><a href="#1" class="mim-tip-reference" title="Beuschlein, F., Fassnacht, M., Assie, G., Calebiro, D., Stratakis, C. A., Osswald, A., Ronchi, C. L., Wieland, T., Sbiera, S., Faucz, F. R., Schaak, K., Schmittfull, A., and 18 others. &lt;strong&gt;Constitutive activation of PKA catalytic subunit in adrenal Cushing&#x27;s syndrome.&lt;/strong&gt; New Eng. J. Med. 370: 1019-1028, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24571724/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24571724&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24571724[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/10.1056/NEJMoa1310359&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24571724">Beuschlein et al. (2014)</a> reported 5 patients, including a mother and son, with bilateral ACTH-independent adrenal hyperplasia resulting in clinical Cushing syndrome symptoms. The other 3 patients were boys between 3 and 9 years of age. Four patients were diagnosed with primary pigmented nodular adrenocortical disease (PPNAD) and 1 with ACTH-independent macronodular adrenal hyperplasia (AIMAH). The diagnosis of ACTH-independent Cushing syndrome was based on biochemical hallmarks of hypercortisolism, suppressed plasma corticotropin levels, and nonsuppressible serum cortisol levels after dexamethasone administration. Catabolic features included muscle weakness, skin fragility, and osteoporosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24571724" 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="Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P. &lt;strong&gt;Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.&lt;/strong&gt; Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24747643/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24747643&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24747643[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/10.1038/ng.2956&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24747643">Goh et al. (2014)</a> reported 13 unrelated patients with Cushing syndrome due to a cortisol-producing adrenocortical adenoma. Clinical symptoms were variable, but included Cushingoid appearance with recent weight gain, 'moon facies,' hirsutism, thinning of hair, acne, dordocervical fat pad, proximal muscle weakness, ecchymoses, osteopenia, diabetes mellitus, hypertension, and emotional lability or depression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24747643" 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="Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others. &lt;strong&gt;Recurrent somatic mutations underlie corticotropin-independent Cushing&#x27;s syndrome.&lt;/strong&gt; Science 344: 917-920, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24855271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24855271&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1252328&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24855271">Sato et al. (2014)</a> found that patients with adrenocortical adenomas associated with the somatic L206R mutation in the PRKACA gene had clinical symptoms of Cushing syndrome and tended to have significantly smaller adenoma sizes as well as higher cortisol production compared to individuals with non-PRKACA-mutated adrenal adenomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24855271" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="cytogenetics" class="mim-anchor"></a>
<h4 href="#mimCytogeneticsFold" id="mimCytogeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Cytogenetics</strong>
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<p>In 5 of 35 patients with overt ACTH-independent Cushing syndrome due to bilateral adrenal adenomas, <a href="#1" class="mim-tip-reference" title="Beuschlein, F., Fassnacht, M., Assie, G., Calebiro, D., Stratakis, C. A., Osswald, A., Ronchi, C. L., Wieland, T., Sbiera, S., Faucz, F. R., Schaak, K., Schmittfull, A., and 18 others. &lt;strong&gt;Constitutive activation of PKA catalytic subunit in adrenal Cushing&#x27;s syndrome.&lt;/strong&gt; New Eng. J. Med. 370: 1019-1028, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24571724/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24571724&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24571724[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/10.1056/NEJMoa1310359&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24571724">Beuschlein et al. (2014)</a> identified germline heterozygous duplications of chromosome 19p13. The duplications ranged in size from 294 kb to 2.7 Mb, but all included the entire PRKACA gene. Patient cells showed increased protein levels of the PKA catalytic subunit as well as increased basal protein kinase A activity, consistent with a gain of function. No PRKACA whole-gene duplications were found in the Database of Genomic Variants or in an in-house database of 2,000 persons with intellectual disability, congenital malformation, or both. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24571724" 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="Lodish, M. B., Yuan, B., Levy, I., Braunstein, G. D., Lyssikaos, C., Salpea, P., Szarek, E., Karageorgiadis, A. S. Belyavskaya, E., Raygada, M., Faucz, F. R., Izatt, L., Brain, C., Gardner, J., Quezado, M., Carney, J. A., Lupski, J. R., Stratakis, C. A. &lt;strong&gt;Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations.&lt;/strong&gt; Europ. J. Endocr. 172: 803-811, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25924874/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25924874&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1530/EJE-14-1154&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25924874">Lodish et al. (2015)</a> reported 5 patients, including a mother and a son, with germline genomic rearrangements at chromosome 19p13.2-p13.12 resulting in amplification of the PRKACA gene. All 5 patients had ACTH-independent Cushing syndrome; the mother and son (patients 4 and 5) presented with macronodular bilateral adrenal hyperplasia as adults, whereas the other 3 patients (patients 1, 2, and 3) had bilateral adrenal hyperplasia and underwent bilateral adrenalectomy in childhood. <a href="#4" class="mim-tip-reference" title="Lodish, M. B., Yuan, B., Levy, I., Braunstein, G. D., Lyssikaos, C., Salpea, P., Szarek, E., Karageorgiadis, A. S. Belyavskaya, E., Raygada, M., Faucz, F. R., Izatt, L., Brain, C., Gardner, J., Quezado, M., Carney, J. A., Lupski, J. R., Stratakis, C. A. &lt;strong&gt;Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations.