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<title>
Entry
- #219080 - ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA; AIMAH1
- OMIM
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<span class="h4">#219080</span>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/219080"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS219080"> <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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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</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 style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=(ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA) OR (GNAS)" class="mim-tip-hint" title="Clinical Trials" 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.diseaseinfosearch.org/x/2039" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=219080[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><a href="https://www.possumcore.com/nuxeo/nxdoc/default/e5b66118-4b8c-4b5a-83ef-68ebbae0d055/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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<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">
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<div style="display: table-cell;">Animal Models</div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0111623" 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/219080" 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://omia.org/results?search_type=advanced&omia_id=000247,001937" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0111623" 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>
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</div>
</div>
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<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>
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</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> 0111623<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>
219080
</span>
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</div>
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<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA; AIMAH1
</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">
ACTH-INDEPENDENT MACRONODULAR ADRENOCORTICAL HYPERPLASIA<br />
ADRENOCORTICOTROPIC HORMONE-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA<br />
CORTICOTROPIN-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA<br />
CUSHING SYNDROME, ADRENAL, DUE TO AIMAH
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/426?start=-3&limit=10&highlight=426">
20q13.32
</a>
</span>
</td>
<td>
<span class="mim-font">
ACTH-independent macronodular adrenal hyperplasia 1, somatic
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/219080"> 219080 </a>
</span>
</td>
<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">
GNAS
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/139320"> 139320 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
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<a href="/clinicalSynopsis/219080" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
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<a href="/phenotypicSeries/PS219080" class="btn btn-info" role="button"> Phenotypic Series </a>
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&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/219080" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/219080" 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">
- Somatic mutation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/124975008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">124975008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866227&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866227</a>, <a href="https://bioportal.bioontology.org/search?q=C0544886&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0544886</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</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">
- Truncal obesity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248311001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248311001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551560&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551560</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001956" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001956</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001956" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001956</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">
- Round face <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239479&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239479</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000311</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000311</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=2ab9bbad3c428d627c2b454902c17fa0" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Face,Round-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=2ab9bbad3c428d627c2b454902c17fa0&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> 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">
- Decreased bone mineral density <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=C2674432&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674432</a>, <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>, <a href="https://hpo.jax.org/app/browse/term/HP:0004349" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004349</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004349" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004349</a>]</span><br /> -
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 />
</span>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spine </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Kyphosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/71311003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">71311003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/414564002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">414564002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413428007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413428007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M40.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M40.20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q76.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q76.41</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/737.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">737.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0265673&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265673</a>, <a href="https://bioportal.bioontology.org/search?q=C0022821&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022821</a>, <a href="https://bioportal.bioontology.org/search?q=C2115817&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2115817</a>, <a href="https://bioportal.bioontology.org/search?q=C0022822&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022822</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002808</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002808</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Thin skin <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/277797007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">277797007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423757&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423757</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000963" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000963</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000963" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000963</a>]</span><br /> -
Striae <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> 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> <span class="mim-feature-ids hidden">[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 />
</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">
- Muscle wasting <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/88092000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">88092000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0541794&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0541794</a>, <a href="https://bioportal.bioontology.org/search?q=C0026846&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026846</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003202" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003202</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003202" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003202</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cognitive decline <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386806002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386806002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0338656&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0338656</a>, <a href="https://bioportal.bioontology.org/search?q=C0234985&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234985</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100543" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100543</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001268</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001268</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Mood changes <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 /> -
Agitation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/24199005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">24199005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085631&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085631</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000713" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000713</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000713" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000713</a>]</span><br /> -
