3840 lines
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Entry
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- #300200 - ADRENAL HYPOPLASIA, CONGENITAL; AHC
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- OMIM
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<p>
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<span class="h4">#300200</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/300200"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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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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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<div style="display: table-cell;">External Links</div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=ADRENAL HYPOPLASIA, CONGENITAL" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=12657&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>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1431/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/7542" 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>
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<div><a href="https://medlineplus.gov/genetics/condition/x-linked-adrenal-hypoplasia-congenita" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300200[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>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=95702" 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>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/c5b11b84-3947-49d8-a7d8-0055ded26feb/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>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0080156" 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>
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<div><a href="http://www.informatics.jax.org/disease/300200" 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>
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<div><a href="https://omia.org/OMIA002060/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:300200" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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<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">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 237764004<br />
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<strong>ORPHA:</strong> 95702<br />
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<strong>DO:</strong> 0080156<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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300200
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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ADRENAL HYPOPLASIA, CONGENITAL; AHC
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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ADRENAL HYPOPLASIA, CONGENITAL, WITH HYPOGONADOTROPIC HYPOGONADISM; AHCH<br />
|
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ADDISON DISEASE, X-LINKED; AHX<br />
|
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AHC WITH HHG<br />
|
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CYTOMEGALIC ADRENOCORTICAL HYPOPLASIA<br />
|
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AHC WITH ISOLATED GONADOTROPIN DEFICIENCY
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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|
<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/X/144?start=-3&limit=10&highlight=144">
|
|
Xp21.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Adrenal hypoplasia, congenital
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/300200"> 300200 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
NR0B1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/300473"> 300473 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/300200" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
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|
|
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|
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|
|
<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/300200" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/300200" 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>
|
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|
|
|
<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">
|
|
|
|
- X-linked recessive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845977</a>, <a href="https://bioportal.bioontology.org/search?q=C1279481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279481</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</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> Other </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GENITOURINARY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> External Genitalia (Male) </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hypogonadotropic hypogonadism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22053006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22053006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/33927004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">33927004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405769009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405769009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E23.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E23.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q98.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q98.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q98.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q98.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/758.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">758.7</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0271623&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0271623</a>, <a href="https://bioportal.bioontology.org/search?q=C0022735&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022735</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000044" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000044</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000044" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000044</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Internal Genitalia (Male) </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Cryptorchidism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204878001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204878001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q53.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q53.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/752.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">752.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0010417&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010417</a>, <a href="https://bioportal.bioontology.org/search?q=C5441920&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5441920</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000028</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000028</a>]</span><br /> -