&lt;/strong&gt; Europ. J. Endocr. 172: 803-811, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25924874/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25924874&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1530/EJE-14-1154&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25924874">Lodish et al. (2015)</a> examined the chromosome rearrangements using a combination of a commercially available CGH array and customized high density-aCGH (HD-aCGH) targeting the critical region. Patient 1, who presented at age 8 years, had a 2.7-Mb duplication encompassing PRKACA. Patient 2, who presented at age 2 years, had a distal duplication followed by a proximal triplication, which included PRKACA. In patient 3, who presented at age 2 years, the CGH array showed a 551-kb gain and the HD-aCGH revealed a distal duplication followed by a proximal triplication and another proximal duplication, with PRKACA located in the triplication. In patients 4 and 5, the CGH array showed a 616-kb gain. <a href="#4" class="mim-tip-reference" title="Lodish, M. B., Yuan, B., Levy, I., Braunstein, G. D., Lyssikaos, C., Salpea, P., Szarek, E., Karageorgiadis, A. S. Belyavskaya, E., Raygada, M., Faucz, F. R., Izatt, L., Brain, C., Gardner, J., Quezado, M., Carney, J. A., Lupski, J. R., Stratakis, C. A. &lt;strong&gt;Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations.&lt;/strong&gt; Europ. J. Endocr. 172: 803-811, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25924874/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25924874&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1530/EJE-14-1154&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25924874">Lodish et al. (2015)</a> suggested that a PRKACA triplication may result in a more severe phenotype than a PRKACA duplication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25924874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
<a id="molecularGenetics" class="mim-anchor"></a>
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimMolecularGeneticsToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
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<strong>Molecular Genetics</strong>
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<p>In 8 of 10 cortisol-secreting adrenal adenomas from patients with overt Cushing syndrome, <a href="#1" class="mim-tip-reference" title="Beuschlein, F., Fassnacht, M., Assie, G., Calebiro, D., Stratakis, C. A., Osswald, A., Ronchi, C. L., Wieland, T., Sbiera, S., Faucz, F. R., Schaak, K., Schmittfull, A., and 18 others. &lt;strong&gt;Constitutive activation of PKA catalytic subunit in adrenal Cushing&#x27;s syndrome.&lt;/strong&gt; New Eng. J. Med. 370: 1019-1028, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24571724/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24571724&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24571724[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/10.1056/NEJMoa1310359&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24571724">Beuschlein et al. (2014)</a> identified a somatic heterozygous mutation in the PRKACA gene. Seven of the tumors carried the same L206R mutation (<a href="/entry/601639#0001">601639.0001</a>) that was demonstrated in vitro to result in constitutive activation of protein kinase A that could not be suppressed by the regulatory subunit. The mutations were found by whole-exome sequencing. Subsequent analysis of the PRKACA gene in 129 additional adenomas found the somatic L206R variant in tumor tissue from 14 patients with overt Cushing syndrome. Overall, 22 (37%) of 59 patients with overt Cushing syndrome due to a unilateral adrenal adenoma carried a somatic heterozygous PRKACA mutation. PRKACA genomic alterations were not found in patients with subclinical Cushing syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24571724" 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>Simultaneously and independently, <a href="#2" class="mim-tip-reference" title="Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others. &lt;strong&gt;Activating hotspot L205R mutation in PRKACA and adrenal Cushing&#x27;s syndrome.&lt;/strong&gt; Science 344: 913-917, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24700472/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24700472&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1249480&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24700472">Cao et al. (2014)</a>, <a href="#5" class="mim-tip-reference" title="Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others. &lt;strong&gt;Recurrent somatic mutations underlie corticotropin-independent Cushing&#x27;s syndrome.&lt;/strong&gt; Science 344: 917-920, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24855271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24855271&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1252328&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24855271">Sato et al. (2014)</a>, and <a href="#3" class="mim-tip-reference" title="Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P. &lt;strong&gt;Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.&lt;/strong&gt; Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24747643/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24747643&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24747643[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/10.1038/ng.2956&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24747643">Goh et al. (2014)</a> found the recurrent L206R somatic mutation in adrenocortical tumors derived from patients with clinical Cushing syndrome. The mutations, which were found by whole-exome sequencing, were confirmed in additional cohorts of tumor samples. <a href="#2" class="mim-tip-reference" title="Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others. &lt;strong&gt;Activating hotspot L205R mutation in PRKACA and adrenal Cushing&#x27;s syndrome.