Anxiety <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48694002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48694002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197480006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197480006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F41.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F41.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F41.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F41.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003469&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003469</a>, <a href="https://bioportal.bioontology.org/search?q=C0003467&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003467</a>, <a href="https://bioportal.bioontology.org/search?q=C0860603&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0860603</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000739" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000739</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000739" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000739</a>]</span><br /> -
Psychosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/191525009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">191525009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/69322001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">69322001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F29" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F29</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/298.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">298.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/290-299.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">290-299.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349204&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349204</a>, <a href="https://bioportal.bioontology.org/search?q=C0033975&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033975</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000709" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000709</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000709" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000709</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
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<strong> ENDOCRINE FEATURES </strong>
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<div style="margin-left: 2em;">
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- 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 /> -
Enlarged adrenal glands <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237782001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237782001</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">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1621895&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1621895</a>, <a href="https://bioportal.bioontology.org/search?q=C0342499&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0342499</a> 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> <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 /> -
Macronodular adrenal hyperplasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237778003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237778003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0342495&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0342495</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008231" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008231</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008231" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008231</a>]</span><br />
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<strong> NEOPLASIA </strong>
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- No progression to cancer <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1968778&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1968778</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 /> -
Cortisol does not decrease on dexamethasone suppression test <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1968779&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1968779</a>]</span><br /> -
Decreased serum ACTH <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1968856&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1968856</a>]</span><br />
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<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
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- Adult onset (40 to 60 years old) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853562&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853562</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span><br /> -
Variable expressivity, some patients may be clinically asymptomatic<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by somatic mutation in the GNAS gene (GNAS1, <a href="/entry/139320#0009">139320.0009</a>)<br />
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<h5>
ACTH-independent macronodular adrenal hyperplasia
- <a href="/phenotypicSeries/PS219080">PS219080</a>
- 3 Entries
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<strong>Phenotype</strong>
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<strong>Inheritance</strong>
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<strong>Gene/Locus</strong>
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<strong>Gene/Locus<br />MIM number</strong>
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<span class="mim-font">
<a href="/geneMap/1/265?start=-3&limit=10&highlight=265"> 1p36.12 </a>
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<a href="/entry/620990"> {ACTH-independent macronodular adrenal hyperplasia 3} </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/620990"> 620990 </a>
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<a href="/entry/609132"> KDM1A </a>
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<a href="/entry/609132"> 609132 </a>
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<a href="/geneMap/16/392?start=-3&limit=10&highlight=392"> 16p11.2 </a>
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<a href="/entry/615954"> {ACTH-independent macronodular adrenal hyperplasia 2} </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/615954"> 615954 </a>
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<a href="/entry/615549"> ARMC5 </a>
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<a href="/entry/615549"> 615549 </a>
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<a href="/geneMap/20/426?start=-3&limit=10&highlight=426"> 20q13.32 </a>
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<a href="/entry/219080"> ACTH-independent macronodular adrenal hyperplasia 1, somatic </a>
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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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<a href="/entry/219080"> 219080 </a>
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<a href="/entry/139320"> GNAS </a>
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<span class="mim-font">
<a href="/entry/139320"> 139320 </a>
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<p>A number sign (#) is used with this entry because ACTH-independent macronodular adrenal hyperplasia (AIMAH) can be caused by somatic mutation in the GNAS1 gene (<a href="/entry/139320">139320</a>) on chromosome 20q13. Bilateral adrenocortical nodular hyperplasia can also be found in McCune-Albright syndrome (<a href="/entry/174800">174800</a>), which is also caused by mutation in the GNAS1 gene.</p>
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<strong>Description</strong>
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<p>ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an endogenous form of adrenal Cushing syndrome characterized by multiple bilateral adrenocortical nodules that cause a striking enlargement of the adrenal glands. Although some familial cases have been reported, the vast majority of AIMAH cases are sporadic. Patients typically present in the fifth or sixth decade of life, approximately 10 years later than most patients with other causes of Cushing syndrome (<a href="#23" class="mim-tip-reference" title="Swain, J. M., Grant, C. S., Schlinkert, R. T., Thompson, G. B., van Heerden, J. A., Lloyd, R. V., Young, W. F. &lt;strong&gt;Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation.&lt;/strong&gt; Arch. Surg. 133: 541-546, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9605918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9605918&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archsurg.133.5.541&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9605918">Swain et al., 1998</a>; <a href="#5" class="mim-tip-reference" title="Christopoulos, S., Bourdeau, I., Lacroix, A. &lt;strong&gt;Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors.&lt;/strong&gt; Horm. Res. 64: 119-131, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16215323/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16215323&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000088818&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16215323">Christopoulos et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16215323+9605918" 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>Approximately 10 to 15% of adrenal Cushing syndrome is due to primary bilateral ACTH-independent adrenocortical pathology. The 2 main subtypes are AIMAH and primary pigmented nodular adrenocortical disease (PPNAD; see <a href="/entry/610489">610489</a>), which is often a component of the Carney complex (<a href="/entry/160980">160980</a>) and associated with mutations in the PRKAR1A gene (<a href="/entry/188830">188830</a>). AIMAH is rare, representing less than 1% of endogenous causes of Cushing syndrome (<a href="#23" class="mim-tip-reference" title="Swain, J. M., Grant, C. S., Schlinkert, R. T., Thompson, G. B., van Heerden, J. A., Lloyd, R. V., Young, W. F. &lt;strong&gt;Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation.&lt;/strong&gt; Arch. Surg. 133: 541-546, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9605918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9605918&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archsurg.133.5.541&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9605918">Swain et al., 1998</a>; <a href="#5" class="mim-tip-reference" title="Christopoulos, S., Bourdeau, I., Lacroix, A. &lt;strong&gt;Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors.&lt;/strong&gt; Horm. Res. 64: 119-131, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16215323/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16215323&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000088818&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16215323">Christopoulos et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16215323+9605918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>See also ACTH-independent Cushing syndrome (<a href="/entry/615830">615830</a>) due to somatic mutation in the PRKACA gene (<a href="/entry/601639">601639</a>).</p><p>Cushing 'disease' (<a href="/entry/219090">219090</a>) is an ACTH-dependent disorder caused in most cases by pituitary adenomas that secrete excessive ACTH.</p><p><strong><em>Genetic Heterogeneity of ACTH-Independent Macronodular Adrenal Hyperplasia</em></strong></p><p>