|
|
Oligospermia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/88311004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">88311004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N46.11" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N46.11</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N46.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N46.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/606.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">606.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0868910&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0868910</a>, <a href="https://bioportal.bioontology.org/search?q=C0028960&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028960</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000798" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000798</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000798" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000798</a>]</span><br /> -
|
|
Azoospermia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/425558002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">425558002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48188009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48188009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N46.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N46.01</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N46.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N46.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/606.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">606.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004509&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004509</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000027</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000027</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">
|
|
|
|
- Hyperpigmentation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/4830009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">4830009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/49765009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">49765009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162834&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162834</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000953" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000953</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> METABOLIC FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Dehydration <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/34095006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">34095006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E86.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E86.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/276.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">276.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011175&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011175</a>, <a href="https://bioportal.bioontology.org/search?q=C2062903&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2062903</a>, <a href="https://bioportal.bioontology.org/search?q=C4284399&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4284399</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001944" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001944</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001944" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001944</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> ENDOCRINE FEATURES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Primary adrenocortical failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/373662000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">373662000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E27.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E27.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5848257&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5848257</a>, <a href="https://bioportal.bioontology.org/search?q=C3887896&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887896</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008207" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008207</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008207" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008207</a>]</span><br /> -
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Adrenal insufficiency <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386584007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386584007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237785004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237785004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/255.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">255.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0405580&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0405580</a>, <a href="https://bioportal.bioontology.org/search?q=C0001623&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001623</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000846" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000846</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0008207" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008207</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000846" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000846</a>]</span><br /> -
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Hypoplastic adrenal glands <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1846223&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846223</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000835" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000835</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000835" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000835</a>]</span><br /> -
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'Cytomegalic' cells (large, pale) in adrenal glands <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1846224&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846224</a>]</span><br /> -
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Glucocorticoid insufficiency <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836623&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836623</a>, <a href="https://bioportal.bioontology.org/search?q=C1846225&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846225</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008163" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008163</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008163" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008163</a>]</span><br /> -