&lt;/strong&gt; Science 344: 913-917, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24700472/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24700472&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1249480&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24700472">Cao et al. (2014)</a> identified the mutation in up to 69.2% of samples, <a href="#5" class="mim-tip-reference" title="Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others. &lt;strong&gt;Recurrent somatic mutations underlie corticotropin-independent Cushing&#x27;s syndrome.&lt;/strong&gt; Science 344: 917-920, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24855271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24855271&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1252328&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24855271">Sato et al. (2014)</a> in 52.3%, and <a href="#3" class="mim-tip-reference" title="Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P. &lt;strong&gt;Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.&lt;/strong&gt; Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24747643/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24747643&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24747643[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/10.1038/ng.2956&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24747643">Goh et al. (2014)</a> in 35%. Each group demonstrated in vitro that the mutation resulted in cAMP-independent activation of protein kinase A with increased substrate phosphorylation. <a href="#5" class="mim-tip-reference" title="Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others. &lt;strong&gt;Recurrent somatic mutations underlie corticotropin-independent Cushing&#x27;s syndrome.&lt;/strong&gt; Science 344: 917-920, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24855271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24855271&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1252328&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24855271">Sato et al. (2014)</a> and <a href="#3" class="mim-tip-reference" title="Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P. &lt;strong&gt;Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.&lt;/strong&gt; Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24747643/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24747643&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24747643[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/10.1038/ng.2956&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24747643">Goh et al. (2014)</a> found that the L206R variant disrupted the interface of the catalytic and regulatory subunits, resulting in constitutive activation of protein kinase A and a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24855271+24700472+24747643" 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="Beuschlein2014" class="mim-anchor"></a>
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Beuschlein, F., Fassnacht, M., Assie, G., Calebiro, D., Stratakis, C. A., Osswald, A., Ronchi, C. L., Wieland, T., Sbiera, S., Faucz, F. R., Schaak, K., Schmittfull, A., and 18 others.
<strong>Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.</strong>
New Eng. J. Med. 370: 1019-1028, 2014.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24571724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24571724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24571724[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=24571724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa1310359" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
<a id="Cao2014" class="mim-anchor"></a>
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Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others.
<strong>Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome.</strong>
Science 344: 913-917, 2014.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24700472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24700472</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24700472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.1249480" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
<a id="Goh2014" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P.
<strong>Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.</strong>
Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24747643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24747643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24747643[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=24747643" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng.2956" target="_blank">Full Text</a>]
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<a id="Lodish2015" class="mim-anchor"></a>
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Lodish, M. B., Yuan, B., Levy, I., Braunstein, G. D., Lyssikaos, C., Salpea, P., Szarek, E., Karageorgiadis, A. S. Belyavskaya, E., Raygada, M., Faucz, F. R., Izatt, L., Brain, C., Gardner, J., Quezado, M., Carney, J. A., Lupski, J. R., Stratakis, C. A.
<strong>Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations.</strong>
Europ. J. Endocr. 172: 803-811, 2015.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25924874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25924874</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25924874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1530/EJE-14-1154" target="_blank">Full Text</a>]
</p>
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<a id="5" class="mim-anchor"></a>
<a id="Sato2014" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others.