AIMAH2 (<a href="/entry/615954">615954</a>) is caused by germline mutation on 1 allele of the ARMC5 gene (<a href="/entry/615549">615549</a>) coupled with a somatic mutation in the other allele. AIMAH3 (<a href="/entry/620990">620990</a>) is caused by germline mutation on 1 allele of the KDM1A gene (<a href="/entry/609132">609132</a>) coupled with a somatic mutation in the other allele.</p>
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<p><a href="#9" class="mim-tip-reference" title="Kirschner, M. A., Powell, R. D., Jr., Lipsett, M. B. &lt;strong&gt;Cushing&#x27;s syndrome: nodular cortical hyperplasia of adrenal glands with clinical and pathological features suggesting adrenocortical tumor.&lt;/strong&gt; J. Clin. Endocr. 24: 947-955, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14228534/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14228534&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem-24-10-947&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14228534">Kirschner et al. (1964)</a> first reported AIMAH in a 40-year-old woman with long-standing Cushing syndrome (<a href="#5" class="mim-tip-reference" title="Christopoulos, S., Bourdeau, I., Lacroix, A. &lt;strong&gt;Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors.&lt;/strong&gt; Horm. Res. 64: 119-131, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16215323/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16215323&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000088818&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16215323">Christopoulos et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16215323+14228534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Findlay, J. C., Sheeler, L. R., Engeland, W. C., Aron, D. C. &lt;strong&gt;Familial adrenocorticotropin-independent Cushing&#x27;s syndrome with bilateral macronodular adrenal hyperplasia.&lt;/strong&gt; J. Clin. Endocr. Metab. 76: 189-191, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8380604/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8380604&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.76.1.8380604&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8380604">Findlay et al. (1993)</a> reported a mother and daughter who each presented with clinical features of Cushing syndrome at age 38 years and were found to have AIMAH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8380604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Minami, S., Sugihara, H., Sato, J., Tatsukuchi, A., Sugisaki, Y., Sasano, H., Wakabayashi, I. &lt;strong&gt;ACTH independent Cushing&#x27;s syndrome occurring in siblings.&lt;/strong&gt; Clin. Endocr. 44: 483-488, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8706318/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8706318&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1046/j.1365-2265.1996.682504.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8706318">Minami et al. (1996)</a> reported 2 Japanese sibs with Cushing syndrome due to AIMAH. The proband was a 69-year-old woman who presented with easy bruising, fatigability, muscle weakness, hypertension, and cognitive decline. She had truncal obesity, 'moon facies,' muscle wasting, and pretibial edema. Serum cortisol was elevated and did not respond to dexamethasone; CT scan showed bilateral adrenal enlargement. The patient died of subarachnoid hemorrhage and postmortem examination confirmed AIMAH. Family history revealed an older brother with AIMAH who had died postoperatively. Two additional sibs showed bilateral enlargement of the adrenal glands as well as impaired response to dexamethasone, although they were not clinically Cushingoid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8706318" 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="#23" class="mim-tip-reference" title="Swain, J. M., Grant, C. S., Schlinkert, R. T., Thompson, G. B., van Heerden, J. A., Lloyd, R. V., Young, W. F. &lt;strong&gt;Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation.&lt;/strong&gt; Arch. Surg. 133: 541-546, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9605918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9605918&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archsurg.133.5.541&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9605918">Swain et al. (1998)</a> reported 9 unrelated patients with AIMAH who underwent curative bilateral adrenalectomy. The mean age was 56 years. All patients had increased serum cortisol, decreased serum ACTH, and failed to show suppression of cortisol excretion following dexamethasone administration. All patients except 1 had hypertension; subtle signs or symptoms consistent with Cushing syndrome were noted in patients' histories dating back up to 20 years. Pathologic examination showed bilateral adrenal cortical nodules that were yellow and ranged in size from 1 to 4.2 cm within enlarged adrenal glands weighing from 16.7 to 218 g combined. Microscopic analysis showed hyperplastic nodules composed of clear cells in cord-like arrangements and compact eosinophilic cells occasionally interspersed with atrophic nonnodular cortex. <a href="#23" class="mim-tip-reference" title="Swain, J. M., Grant, C. S., Schlinkert, R. T., Thompson, G. B., van Heerden, J. A., Lloyd, R. V., Young, W. F. &lt;strong&gt;Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation.&lt;/strong&gt; Arch. Surg. 133: 541-546, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9605918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9605918&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archsurg.133.5.541&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9605918">Swain et al. (1998)</a> cited studies (<a href="#1" class="mim-tip-reference" title="Aiba, M., Hirayama, A., Iri, H., Ito, Y., Fujimoto, Y., Mabuchi, G., Murai, M., Tazaki, H., Maruyama, H., Saruta, T., Suda, T., Demura, H. &lt;strong&gt;Adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia as a distinct subtype of Cushing&#x27;s syndrome: enzyme histochemical and ultrastructural study of four cases with a review of the literature.&lt;/strong&gt; Am. J. Clin. Path. 96: 334-340, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1652202/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1652202&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/ajcp/96.3.334&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1652202">Aiba et al., 1991</a>; <a href="#21" class="mim-tip-reference" title="Sasano, H., Suzuki, T., Nagura, H. &lt;strong&gt;ACTH-independent macronodular adrenocortical hyperplasia: immunohistochemical and in situ hybridization studies of steroidogenic enzymes.&lt;/strong&gt; Mod. Path. 7: 215-219, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8008746/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8008746&lt;/a&gt;]" pmid="8008746">Sasano et al., 1994</a>; <a href="#18" class="mim-tip-reference" title="Morioka, M., Ohashi, Y., Watanabe, H., Komatsu, F., Jin, T.-X., Suyama, B., Tanaka, H. &lt;strong&gt;ACTH-independent macronodular adrenocortical hyperplasia (AIMAH): report of two cases and the analysis of steroidogenic activity in adrenal nodules.&lt;/strong&gt; Endocr. J. 44: 65-72, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9152616/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9152616&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1507/endocrj.44.65&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9152616">Morioka et al., 1997</a>; <a href="#10" class="mim-tip-reference" title="Koizumi, S., Beniko, M., Ikota, A., Mizumoto, H., Matsuya, K., Matsuda, A., Sakuma, S., Mashio, Y., Kunita, H., Okamoto, K., Sasano, H. &lt;strong&gt;Adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia: a case report and immunohistochemical studies.&lt;/strong&gt; Endocr. J. 41: 429-435, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8528359/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8528359&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1507/endocrj.41.429&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8528359">Koizumi et al., 1994</a>) indicating that AIMAH nodules show impaired steroidogenesis, suggesting a primary intrinsic alteration in the adrenal cells. Importantly, none of the patients developed Nelson syndrome (pituitary tumor) after adrenalectomy and none showed any sign of malignancy. <a href="#23" class="mim-tip-reference" title="Swain, J. M., Grant, C. S., Schlinkert, R. T., Thompson, G. B., van Heerden, J. A., Lloyd, R. V., Young, W. F. &lt;strong&gt;Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation.&lt;/strong&gt; Arch. Surg. 133: 541-546, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9605918/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9605918&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archsurg.133.5.541&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9605918">Swain et al. (1998)</a> concluded that AIMAH is a distinct and legitimate disease entity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8008746+1652202+9152616+8528359+9605918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Doppman, J. L., Chrousos, G. P., Papanicolaou, D. A., Stratakis, C. A., Alexander, H. R., Nieman, L. K. &lt;strong&gt;Adrenocorticotropin-independent macronodular adrenal hyperplasia: an uncommon cause of primary adrenal hypercortisolism.