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Mineralocorticoid insufficiency <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1846226&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846226</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004319</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004319</a>]</span><br /> -
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Salt-wasting <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1846347&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846347</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000127" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000127</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000127" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000127</a>]</span><br /> -
|
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Gonadotropin insufficiency <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4552011&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4552011</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008213" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008213</a>]</span><br /> -
|
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Absence of pubertal development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1846228&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846228</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008197" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008197</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008197" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008197</a>]</span><br /> -
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Delayed puberty <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/400003000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">400003000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/123526007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">123526007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E30.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E30.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034012&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034012</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000823" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000823</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000823" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000823</a>]</span><br /> -
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Precocious puberty <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/400179000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">400179000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E30.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E30.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034013&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034013</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000826" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000826</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000826" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000826</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Hyponatremia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/89627008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">89627008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020625&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020625</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002902" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002902</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002902" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002902</a>]</span><br /> -
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Decreased serum cortisol <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241002&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241002</a>]</span><br /> -
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Decreased serum luteinizing hormone (LH) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1846229&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846229</a>]</span><br /> -
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Decreased serum follicle-stimulating hormone (FSH) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1846230&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846230</a>]</span><br /> -
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Decreased serum androgens <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1846231&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846231</a>]</span><br /> -
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Decreased serum testosterone <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0857983&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0857983</a>]</span><br /> -
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Increased adrenocorticotropic hormone (ACTH) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1846232&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846232</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Clinical variability<br /> -
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Onset usually within first weeks of life<br /> -
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Later onset may occur (1 to 11 years)<br /> -
|
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Transient recovery of adrenal function may occur in childhood<br /> -
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Poor gonadotropin response to gonadotropin releasing hormone (GnRH)<br /> -
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May be seen in combination with Duchenne muscular dystrophy (DMD, <a href="/entry/310200">310200</a>) and/or glycerol kinase deficiency (<a href="/entry/307030">307030</a>) as part of a contiguous gene deletion syndrome<br />
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</span>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the nuclear receptor subfamily 0, group B, member 1 gene (NR0B1, <a href="/entry/300473#0001">300473.0001</a>)<br />
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<div>
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<br />
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism is caused by mutation in the NR0B1 gene (<a href="/entry/300473">300473</a>).</p>