<strong>Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome.</strong>
Science 344: 917-920, 2014.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24855271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24855271</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24855271" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.1252328" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 11/13/2020
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Cassandra L. Kniffin - updated : 7/7/2014
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Cassandra L. Kniffin : 6/3/2014
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carol : 09/26/2014<br>carol : 7/9/2014<br>mcolton : 7/7/2014<br>ckniffin : 7/7/2014<br>carol : 6/4/2014<br>carol : 6/4/2014<br>mcolton : 6/3/2014<br>ckniffin : 6/3/2014
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<strong>#</strong> 615830
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PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 4; PPNAD4
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<em>Alternative titles; symbols</em>
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CUSHING SYNDROME, ADRENAL, DUE TO PPNAD4<br />
CHROMOSOME 19p13 DUPLICATION SYNDROME
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Other entities represented in this entry:
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ACTH-INDEPENDENT ADRENAL CUSHING SYNDROME, SOMATIC, INCLUDED
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<strong>ORPHA:</strong> 189427; &nbsp;
<strong>DO:</strong> 0070549; &nbsp;
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Cytogenetic location: 19p13
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:1-19,900,000 </span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Inheritance
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Phenotype <br /> mapping key
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19p13
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Pigmented nodular adrenocortical disease, primary, 4
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615830
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Autosomal dominant
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4
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because primary pigmented nodular adrenocortical disease-4 (PPNAD4) is caused by a duplication on chromosome 19p13 that includes the PRKACA gene (601639). A recurrent somatic mutation in the PRKACA gene has been found in up to 70% of cortisol-secreting adrenocortical adenomas.</p><p>For a general phenotypic description and a discussion of genetic heterogeneity of primary pigmented nodular adrenocortical disease, see PPNAD1 (610489).</p>
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<strong>Description</strong>
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<p>Cushing syndrome is a clinical designation for the systemic signs and symptoms arising from excess cortisol production. Affected individuals typically show hypertension, impaired glucose tolerance, central obesity, osteoporosis, and sometimes depression. Corticotropin-independent Cushing syndrome results from autonomous cortisol production by the adrenal glands, often associated with adrenocortical tumors. Adrenocortical tumors are most common in adult females (summary by Cao et al., 2014; Sato et al., 2014). </p>
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<strong>Clinical Features</strong>
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<p>Beuschlein et al. (2014) reported 5 patients, including a mother and son, with bilateral ACTH-independent adrenal hyperplasia resulting in clinical Cushing syndrome symptoms. The other 3 patients were boys between 3 and 9 years of age. Four patients were diagnosed with primary pigmented nodular adrenocortical disease (PPNAD) and 1 with ACTH-independent macronodular adrenal hyperplasia (AIMAH). The diagnosis of ACTH-independent Cushing syndrome was based on biochemical hallmarks of hypercortisolism, suppressed plasma corticotropin levels, and nonsuppressible serum cortisol levels after dexamethasone administration. Catabolic features included muscle weakness, skin fragility, and osteoporosis. </p><p>Goh et al. (2014) reported 13 unrelated patients with Cushing syndrome due to a cortisol-producing adrenocortical adenoma. Clinical symptoms were variable, but included Cushingoid appearance with recent weight gain, 'moon facies,' hirsutism, thinning of hair, acne, dordocervical fat pad, proximal muscle weakness, ecchymoses, osteopenia, diabetes mellitus, hypertension, and emotional lability or depression. </p><p>Sato et al. (2014) found that patients with adrenocortical adenomas associated with the somatic L206R mutation in the PRKACA gene had clinical symptoms of Cushing syndrome and tended to have significantly smaller adenoma sizes as well as higher cortisol production compared to individuals with non-PRKACA-mutated adrenal adenomas. </p>
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<strong>Cytogenetics</strong>