&lt;/strong&gt; Radiology 216: 797-802, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10966714/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10966714&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1148/radiology.216.3.r00au40797&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10966714">Doppman et al. (2000)</a> reported the radiographic findings of 11 patients with AIMAH and noted that the adrenal glands are often massive with combined weights up to 300 g and individual nodules up to 5 cm in diameter. One male patient reportedly had a brother with surgically-proven AIMAH. The authors commented that the clinical manifestations of Cushing syndrome are mild in many patients with AIMAH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10966714" 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="#20" class="mim-tip-reference" title="Nies, C., Bartsch, D. K., Ehlenz, K., Wild, A., Langer, P., Fleischhacker, S., Rothmund, M. &lt;strong&gt;Familial ACTH-independent Cushing&#x27;s syndrome with bilateral macronodular adrenal hyperplasia clinically affecting only female family members.&lt;/strong&gt; Exp. Clin. Endocr. Diabetes 110: 277-283, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12373631/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12373631&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1055/s-2002-34590&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12373631">Nies et al. (2002)</a> reported a family in which 3 female members had clinically symptomatic AIMAH. Three deceased female family members were reportedly affected. Although the father, who was determined to be an obligate carrier, had no overt symptoms, his adrenal glands showed nodular hyperplasia and he had impaired cortisol suppression on dexamethasone administration. <a href="#20" class="mim-tip-reference" title="Nies, C., Bartsch, D. K., Ehlenz, K., Wild, A., Langer, P., Fleischhacker, S., Rothmund, M. &lt;strong&gt;Familial ACTH-independent Cushing&#x27;s syndrome with bilateral macronodular adrenal hyperplasia clinically affecting only female family members.&lt;/strong&gt; Exp. Clin. Endocr. Diabetes 110: 277-283, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12373631/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12373631&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1055/s-2002-34590&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12373631">Nies et al. (2002)</a> suggested autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12373631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Lee, S., Hwang, R., Lee, J., Rhee, Y., Kim, D. J., Chung, U., Lim, S.-K. &lt;strong&gt;Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia.&lt;/strong&gt; Clin. Endocr. 63: 625-630, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16343095/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16343095&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2265.2005.02387.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16343095">Lee et al. (2005)</a> reported 2 Asian sisters who developed AIMAH at ages 46 and 58 years, respectively. Both patients had typical Cushingoid features, including 'moon facies,' dorsocervical fat pad ('buffalo hump'), and central obesity; 1 had purple striae. Both had increased serum cortisol and bilateral adrenal masses, and both had meningiomas, which may or may not have been related. Pituitary tumors were not present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16343095" 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="pathogenesis" class="mim-anchor"></a>
<h4 href="#mimPathogenesisFold" id="mimPathogenesisToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Pathogenesis</strong>
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<p><strong><em>Aberrant Hormone Receptors</em></strong></p><p>
Several groups have shown that cortisol hypersecretion in AIMAH can be regulated by hormones other than ACTH via the ectopic expression or the overactive eutopic expression of several membrane-bound hormone receptors in the adrenal cortex. These include gastric inhibitory polypeptide receptor (GIPR; <a href="/entry/137241">137241</a>), various vasopressin receptors (AVPR1A, <a href="/entry/600821">600821</a>; AVPR1B, <a href="/entry/600264">600264</a>; AVPR2; <a href="/entry/300538">300538</a>), beta-adrenergic receptors (see, e.g., ADRB1; <a href="/entry/109630">109630</a>), the LH/human CG receptor (LHCGR; <a href="/entry/152790">152790</a>), the serotonin 5-HT4 receptor (HTR4; <a href="/entry/602164">602164</a>), and the angiotensin receptor (AGTR1; <a href="/entry/106165">106165</a>) (<a href="#5" class="mim-tip-reference" title="Christopoulos, S., Bourdeau, I., Lacroix, A. &lt;strong&gt;Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors.&lt;/strong&gt; Horm. Res. 64: 119-131, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16215323/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16215323&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000088818&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16215323">Christopoulos et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16215323" 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="#13" class="mim-tip-reference" title="Lacroix, A., Tremblay, J., Touyz, R. M., Deng, L. Y., Lariviere, R., Cusson, J. R., Schiffrin, E. L., Hamet, P. &lt;strong&gt;Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing&#x27;s syndrome, and orthostatic hypotension.&lt;/strong&gt; J. Clin. Endocr. Metab. 82: 2414-2422, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9253310/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9253310&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.82.8.4140&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9253310">Lacroix et al. (1997)</a> reported a 36-year-old woman with Cushing syndrome due to AIMAH who had orthostatic hypotension. During upright posture, the patient's cortisol and aldosterone levels were stimulated despite suppression of ACTH and renin. Arginine vasopressin (AVP; <a href="/entry/192340">192340</a>) was found to increase plasma cortisol, aldosterone, and androgens in this patient but not in controls. Following adrenalectomy, orthostatic hypotension persisted; a prolonged vasoconstrictive response to AVP was found in vitro in the patient's small arteries. <a href="#13" class="mim-tip-reference" title="Lacroix, A., Tremblay, J., Touyz, R. M., Deng, L. Y., Lariviere, R., Cusson, J. R., Schiffrin, E. L., Hamet, P. &lt;strong&gt;Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing&#x27;s syndrome, and orthostatic hypotension.&lt;/strong&gt; J. Clin. Endocr. Metab. 82: 2414-2422, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9253310/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9253310&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.82.8.4140&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9253310">Lacroix et al. (1997)</a> suggested altered adrenal and vascular responses of the AVP V1 receptor (see <a href="/entry/600821">600821</a>). <a href="#19" class="mim-tip-reference" title="Mune, T., Murase, H., Yamakita, N., Fukuda, T., Murayama, M., Miura, A., Suwa, T., Hanafusa, J., Daido, H., Morita, H., Yasuda, K. &lt;strong&gt;Eutopic overexpression of vasopressin V1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia.&lt;/strong&gt; J. Clin. Endocr. Metab. 87: 5706-5713, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12466375/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12466375&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2002-020067&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12466375">Mune et al. (2002)</a> found increased levels of AVPR1A mRNA in adrenal tissue from 4 patients with AIMAH, suggesting that eutopic V1A receptor overexpression is involved in the etiology. <a href="#17" class="mim-tip-reference" title="Miyamura, N., Taguchi, T., Murata, Y., Taketa, K., Iwashita, S., Matsumoto, K., Nishikawa, T., Toyonaga, T., Sakakida, M., Araki, E. &lt;strong&gt;Inherited adrenocorticotropin-independent macronodular adrenal hyperplasia with abnormal cortisol secretion by vasopressin and catecholamines: detection of the aberrant hormone receptors on adrenal gland.&lt;/strong&gt; Endocrine 19: 319-326, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12624433/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12624433&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1385/ENDO:19:3:319&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12624433">Miyamura et al. (2002)</a> reported a mother and son with AIMAH in whom AVP and catecholamines promoted cortisol secretion. RT-PCR of adrenal tissue from the mother showed abnormal expression of AVPR1B, AVPR2, and LHCGR, none of which was observed in a normal control. In 2 sisters with AIMAH, <a href="#14" class="mim-tip-reference" title="Lee, S., Hwang, R., Lee, J., Rhee, Y., Kim, D. J., Chung, U., Lim, S.-K. &lt;strong&gt;Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia.&lt;/strong&gt; Clin. Endocr. 63: 625-630, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16343095/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16343095&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2265.2005.02387.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16343095">Lee et al. (2005)</a> demonstrated that AVP promoted cortisol secretion through overexpression of AVPR1A. In addition, RT-PCR analysis revealed abnormal cDNA expression of AVPR1B and AVPR2, which are normally not expressed in the adrenal gland. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9253310+12466375+16343095+12624433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Lacroix, A., Tremblay, J., Rousseau, G., Bouvier, M., Hamet, P. &lt;strong&gt;Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing&#x27;s syndrome.&lt;/strong&gt; New Eng. J. Med. 337: 1429-1434, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9358140/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9358140&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199711133372004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9358140">Lacroix et al. (1997)</a> reported a 56-year-old man with AIMAH who showed increased serum cortisol when changing from a supine to upright posture and in response to insulin-induced hypoglycemia, suggesting mediation by a beta-adrenergic receptor. Treatment with propranolol was effective, and the authors suggested that ectopic receptor expression led to catecholamine-induced adrenal hyperplasia in this patient. <a href="#11" class="mim-tip-reference" title="Lacroix, A., Hamet, P., Boutin, J.-M. &lt;strong&gt;Leuprolide acetate therapy in luteinizing hormone-dependent Cushing&#x27;s syndrome.