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<p>Congenital adrenal hypoplasia (AHC) is a rare disorder that can be inherited in an X-linked or autosomal recessive (see <a href="/entry/240200">240200</a>) pattern. In X-linked AHC, primary adrenocortical failure occurs because the adrenal glands lack the permanent adult cortical zone. The remaining cells are termed 'cytomegalic' because they are larger than typical fetal adrenal cells (<a href="#9" class="mim-tip-reference" title="Hay, I. D., Smail, P. J., Forsyth, C. C. <strong>Familial cytomegalic adrenocortical hypoplasia: an X-linked syndrome of pubertal failure.</strong> Arch. Dis. Child. 56: 715-721, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7197507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7197507</a>] [<a href="https://doi.org/10.1136/adc.56.9.715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7197507">Hay et al., 1981</a>; <a href="#28" class="mim-tip-reference" title="Reutens, A. T., Achermann, J. C., Ito, M., Ito, M., Gu, W.-X., Habiby, R. L., Donohoue, P. A., Pang, S., Hindmarsh, P. C., Jameson, J. L. <strong>Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita.</strong> J. Clin. Endocr. Metab. 84: 504-511, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10022408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10022408</a>] [<a href="https://doi.org/10.1210/jcem.84.2.5468" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10022408">Reutens et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7197507+10022408" 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>Patients with AHC usually present in early infancy with primary adrenal failure. Hypogonadotropic hypogonadism (HHG) is a hallmark of the disorder, and is recognized during adolescence because of the absence or interruption of normal pubertal development. Abnormal spermatogenesis has also been observed in these patients. Milder forms of the disease have been described, with adrenal insufficiency sometimes occurring in childhood or even early adulthood. A few cases of partial HHG have been reported (summary by <a href="#27" class="mim-tip-reference" title="Raffin-Sanson, M.-L., Oudet, B., Salenave, S., Brailly-Tabard, S., Pehuet, M., Christin-Maitre, S., Morel, Y., Young, J. <strong>A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic-pituitary-gonadal axis but deteriorating oligospermia during long-term follow-up.</strong> Europ. J. Endocr. 168: K45-K50, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23384712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23384712</a>] [<a href="https://doi.org/10.1530/EJE-12-1055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23384712">Raffin-Sanson et al., 2013</a>). Transient precocious sexual development in infancy or early childhood can be a prominent feature of AHC (<a href="#14" class="mim-tip-reference" title="Landau, Z., Hanukoglu, A., Sack, J., Goldstein, N., Weintrob, N., Eliakim, A., Gillis, D., Sagi, M., Shomrat, R., Kosinovsky, E. B., Anikster, Y. <strong>Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations.</strong> Clin. Endocr. 72: 448-454, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508677</a>] [<a href="https://doi.org/10.1111/j.1365-2265.2009.03652.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508677">Landau et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23384712+19508677" 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 contiguous gene syndrome involving a combination of congenital adrenal hypoplasia, glycerol kinase deficiency (<a href="/entry/307030">307030</a>), and Duchenne muscular dystrophy (DMD; <a href="/entry/310200">310200</a>) is caused by deletion of multiple genes on chromosome Xp21 (see <a href="/entry/300679">300679</a>).</p>
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<p><a href="#36" class="mim-tip-reference" title="Weiss, L., Mellinger, R. C. <strong>Congenital adrenal hypoplasia--an X-linked disease.</strong> J. Med. Genet. 7: 27-32, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5312341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5312341</a>] [<a href="https://doi.org/10.1136/jmg.7.1.27" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5312341">Weiss and Mellinger (1970)</a> described an X-linked form of congenital adrenal hypoplasia in 3 of 4 brothers, each of whom had a different father. Histologically, there was hypoplasia of the adrenal cortex and lack of organization of the cortex into cords, as well as clumps of large pale-staining cells. Several other families consistent with X-linked inheritance had been reported (e.g., <a href="#2" class="mim-tip-reference" title="Boyd, J. F., MacDonald, A. M. <strong>Adrenal cortical hypoplasia in siblings.</strong> Arch. Dis. Child. 35: 561-568, 1960.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21032374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21032374</a>] [<a href="https://doi.org/10.1136/adc.35.184.561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21032374">Boyd and MacDonald, 1960</a>; <a href="#34" class="mim-tip-reference" title="Uttley, W. S. <strong>Familial congenital adrenal hypoplasia.</strong> Arch. Dis. Child. 43: 724-730, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5702234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5702234</a>] [<a href="https://doi.org/10.1136/adc.43.232.724" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5702234">Uttley, 1968</a>; <a href="#32" class="mim-tip-reference" title="Stempfel, R. S., Jr., Engel, F. L. <strong>A congenital, familial syndrome of adrenocortical insufficiency without hypoaldosteronism.</strong> J. Pediat. 57: 443-451, 1960."None>Stempfel and Engel, 1960</a>). <a href="#3" class="mim-tip-reference" title="Brochner-Mortensen, K. <strong>Familial occurrence of Addison's disease.</strong> Acta Med. Scand. 156: 205-209, 1956.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13381433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13381433</a>] [<a href="https://doi.org/10.1111/j.0954-6820.1956.tb00077.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13381433">Brochner-Mortensen (1956)</a> described Addison disease in 2 brothers and 2 of their maternal uncles. Three of the patients had died at ages 19, 26, and 33 years. In brothers reported by <a href="#19" class="mim-tip-reference" title="Meakin, J. W., Nelson, D. H., Thorn, G. W. <strong>Addison's disease in two brothers.</strong> J. Clin. Endocr. Metab. 19: 726-731, 1959.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13654502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13654502</a>] [<a href="https://doi.org/10.1210/jcem-19-6-726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13654502">Meakin et al. (1959)</a>, the diagnosis was made in the elder at 9 years of age and in the second at 6 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5702234+13654502+21032374+5312341+13381433" 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>Congenital adrenal hypoplasia with hypogonadotropic hypogonadism (HHG) was observed by <a href="#8" class="mim-tip-reference" title="Hay, I. D. <strong>Pubertal failure in congenital adrenocortical hypoplasia.</strong> Lancet 310: 1035-1036, 1977. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/72939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">72939</a>] [<a href="https://doi.org/10.1016/s0140-6736(77)92942-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="72939">Hay (1977)</a>, who suggested that hypogonadism might be a consequence of absence of adrenal androgen secretion. <a href="#9" class="mim-tip-reference" title="Hay, I. D., Smail, P. J., Forsyth, C. C. <strong>Familial cytomegalic adrenocortical hypoplasia: an X-linked syndrome of pubertal failure.</strong> Arch. Dis. Child. 56: 715-721, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7197507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7197507</a>] [<a href="https://doi.org/10.1136/adc.56.9.715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7197507">Hay et al. (1981)</a> described 5 boys with cytomegalic adrenocortical hypoplasia who had been followed for many years. Despite treatment with replacement corticosteroids, all 5 failed to show a spontaneous onset of puberty, and when assessed at ages 13 to 19 years, all had both sexual infantilism and skeletal immaturity. Hypogonadism was confirmed by low levels of plasma testosterone and inadequate pituitary reserve of gonadotropin. Treatment with either testosterone or gonadotropin resulted in advances in pubertal staging in all 5 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=72939+7197507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Hay, I. D., Smail, P. J., Forsyth, C. C. <strong>Familial cytomegalic adrenocortical hypoplasia: an X-linked syndrome of pubertal failure.</strong> Arch. Dis. Child. 56: 715-721, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7197507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7197507</a>] [<a href="https://doi.org/10.1136/adc.56.9.715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7197507">Hay et al. (1981)</a> noted that the association of hypogonadotrophic hypogonadism with familial cytomegalic adrenocortical hypoplasia is a common finding. <a href="#26" class="mim-tip-reference" title="Prader, A., Zachmann, M., Illig, R. <strong>Luteinizing hormone deficiency in hereditary congenital adrenal hypoplasia.</strong> J. Pediat. 86: 421-422, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1113233/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1113233</a>] [<a href="https://doi.org/10.1016/s0022-3476(75)80978-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1113233">Prader et al. (1975)</a>, <a href="#6" class="mim-tip-reference" title="Golden, M. P., Lippe, B. M., Kaplan, S. A. <strong>Congenital adrenal hypoplasia and hypogonadotropic hypogonadism.</strong> Am. J. Dis. Child. 131: 1117-1118, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/910763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">910763</a>] [<a href="https://doi.org/10.1001/archpedi.1977.02120230063010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="910763">Golden et al. (1977)</a>, and <a href="#39" class="mim-tip-reference" title="Zachmann, M., Illig, R., Prader, A. <strong>Gonadotropin deficiency and cryptorchidism in three prepubertal brothers with congenital adrenal hypoplasia.</strong> J. Pediat. 97: 255-257, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6105176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6105176</a>] [<a href="https://doi.org/10.1016/s0022-3476(80)80486-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6105176">Zachmann et al. (1980)</a> also described this association. <a href="#17" class="mim-tip-reference" title="Martin, M. M. <strong>Familial Addison's disease.</strong> Birth Defects Orig. Art. Ser. VII(6): 98-100, 1971."None>Martin (1971)</a> described a pair of brothers in whom the signs of Addison disease developed at age 5. Gonadotropin deficiency was later demonstrated in both brothers (<a href="#18" class="mim-tip-reference" title="Martin, M. M. <strong>Personal Communication.</strong> Washington, D. C. 10/27/1980."None>Martin, 1980</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6105176+7197507+1113233+910763" 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>An extensive Greenlandic pedigree was reported by <a href="#25" class="mim-tip-reference" title="Petersen, K. E., Bille, T., Jacobsen, B. B., Iversen, T. <strong>X-linked congenital adrenal hypoplasia: a study of five generations of a Greenlandic family.</strong> Acta Paediat. Scand. 71: 947-951, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6891556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6891556</a>] [<a href="https://doi.org/10.1111/j.1651-2227.1982.tb09554.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6891556">Petersen et al. (1982)</a>. Over 5 generations, 11 boys had died with a clinical picture of adrenocortical insufficiency within 3 weeks of birth. In 3 treated males who survived, the adrenal glands could not be identified by computed tomography. Pubertal development was delayed in 2 patients aged 14 years. Subsequently, <a href="#31" class="mim-tip-reference" title="Schwartz, M., Blichfeldt, S., Muller, J. <strong>X-linked adrenal hypoplasia in a large Greenlandic family. Detection of a missense mutation (N4401) in the DAX-1 gene; implication for genetic counselling and carrier diagnosis.</strong> Hum. Genet. 99: 83-87, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9003500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9003500</a>] [<a href="https://doi.org/10.1007/s004390050316" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9003500">Schwartz et al. (1997)</a> identified a missense mutation (<a href="/entry/300473#0008">300473.0008</a>) in the DAX1 gene in 3 affected members of this Greenlandic family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6891556+9003500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Reutens, A. T., Achermann, J. C., Ito, M., Ito, M., Gu, W.-X., Habiby, R. L., Donohoue, P. A., Pang, S., Hindmarsh, P. C., Jameson, J. L. <strong>Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita.</strong> J. Clin. Endocr. Metab. 84: 504-511, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10022408/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10022408</a>] [<a href="https://doi.org/10.1210/jcem.84.2.5468" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10022408">Reutens et al. (1999)</a> described the clinical features and genetic alterations in 6 families with AHC. Most patients presented within the first year of life with variable signs and symptoms, including hyperpigmentation, salt-wasting crisis, vomiting, and malaise. One patient had a delayed presentation at the age of 7 years, after a hypotensive episode and hyponatremia during an acute asthma attack. A review of the literature showed an apparent bimodal distribution for age at diagnosis. The majority of patients were diagnosed within the first 2 months of life, and another group of patients were diagnosed from 1 to 11 years. Nonsense mutations in the DAX1 gene were identified in 3 cases, and frameshift mutations resulting in a premature stop codon were found in the other 3 families. There were no obvious genotype/phenotype correlations. The authors concluded that the clinical presentation of DAX1 mutations is variable and emphasized the value of genetic testing in boys with primary adrenal insufficiency and suspected X-linked AHC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10022408" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The review of <a href="#13" class="mim-tip-reference" title="Kletter, G. B., Gorski, J. L., Kelch, R. P. <strong>Congenital adrenal hypoplasia and isolated gonadotropin deficiency.