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<p>In 5 of 35 patients with overt ACTH-independent Cushing syndrome due to bilateral adrenal adenomas, Beuschlein et al. (2014) identified germline heterozygous duplications of chromosome 19p13. The duplications ranged in size from 294 kb to 2.7 Mb, but all included the entire PRKACA gene. Patient cells showed increased protein levels of the PKA catalytic subunit as well as increased basal protein kinase A activity, consistent with a gain of function. No PRKACA whole-gene duplications were found in the Database of Genomic Variants or in an in-house database of 2,000 persons with intellectual disability, congenital malformation, or both. </p><p>Lodish et al. (2015) reported 5 patients, including a mother and a son, with germline genomic rearrangements at chromosome 19p13.2-p13.12 resulting in amplification of the PRKACA gene. All 5 patients had ACTH-independent Cushing syndrome; the mother and son (patients 4 and 5) presented with macronodular bilateral adrenal hyperplasia as adults, whereas the other 3 patients (patients 1, 2, and 3) had bilateral adrenal hyperplasia and underwent bilateral adrenalectomy in childhood. Lodish et al. (2015) examined the chromosome rearrangements using a combination of a commercially available CGH array and customized high density-aCGH (HD-aCGH) targeting the critical region. Patient 1, who presented at age 8 years, had a 2.7-Mb duplication encompassing PRKACA. Patient 2, who presented at age 2 years, had a distal duplication followed by a proximal triplication, which included PRKACA. In patient 3, who presented at age 2 years, the CGH array showed a 551-kb gain and the HD-aCGH revealed a distal duplication followed by a proximal triplication and another proximal duplication, with PRKACA located in the triplication. In patients 4 and 5, the CGH array showed a 616-kb gain. Lodish et al. (2015) suggested that a PRKACA triplication may result in a more severe phenotype than a PRKACA duplication. </p>
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<span class="mim-font">
<strong>Molecular Genetics</strong>
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<p>In 8 of 10 cortisol-secreting adrenal adenomas from patients with overt Cushing syndrome, Beuschlein et al. (2014) identified a somatic heterozygous mutation in the PRKACA gene. Seven of the tumors carried the same L206R mutation (601639.0001) that was demonstrated in vitro to result in constitutive activation of protein kinase A that could not be suppressed by the regulatory subunit. The mutations were found by whole-exome sequencing. Subsequent analysis of the PRKACA gene in 129 additional adenomas found the somatic L206R variant in tumor tissue from 14 patients with overt Cushing syndrome. Overall, 22 (37%) of 59 patients with overt Cushing syndrome due to a unilateral adrenal adenoma carried a somatic heterozygous PRKACA mutation. PRKACA genomic alterations were not found in patients with subclinical Cushing syndrome. </p><p>Simultaneously and independently, Cao et al. (2014), Sato et al. (2014), and Goh et al. (2014) found the recurrent L206R somatic mutation in adrenocortical tumors derived from patients with clinical Cushing syndrome. The mutations, which were found by whole-exome sequencing, were confirmed in additional cohorts of tumor samples. Cao et al. (2014) identified the mutation in up to 69.2% of samples, Sato et al. (2014) in 52.3%, and Goh et al. (2014) in 35%. Each group demonstrated in vitro that the mutation resulted in cAMP-independent activation of protein kinase A with increased substrate phosphorylation. Sato et al. (2014) and Goh et al. (2014) found that the L206R variant disrupted the interface of the catalytic and regulatory subunits, resulting in constitutive activation of protein kinase A and a gain-of-function effect. </p>
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<strong>REFERENCES</strong>
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Beuschlein, F., Fassnacht, M., Assie, G., Calebiro, D., Stratakis, C. A., Osswald, A., Ronchi, C. L., Wieland, T., Sbiera, S., Faucz, F. R., Schaak, K., Schmittfull, A., and 18 others.
<strong>Constitutive activation of PKA catalytic subunit in adrenal Cushing&#x27;s syndrome.</strong>
New Eng. J. Med. 370: 1019-1028, 2014.
[PubMed: 24571724]
[Full Text: https://doi.org/10.1056/NEJMoa1310359]
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Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., and 13 others.
<strong>Activating hotspot L205R mutation in PRKACA and adrenal Cushing&#x27;s syndrome.</strong>
Science 344: 913-917, 2014.
[PubMed: 24700472]
[Full Text: https://doi.org/10.1126/science.1249480]
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Goh, G., Scholl, U. I., Healy, J. M., Choi, M., Prasad, M. L., Nelson-Williams, C., Kunstman, J. W., Korah, R., Suttorp, A.-C., Dietrich, D., Haase, M., Willenberg, H. S., Stalberg, P., Hellman, P., Akerstrom, G., Bjorklund, P., Carling, T., Lifton, R. P.
<strong>Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.</strong>
Nature Genet. 46: 613-617, 2014. Note: Erratum: Nature Genet. 46: 759 only, 2014.
[PubMed: 24747643]
[Full Text: https://doi.org/10.1038/ng.2956]
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Lodish, M. B., Yuan, B., Levy, I., Braunstein, G. D., Lyssikaos, C., Salpea, P., Szarek, E., Karageorgiadis, A. S. Belyavskaya, E., Raygada, M., Faucz, F. R., Izatt, L., Brain, C., Gardner, J., Quezado, M., Carney, J. A., Lupski, J. R., Stratakis, C. A.
<strong>Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations.</strong>
Europ. J. Endocr. 172: 803-811, 2015.
[PubMed: 25924874]
[Full Text: https://doi.org/10.1530/EJE-14-1154]
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Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., and 11 others.
<strong>Recurrent somatic mutations underlie corticotropin-independent Cushing&#x27;s syndrome.</strong>
Science 344: 917-920, 2014.
[PubMed: 24855271]
[Full Text: https://doi.org/10.1126/science.1252328]
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Hilary J. Vernon - updated : 11/13/2020<br>Cassandra L. Kniffin - updated : 7/7/2014
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carol : 11/13/2020<br>carol : 09/26/2014<br>carol : 7/9/2014<br>mcolton : 7/7/2014<br>ckniffin : 7/7/2014<br>carol : 6/4/2014<br>carol : 6/4/2014<br>mcolton : 6/3/2014<br>ckniffin : 6/3/2014
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