&lt;/strong&gt; New Eng. J. Med. 341: 1577-1581, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10564687/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10564687&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199911183412104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10564687">Lacroix et al. (1999)</a> reported a woman with AIMAH that was clinically manifest transiently during pregnancy. Studies showed that the cortisol secretion was stimulated by luteinizing hormone (LH; <a href="/entry/152780">152780</a>), HCG (<a href="/entry/118850">118850</a>), and by drugs that activated 5HT-4 receptors. Long-term suppression of LH secretion with leuprolide led to reversal of symptoms. <a href="#11" class="mim-tip-reference" title="Lacroix, A., Hamet, P., Boutin, J.-M. &lt;strong&gt;Leuprolide acetate therapy in luteinizing hormone-dependent Cushing&#x27;s syndrome.&lt;/strong&gt; New Eng. J. Med. 341: 1577-1581, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10564687/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10564687&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199911183412104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10564687">Lacroix et al. (1999)</a> noted that the identification of ectopic adrenal receptors could lead to medical treatment for such patients as alternatives to adrenalectomy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9358140+10564687" 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="Cartier, D., Lihrmann, I., Parmentier, F., Bastard, C., Bertherat, J., Caron, P., Kuhn, J.-M., Lacroix, A., Tabarin, A., Young, J., Vaudry, H., Lefebvre, H. &lt;strong&gt;Overexpression of serotonin-4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing&#x27;s syndrome.&lt;/strong&gt; J. Clin. Endocr. Metab. 88: 248-254, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12519861/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12519861&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2002-021107&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12519861">Cartier et al. (2003)</a> reported overexpression of 5HT-4 receptors in adrenal tissue from 4 of 6 patients with cisapride-responsive AIMAH. Sequencing of the 5HT4 receptor gene in 2 patients did not reveal any mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12519861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Mircescu, H., Jilwan, J., N&#x27;Diaye, N., Bourdeau, I., Tremblay, J., Hamet, P., Lacroix, A. &lt;strong&gt;Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing&#x27;s syndrome?&lt;/strong&gt; J. Clin. Endocr. Metab. 85: 3531-3536, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11061496/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11061496&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.85.10.6865&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11061496">Mircescu et al. (2000)</a> found 1 or 2 abnormal hormone receptors in adrenal tissue from all 6 patients with AIMAH who were studied. The findings suggested that aberrant hormone receptors in adrenal tissue are common in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11061496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review, <a href="#5" class="mim-tip-reference" title="Christopoulos, S., Bourdeau, I., Lacroix, A. &lt;strong&gt;Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors.&lt;/strong&gt; Horm. Res. 64: 119-131, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16215323/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16215323&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000088818&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16215323">Christopoulos et al. (2005)</a> stated that most patients with AIMAH, when screened, have been shown to have aberrant expression of receptors in the adrenal gland resulting in increased cortisol secretion; many patients show aberrant expression of more than 1 receptor. The authors suggested that dysregulation of tissue-specific receptor expression may indicate a disruption of gene regulatory elements in the early stages of embryogenesis since the pathology involves the entire adrenal cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16215323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p><a href="#8" class="mim-tip-reference" title="Fragoso, M. C. B. V., Domenice, S., Latronico, A. C., Martin, R. M., Pereira, M. A. A., Zerbini, M. C. N., Lucon, A. M., Mendonca, B. B. &lt;strong&gt;Cushing&#x27;s syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene.&lt;/strong&gt; J. Clin. Endocr. Metab. 88: 2147-2151, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12727968/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12727968&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2002-021362&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12727968">Fragoso et al. (2003)</a> identified somatic heterozygous mutations in the GNAS1 gene (R201H, <a href="/entry/139320#0009">139320.0009</a> and R201S, <a href="/entry/139320#0013">139320.0013</a>) in adrenal tissue from 3 unrelated patients with AIMAH. The mutations resulted in constitutive activation of the G protein. The mutations were not present in peripheral blood, and none of the patients had signs of McCune-Albright syndrome. <a href="#8" class="mim-tip-reference" title="Fragoso, M. C. B. V., Domenice, S., Latronico, A. C., Martin, R. M., Pereira, M. A. A., Zerbini, M. C. N., Lucon, A. M., Mendonca, B. B. &lt;strong&gt;Cushing&#x27;s syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene.&lt;/strong&gt; J. Clin. Endocr. Metab. 88: 2147-2151, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12727968/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12727968&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2002-021362&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12727968">Fragoso et al. (2003)</a> discussed whether the patients could be considered part of the spectrum of McCune-Albright syndrome or whether they represent isolated cases of AIMAH associated with somatic mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12727968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By cDNA microarray analysis of adrenal tissue from 8 AIMAH patients, <a href="#2" class="mim-tip-reference" title="Bourdeau, I., Antonini, S. R., Lacroix, A., Kirschner, L. S., Matyakhina, L., Lorang, D., Libutti, S. K., Stratakis, C. A. &lt;strong&gt;Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators.&lt;/strong&gt; Oncogene 23: 1575-1585, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14767469/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14767469&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.onc.1207277&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14767469">Bourdeau et al. (2004)</a> found upregulation of several genes involved in transcription, chromatin remodeling, and cell cycle and adhesion. There were differences in gene expression between those with and without GIP-dependent AIMAH, confirming clinical heterogeneity and suggesting distinct diagnostic subgroups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14767469" 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="#22" 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> identified 2 different somatic heterozygous mutations in the GNAS1 gene, both affecting the codon R201 (R201H, <a href="/entry/139320#0009">139320.0009</a> and R201C, <a href="/entry/139320#0008">139320.0008</a>), in 11 (16.9%) of 65 cases of corticotropin-independent adrenal Cushing syndrome. The mutations were confirmed to be somatic in all 6 cases tested. GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported. <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><p><a href="#3" class="mim-tip-reference" title="Bourdeau, I., Matyakhina, L., Stergiopoulos, S. G., Sandrini, F., Boikos, S., Stratakis, C. A. &lt;strong&gt;17q22-24 chromosomal losses and alterations of protein kinase A subunit expression and activity in adrenocorticotropin-independent macronodular adrenal hyperplasia.&lt;/strong&gt; J. Clin. Endocr. Metab. 91: 3626-3632, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16772351/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16772351&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2005-2608&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16772351">Bourdeau et al. (2006)</a> did not identify mutations in the PRKAR1A gene in 14 unrelated patients with sporadic AIMAH. However, 91% of the tumor tissue samples showed somatic loss of heterozygosity (LOH) of chromosome 2p16, where Carney complex-2 (CNC2; <a href="/entry/605244">605244</a>) has been mapped, and 73% of tissue samples showed somatic LOH of 17q22-q24, where the PRKAR1A gene is located. Total protein kinase A activity was higher in AIMAH tissue compared to normal adrenal glands. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16772351" 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="Bourdeau2004" class="mim-anchor"></a>
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Bourdeau, I., Antonini, S. R., Lacroix, A., Kirschner, L. S., Matyakhina, L., Lorang, D., Libutti, S. K., Stratakis, C. A.
<strong>Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators.</strong>
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<a id="Bourdeau2006" class="mim-anchor"></a>
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<p class="mim-text-font">
Bourdeau, I., Matyakhina, L., Stergiopoulos, S. G., Sandrini, F., Boikos, S., Stratakis, C. A.
<strong>17q22-24 chromosomal losses and alterations of protein kinase A subunit expression and activity in adrenocorticotropin-independent macronodular adrenal hyperplasia.</strong>
J. Clin. Endocr. Metab. 91: 3626-3632, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16772351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16772351</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16772351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Cartier2003" class="mim-anchor"></a>
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Cartier, D., Lihrmann, I., Parmentier, F., Bastard, C., Bertherat, J., Caron, P., Kuhn, J.-M., Lacroix, A., Tabarin, A., Young, J., Vaudry, H., Lefebvre, H.
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[<a href="https://doi.org/10.1210/jc.2002-021107" target="_blank">Full Text</a>]
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<a id="Christopoulos2005" class="mim-anchor"></a>
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Christopoulos, S., Bourdeau, I., Lacroix, A.