</strong> Trends Endocr. Metab. 2: 123-128, 1991."None>Kletter et al. (1991)</a> suggested that gonadotropin deficiency is an integral part of X-linked cytomegalic adrenocortical hypoplasia.</p><p><a href="#38" class="mim-tip-reference" title="Zachmann, M., Fuchs, E., Prader, A. <strong>Progressive high frequency hearing loss: an additional feature in the syndrome of congenital adrenal hypoplasia and gonadotrophin deficiency.</strong> Europ. J. Pediat. 151: 167-169, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1601004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1601004</a>] [<a href="https://doi.org/10.1007/BF01954375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1601004">Zachmann et al. (1992)</a> found progressive high frequency hearing loss developing at about the age of 14 years in 3 brothers with X-linked congenital adrenal hypoplasia associated with gonadotropin deficiency. All 3, aged 22, 20, and 18 years, had developed progressive high frequency hearing loss at about 14 years of age. They were doing well on replacement therapy with hydrocortisone, fluorohydrocortisone, and long-acting testosterone. High resolution chromosomal analysis showed no structural anomalies. Although no statement was made concerning the sense of smell, the gonadotropin deficiency may have represented Kallmann syndrome (<a href="/entry/308700">308700</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1601004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Jones, D., Kay, M., Craigen, W., McCabe, E., Hawkins, H., Dominey, A. <strong>Coal-black hyperpigmentation at birth in a child with congenital adrenal hypoplasia.</strong> J. Am. Acad. Derm. 33: 323-326, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7615878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7615878</a>] [<a href="https://doi.org/10.1016/0190-9622(95)91426-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7615878">Jones et al. (1995)</a> reported the case of a Hispanic boy with congenital adrenal hypoplasia who had coal-black hyperpigmentation at birth. Both parents were of light complexion. Usually hyperpigmentation in this condition appears gradually over a period of months to years. Following steroid therapy, the patient's color began to lighten, and at week 7 of life the infant had pigmentation intermediate between coal-black and the color of his Hispanic mother. By 6 months of age, the infant's skin color was similar to that of his mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7615878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Clinical Variability</em></strong></p><p>
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<a href="#33" class="mim-tip-reference" title="Tabarin, A., Achermann, J. C., Recan, D., Bex, V., Bertagna, X., Christin-Maitre, S., Ito, M., Jameson, J. L., Bouchard, P. <strong>A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism.</strong> J. Clin. Invest. 105: 321-328, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10675358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10675358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10675358[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI7212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10675358">Tabarin et al. (2000)</a> reported an unusually mild case in a man who presented with apparently isolated adrenal insufficiency at 28 years of age. Examination revealed partial pubertal development (Tanner stage 3) and undiagnosed incomplete HHG. The patient noted that puberty had occurred at about age 16, and that he had impaired libido and infrequent erections. Severe oligospermia was detected. A mutation in the DAX1 gene (<a href="/entry/300473#0020">300473.0020</a>) was found, extending the clinical spectrum of the disease to include a milder disorder with delayed onset of symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10675358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Domenice, S., Latronico, A. C., Brito, V. N., Arnhold, I. J. P., Kok, F., Mendonca, B. B. <strong>Adrenocorticotropin-dependent precocious puberty of testicular origin in a boy with X-linked adrenal hypoplasia congenita due to a novel mutation in the DAX1 gene.</strong> J. Clin. Endocr. Metab. 86: 4068-4071, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549627</a>] [<a href="https://doi.org/10.1210/jcem.86.9.7816" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549627">Domenice et al. (2001)</a> reported a 2-year-old Brazilian boy with a DAX1 mutation (<a href="/entry/300473#0024">300473.0024</a>). Initial clinical manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. Testosterone levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce testosterone levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and testosterone levels to the prepubertal range. The authors concluded that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549627" 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="#30" class="mim-tip-reference" title="Salvi, R., Gomez, F., Fiaux, M., Schorderet, D., Jameson, J. L., Achermann, J. C., Gaillard, R. C., Pralong, F. P. <strong>Progressive onset of adrenal insufficiency and hypogonadism of pituitary origin caused by a complex genetic rearrangement within DAX-1.</strong> J. Clin. Endocr. Metab. 87: 4094-4100, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12213854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12213854</a>] [<a href="https://doi.org/10.1210/jc.2001-011930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12213854">Salvi et al. (2002)</a> reported a 25-year-old man with a complex rearrangement in the DAX1 gene (<a href="/entry/300473#0026">300473.0026</a>) who was diagnosed with adrenal failure at 6 weeks of age, but who experienced transient recovery of adrenal function of several months' duration later in infancy. He subsequently failed to undergo puberty because of hypogonadotropic hypogonadism (HHG) that was demonstrated to be of pituitary origin, with no pituitary gonadotropin secretion upon stimulation by low-dose pulsatile GnRH or by acute administration of GnRH by intravenous bolus. The patient was also diagnosed with schizophrenia in early adulthood. <a href="#30" class="mim-tip-reference" title="Salvi, R., Gomez, F., Fiaux, M., Schorderet, D., Jameson, J. L., Achermann, J. C., Gaillard, R. C., Pralong, F. P. <strong>Progressive onset of adrenal insufficiency and hypogonadism of pituitary origin caused by a complex genetic rearrangement within DAX-1.