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Horm. Res. 64: 119-131, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16215323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16215323</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16215323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1159/000088818" target="_blank">Full Text</a>]
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<a id="Doppman2000" class="mim-anchor"></a>
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Doppman, J. L., Chrousos, G. P., Papanicolaou, D. A., Stratakis, C. A., Alexander, H. R., Nieman, L. K.
<strong>Adrenocorticotropin-independent macronodular adrenal hyperplasia: an uncommon cause of primary adrenal hypercortisolism.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10966714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10966714</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10966714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1148/radiology.216.3.r00au40797" target="_blank">Full Text</a>]
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<a id="Findlay1993" class="mim-anchor"></a>
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Findlay, J. C., Sheeler, L. R., Engeland, W. C., Aron, D. C.
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[<a href="https://doi.org/10.1210/jcem.76.1.8380604" target="_blank">Full Text</a>]
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Fragoso, M. C. B. V., Domenice, S., Latronico, A. C., Martin, R. M., Pereira, M. A. A., Zerbini, M. C. N., Lucon, A. M., Mendonca, B. B.
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[<a href="https://doi.org/10.1210/jc.2002-021362" target="_blank">Full Text</a>]
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Kirschner, M. A., Powell, R. D., Jr., Lipsett, M. B.
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[<a href="https://doi.org/10.1210/jcem-24-10-947" target="_blank">Full Text</a>]
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Koizumi, S., Beniko, M., Ikota, A., Mizumoto, H., Matsuya, K., Matsuda, A., Sakuma, S., Mashio, Y., Kunita, H., Okamoto, K., Sasano, H.
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[<a href="https://doi.org/10.1507/endocrj.41.429" target="_blank">Full Text</a>]
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Lacroix, A., Hamet, P., Boutin, J.-M.
<strong>Leuprolide acetate therapy in luteinizing hormone-dependent Cushing's syndrome.</strong>
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[<a href="https://doi.org/10.1056/NEJM199911183412104" target="_blank">Full Text</a>]
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<a id="Lacroix1997" class="mim-anchor"></a>
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Lacroix, A., Tremblay, J., Rousseau, G., Bouvier, M., Hamet, P.
<strong>Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing's syndrome.</strong>
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[<a href="https://doi.org/10.1056/NEJM199711133372004" target="_blank">Full Text</a>]
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<a id="Lacroix1997" class="mim-anchor"></a>
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<p class="mim-text-font">
Lacroix, A., Tremblay, J., Touyz, R. M., Deng, L. Y., Lariviere, R., Cusson, J. R., Schiffrin, E. L., Hamet, P.
<strong>Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing's syndrome, and orthostatic hypotension.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9253310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9253310</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9253310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem.82.8.4140" target="_blank">Full Text</a>]
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<a id="Lee2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lee, S., Hwang, R., Lee, J., Rhee, Y., Kim, D. J., Chung, U., Lim, S.-K.
<strong>Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16343095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16343095</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16343095" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1365-2265.2005.02387.x" target="_blank">Full Text</a>]
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<a id="Minami1996" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Minami, S., Sugihara, H., Sato, J., Tatsukuchi, A., Sugisaki, Y., Sasano, H., Wakabayashi, I.
<strong>ACTH independent Cushing's syndrome occurring in siblings.</strong>
Clin. Endocr. 44: 483-488, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8706318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8706318</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8706318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1046/j.1365-2265.1996.682504.x" target="_blank">Full Text</a>]
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<a id="Mircescu2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Mircescu, H., Jilwan, J., N'Diaye, N., Bourdeau, I., Tremblay, J., Hamet, P., Lacroix, A.
<strong>Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing's syndrome?</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11061496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11061496</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11061496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem.85.10.6865" target="_blank">Full Text</a>]
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Miyamura, N., Taguchi, T., Murata, Y., Taketa, K., Iwashita, S., Matsumoto, K., Nishikawa, T., Toyonaga, T., Sakakida, M., Araki, E.
<strong>Inherited adrenocorticotropin-independent macronodular adrenal hyperplasia with abnormal cortisol secretion by vasopressin and catecholamines: detection of the aberrant hormone receptors on adrenal gland.</strong>
Endocrine 19: 319-326, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12624433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12624433</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12624433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1385/ENDO:19:3:319" target="_blank">Full Text</a>]
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Morioka, M., Ohashi, Y., Watanabe, H., Komatsu, F., Jin, T.-X., Suyama, B., Tanaka, H.
<strong>ACTH-independent macronodular adrenocortical hyperplasia (AIMAH): report of two cases and the analysis of steroidogenic activity in adrenal nodules.</strong>
Endocr. J. 44: 65-72, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9152616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9152616</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9152616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1507/endocrj.44.65" target="_blank">Full Text</a>]
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<a id="Mune2002" class="mim-anchor"></a>
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Mune, T., Murase, H., Yamakita, N., Fukuda, T., Murayama, M., Miura, A., Suwa, T., Hanafusa, J., Daido, H., Morita, H., Yasuda, K.
<strong>Eutopic overexpression of vasopressin V1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia.</strong>
J. Clin. Endocr. Metab. 87: 5706-5713, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12466375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12466375</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12466375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jc.2002-020067" target="_blank">Full Text</a>]
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<a id="Nies2002" class="mim-anchor"></a>
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Nies, C., Bartsch, D. K., Ehlenz, K., Wild, A., Langer, P., Fleischhacker, S., Rothmund, M.
<strong>Familial ACTH-independent Cushing's syndrome with bilateral macronodular adrenal hyperplasia clinically affecting only female family members.</strong>
Exp. Clin. Endocr. Diabetes 110: 277-283, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12373631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12373631</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12373631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1055/s-2002-34590" target="_blank">Full Text</a>]
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<a id="Sasano1994" class="mim-anchor"></a>
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Sasano, H., Suzuki, T., Nagura, H.
<strong>ACTH-independent macronodular adrenocortical hyperplasia: immunohistochemical and in situ hybridization studies of steroidogenic enzymes.</strong>
Mod. Path. 7: 215-219, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8008746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8008746</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8008746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Sato2014" class="mim-anchor"></a>
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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'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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<a id="Swain1998" class="mim-anchor"></a>
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Swain, J. M., Grant, C. S., Schlinkert, R. T., Thompson, G. B., van Heerden, J. A., Lloyd, R. V., Young, W. F.
<strong>Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation.</strong>
Arch. Surg. 133: 541-546, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9605918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9605918</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9605918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archsurg.133.5.541" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 8/19/2014
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Cassandra L. Kniffin - reorganized : 10/18/2006<br>Cassandra L. Kniffin - updated : 10/17/2006<br>Victor A. McKusick - updated : 6/30/2006<br>John A. Phillips, III - updated : 4/8/2003<br>John A. Phillips, III - updated : 3/16/2001<br>John A. Phillips, III - updated : 10/30/1997
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Victor A. McKusick : 6/3/1986
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alopez : 10/22/2024
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carol : 02/29/2024<br>joanna : 08/04/2016<br>carol : 09/26/2014<br>alopez : 8/21/2014<br>carol : 8/19/2014<br>mcolton : 8/19/2014<br>ckniffin : 8/19/2014<br>ckniffin : 6/3/2014<br>terry : 9/20/2007<br>carol : 10/18/2006<br>ckniffin : 10/17/2006<br>alopez : 7/5/2006<br>terry : 6/30/2006<br>ckniffin : 8/3/2005<br>alopez : 2/12/2004<br>tkritzer : 4/14/2003<br>tkritzer : 4/9/2003<br>terry : 4/8/2003<br>alopez : 3/16/2001<br>alopez : 8/30/1999<br>dholmes : 10/30/1997<br>dholmes : 10/28/1997<br>dholmes : 10/15/1997<br>mark : 12/26/1996<br>terry : 12/16/1996<br>mimadm : 2/19/1994<br>carol : 7/6/1993<br>carol : 7/2/1993<br>carol : 4/21/1992<br>supermim : 3/16/1992<br>supermim : 3/20/1990
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<strong>#</strong> 219080
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ACTH-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA; AIMAH1
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<em>Alternative titles; symbols</em>
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ACTH-INDEPENDENT MACRONODULAR ADRENOCORTICAL HYPERPLASIA<br />
ADRENOCORTICOTROPIC HORMONE-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA<br />
CORTICOTROPIN-INDEPENDENT MACRONODULAR ADRENAL HYPERPLASIA<br />
CUSHING SYNDROME, ADRENAL, DUE TO AIMAH
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<strong>ORPHA:</strong> 189427; &nbsp;
<strong>DO:</strong> 0111623; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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20q13.32
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ACTH-independent macronodular adrenal hyperplasia 1, somatic
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219080
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3
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GNAS
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139320
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because ACTH-independent macronodular adrenal hyperplasia (AIMAH) can be caused by somatic mutation in the GNAS1 gene (139320) on chromosome 20q13. Bilateral adrenocortical nodular hyperplasia can also be found in McCune-Albright syndrome (174800), which is also caused by mutation in the GNAS1 gene.</p>
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<strong>Description</strong>
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<p>ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an endogenous form of adrenal Cushing syndrome characterized by multiple bilateral adrenocortical nodules that cause a striking enlargement of the adrenal glands. Although some familial cases have been reported, the vast majority of AIMAH cases are sporadic. Patients typically present in the fifth or sixth decade of life, approximately 10 years later than most patients with other causes of Cushing syndrome (Swain et al., 1998; Christopoulos et al., 2005). </p><p>Approximately 10 to 15% of adrenal Cushing syndrome is due to primary bilateral ACTH-independent adrenocortical pathology. The 2 main subtypes are AIMAH and primary pigmented nodular adrenocortical disease (PPNAD; see 610489), which is often a component of the Carney complex (160980) and associated with mutations in the PRKAR1A gene (188830). AIMAH is rare, representing less than 1% of endogenous causes of Cushing syndrome (Swain et al., 1998; Christopoulos et al., 2005). </p><p>See also ACTH-independent Cushing syndrome (615830) due to somatic mutation in the PRKACA gene (601639).</p><p>Cushing 'disease' (219090) is an ACTH-dependent disorder caused in most cases by pituitary adenomas that secrete excessive ACTH.</p><p><strong><em>Genetic Heterogeneity of ACTH-Independent Macronodular Adrenal Hyperplasia</em></strong></p><p>
AIMAH2 (615954) is caused by germline mutation on 1 allele of the ARMC5 gene (615549) coupled with a somatic mutation in the other allele. AIMAH3 (620990) is caused by germline mutation on 1 allele of the KDM1A gene (609132) coupled with a somatic mutation in the other allele.</p>
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<strong>Clinical Features</strong>
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<p>Kirschner et al. (1964) first reported AIMAH in a 40-year-old woman with long-standing Cushing syndrome (Christopoulos et al., 2005). </p><p>Findlay et al. (1993) reported a mother and daughter who each presented with clinical features of Cushing syndrome at age 38 years and were found to have AIMAH. </p><p>Minami et al. (1996) reported 2 Japanese sibs with Cushing syndrome due to AIMAH. The proband was a 69-year-old woman who presented with easy bruising, fatigability, muscle weakness, hypertension, and cognitive decline. She had truncal obesity, 'moon facies,' muscle wasting, and pretibial edema. Serum cortisol was elevated and did not respond to dexamethasone; CT scan showed bilateral adrenal enlargement. The patient died of subarachnoid hemorrhage and postmortem examination confirmed AIMAH. Family history revealed an older brother with AIMAH who had died postoperatively. Two additional sibs showed bilateral enlargement of the adrenal glands as well as impaired response to dexamethasone, although they were not clinically Cushingoid. </p><p>Swain et al. (1998) reported 9 unrelated patients with AIMAH who underwent curative bilateral adrenalectomy. The mean age was 56 years. All patients had increased serum cortisol, decreased serum ACTH, and failed to show suppression of cortisol excretion following dexamethasone administration. All patients except 1 had hypertension; subtle signs or symptoms consistent with Cushing syndrome were noted in patients' histories dating back up to 20 years. Pathologic examination showed bilateral adrenal cortical nodules that were yellow and ranged in size from 1 to 4.2 cm within enlarged adrenal glands weighing from 16.7 to 218 g combined. Microscopic analysis showed hyperplastic nodules composed of clear cells in cord-like arrangements and compact eosinophilic cells occasionally interspersed with atrophic nonnodular cortex. Swain et al. (1998) cited studies (Aiba et al., 1991; Sasano et al., 1994; Morioka et al., 1997; Koizumi et al., 1994) indicating that AIMAH nodules show impaired steroidogenesis, suggesting a primary intrinsic alteration in the adrenal cells. Importantly, none of the patients developed Nelson syndrome (pituitary tumor) after adrenalectomy and none showed any sign of malignancy. Swain et al. (1998) concluded that AIMAH is a distinct and legitimate disease entity. </p><p>Doppman et al. (2000) reported the radiographic findings of 11 patients with AIMAH and noted that the adrenal glands are often massive with combined weights up to 300 g and individual nodules up to 5 cm in diameter. One male patient reportedly had a brother with surgically-proven AIMAH. The authors commented that the clinical manifestations of Cushing syndrome are mild in many patients with AIMAH. </p><p>Nies et al. (2002) reported a family in which 3 female members had clinically symptomatic AIMAH. Three deceased female family members were reportedly affected. Although the father, who was determined to be an obligate carrier, had no overt symptoms, his adrenal glands showed nodular hyperplasia and he had impaired cortisol suppression on dexamethasone administration. Nies et al. (2002) suggested autosomal dominant inheritance. </p><p>Lee et al. (2005) reported 2 Asian sisters who developed AIMAH at ages 46 and 58 years, respectively. Both patients had typical Cushingoid features, including 'moon facies,' dorsocervical fat pad ('buffalo hump'), and central obesity; 1 had purple striae. Both had increased serum cortisol and bilateral adrenal masses, and both had meningiomas, which may or may not have been related. Pituitary tumors were not present. </p>
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<strong>Pathogenesis</strong>
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<p><strong><em>Aberrant Hormone Receptors</em></strong></p><p>
Several groups have shown that cortisol hypersecretion in AIMAH can be regulated by hormones other than ACTH via the ectopic expression or the overactive eutopic expression of several membrane-bound hormone receptors in the adrenal cortex. These include gastric inhibitory polypeptide receptor (GIPR; 137241), various vasopressin receptors (AVPR1A, 600821; AVPR1B, 600264; AVPR2; 300538), beta-adrenergic receptors (see, e.g., ADRB1; 109630), the LH/human CG receptor (LHCGR; 152790), the serotonin 5-HT4 receptor (HTR4; 602164), and the angiotensin receptor (AGTR1; 106165) (Christopoulos et al., 2005). </p><p>Lacroix et al. (1997) reported a 36-year-old woman with Cushing syndrome due to AIMAH who had orthostatic hypotension. During upright posture, the patient's cortisol and aldosterone levels were stimulated despite suppression of ACTH and renin. Arginine vasopressin (AVP; 192340) was found to increase plasma cortisol, aldosterone, and androgens in this patient but not in controls. Following adrenalectomy, orthostatic hypotension persisted; a prolonged vasoconstrictive response to AVP was found in vitro in the patient's small arteries. Lacroix et al. (1997) suggested altered adrenal and vascular responses of the AVP V1 receptor (see 600821). Mune et al. (2002) found increased levels of AVPR1A mRNA in adrenal tissue from 4 patients with AIMAH, suggesting that eutopic V1A receptor overexpression is involved in the etiology. Miyamura et al. (2002) reported a mother and son with AIMAH in whom AVP and catecholamines promoted cortisol secretion. RT-PCR of adrenal tissue from the mother showed abnormal expression of AVPR1B, AVPR2, and LHCGR, none of which was observed in a normal control. In 2 sisters with AIMAH, Lee et al. (2005) demonstrated that AVP promoted cortisol secretion through overexpression of AVPR1A. In addition, RT-PCR analysis revealed abnormal cDNA expression of AVPR1B and AVPR2, which are normally not expressed in the adrenal gland. </p><p>Lacroix et al. (1997) reported a 56-year-old man with AIMAH who showed increased serum cortisol when changing from a supine to upright posture and in response to insulin-induced hypoglycemia, suggesting mediation by a beta-adrenergic receptor. Treatment with propranolol was effective, and the authors suggested that ectopic receptor expression led to catecholamine-induced adrenal hyperplasia in this patient. Lacroix et al. (1999) reported a woman with AIMAH that was clinically manifest transiently during pregnancy. Studies showed that the cortisol secretion was stimulated by luteinizing hormone (LH; 152780), HCG (118850), and by drugs that activated 5HT-4 receptors. Long-term suppression of LH secretion with leuprolide led to reversal of symptoms. Lacroix et al. (1999) noted that the identification of ectopic adrenal receptors could lead to medical treatment for such patients as alternatives to adrenalectomy. </p><p>Cartier et al. (2003) reported overexpression of 5HT-4 receptors in adrenal tissue from 4 of 6 patients with cisapride-responsive AIMAH. Sequencing of the 5HT4 receptor gene in 2 patients did not reveal any mutations. </p><p>Mircescu et al. (2000) found 1 or 2 abnormal hormone receptors in adrenal tissue from all 6 patients with AIMAH who were studied. The findings suggested that aberrant hormone receptors in adrenal tissue are common in these patients. </p><p>In a review, Christopoulos et al. (2005) stated that most patients with AIMAH, when screened, have been shown to have aberrant expression of receptors in the adrenal gland resulting in increased cortisol secretion; many patients show aberrant expression of more than 1 receptor. The authors suggested that dysregulation of tissue-specific receptor expression may indicate a disruption of gene regulatory elements in the early stages of embryogenesis since the pathology involves the entire adrenal cortex. </p>
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<strong>Molecular Genetics</strong>
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<p>Fragoso et al. (2003) identified somatic heterozygous mutations in the GNAS1 gene (R201H, 139320.0009 and R201S, 139320.0013) in adrenal tissue from 3 unrelated patients with AIMAH. The mutations resulted in constitutive activation of the G protein. The mutations were not present in peripheral blood, and none of the patients had signs of McCune-Albright syndrome. Fragoso et al. (2003) discussed whether the patients could be considered part of the spectrum of McCune-Albright syndrome or whether they represent isolated cases of AIMAH associated with somatic mutations. </p><p>By cDNA microarray analysis of adrenal tissue from 8 AIMAH patients, Bourdeau et al. (2004) found upregulation of several genes involved in transcription, chromatin remodeling, and cell cycle and adhesion. There were differences in gene expression between those with and without GIP-dependent AIMAH, confirming clinical heterogeneity and suggesting distinct diagnostic subgroups. </p><p>Sato et al. (2014) identified 2 different somatic heterozygous mutations in the GNAS1 gene, both affecting the codon R201 (R201H, 139320.0009 and R201C, 139320.0008), in 11 (16.9%) of 65 cases of corticotropin-independent adrenal Cushing syndrome. The mutations were confirmed to be somatic in all 6 cases tested. GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported. </p><p>Bourdeau et al. (2006) did not identify mutations in the PRKAR1A gene in 14 unrelated patients with sporadic AIMAH. However, 91% of the tumor tissue samples showed somatic loss of heterozygosity (LOH) of chromosome 2p16, where Carney complex-2 (CNC2; 605244) has been mapped, and 73% of tissue samples showed somatic LOH of 17q22-q24, where the PRKAR1A gene is located. Total protein kinase A activity was higher in AIMAH tissue compared to normal adrenal glands. </p>
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<strong>REFERENCES</strong>
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Aiba, M., Hirayama, A., Iri, H., Ito, Y., Fujimoto, Y., Mabuchi, G., Murai, M., Tazaki, H., Maruyama, H., Saruta, T., Suda, T., Demura, H.
<strong>Adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia as a distinct subtype of Cushing&#x27;s syndrome: enzyme histochemical and ultrastructural study of four cases with a review of the literature.</strong>
Am. J. Clin. Path. 96: 334-340, 1991.
[PubMed: 1652202]
[Full Text: https://doi.org/10.1093/ajcp/96.3.334]
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<li>
<p class="mim-text-font">
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Cassandra L. Kniffin - updated : 8/19/2014<br>Cassandra L. Kniffin - reorganized : 10/18/2006<br>Cassandra L. Kniffin - updated : 10/17/2006<br>Victor A. McKusick - updated : 6/30/2006<br>John A. Phillips, III - updated : 4/8/2003<br>John A. Phillips, III - updated : 3/16/2001<br>John A. Phillips, III - updated : 10/30/1997
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