</strong> J. Clin. Endocr. Metab. 87: 4094-4100, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12213854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12213854</a>] [<a href="https://doi.org/10.1210/jc.2001-011930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12213854">Salvi et al. (2002)</a> noted that heterogeneity both in age at diagnosis and in severity of the adrenal syndrome is a well-recognized feature of AHC, and that variability in the HHG syndrome that classically accompanies AHC has also been reported. They stated that there was evidence in the literature supporting a purely hypothalamic origin of the defect, a pituitary origin, or both, and noted that the results obtained in their patient did not exclude a hypothalamic component to the HHG. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12213854" 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="Landau, Z., Hanukoglu, A., Sack, J., Goldstein, N., Weintrob, N., Eliakim, A., Gillis, D., Sagi, M., Shomrat, R., Kosinovsky, E. B., Anikster, Y. <strong>Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations.</strong> Clin. Endocr. 72: 448-454, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508677</a>] [<a href="https://doi.org/10.1111/j.1365-2265.2009.03652.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508677">Landau et al. (2010)</a> studied 12 patients with AHC from 5 Israeli families. Six patients from 2 families had a contiguous gene deletion involving NR0B1, and those patients also exhibited developmental delay ranging from mild to severe. The remaining 6 patients had point mutations, resulting in a nonsense mutation, a missense mutation, and a splice site mutation, respectively. Signs of transient precocious sexual development were documented in infancy and childhood in 5 patients from 4 families, with enlarged penis in all 5 patients and increased testicular volume in 2 brothers. All 5 patients later exhibited HHG at the age of puberty. <a href="#14" class="mim-tip-reference" title="Landau, Z., Hanukoglu, A., Sack, J., Goldstein, N., Weintrob, N., Eliakim, A., Gillis, D., Sagi, M., Shomrat, R., Kosinovsky, E. B., Anikster, Y. <strong>Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations.</strong> Clin. Endocr. 72: 448-454, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19508677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19508677</a>] [<a href="https://doi.org/10.1111/j.1365-2265.2009.03652.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19508677">Landau et al. (2010)</a> noted that the clinical spectrum of disease in X-linked AHC is quite variable, and that precocious sexual development can be a prominent feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19508677" 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="#27" class="mim-tip-reference" title="Raffin-Sanson, M.-L., Oudet, B., Salenave, S., Brailly-Tabard, S., Pehuet, M., Christin-Maitre, S., Morel, Y., Young, J. <strong>A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic-pituitary-gonadal axis but deteriorating oligospermia during long-term follow-up.</strong> Europ. J. Endocr. 168: K45-K50, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23384712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23384712</a>] [<a href="https://doi.org/10.1530/EJE-12-1055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23384712">Raffin-Sanson et al. (2013)</a> studied a family in which 3 male relatives were hemizygous for a nonsense mutation in the NR0B1 gene (W39X; see MOLECULAR GENETICS), with different adrenal consequences. The proband, 47 years old at the time of the report, had been diagnosed at age 19 years with adrenal insufficiency and with oligospermia at age 23. Evaluation at 32 years of age showed normal external genitalia, and he reported spontaneous onset of puberty at age 13, with normal virilization, growth spurt, and testicular growth. CT scan showed bilateral adrenal atrophy. Over 25 years of follow-up, his LH pulsatile secretion and testosterone level remained normal, consistent with LH-driven preservation of Leydig cell function. However, his sperm counts fell from 4 x 10(6) at age 23 to 0.05 x 10(6) by age 37, and inhibin B (see <a href="/entry/147290">147290</a>) levels also decreased, indicating impaired Sertoli cell function. He fathered 1 child by in vitro fertilization at age 33 and another by spontaneous conception 2 years later. Evaluation of the proband's younger brother at age 36 years revealed complete virilization with normal penile length and testicular volume, but low testosterone level and azoospermia. He also exhibited an abnormal cortisol response to the standard-dose cortrosyn test and was diagnosed with mild asymptomatic adrenal insufficiency. In addition, their sister gave birth to a boy who underwent adrenal crisis during the second week of life. All 3 patients carried the recurrent W39X mutation, which <a href="#27" class="mim-tip-reference" title="Raffin-Sanson, M.-L., Oudet, B., Salenave, S., Brailly-Tabard, S., Pehuet, M., Christin-Maitre, S., Morel, Y., Young, J. <strong>A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic-pituitary-gonadal axis but deteriorating oligospermia during long-term follow-up.</strong> Europ. J. Endocr. 168: K45-K50, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23384712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23384712</a>] [<a href="https://doi.org/10.1530/EJE-12-1055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23384712">Raffin-Sanson et al. (2013)</a> stated had previously been reported in patients with mild phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23384712" 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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Adrenoleukodystrophy (ALD; <a href="/entry/300100">300100</a>) is a well-established X-linked disorder. Since adrenal insufficiency can precede neurologic symptoms by several years in ALD, and may in fact be the only manifestation in one form of the disorder, some reported cases of X-linked Addison disease may represent that disorder. For example, <a href="#29" class="mim-tip-reference" title="Sadeghi-Nejad, A., Senior, B. <strong>Adrenomyeloneuropathy presenting as Addison's disease in childhood.</strong> New Eng. J. Med. 322: 13-16, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2294415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2294415</a>] [<a href="https://doi.org/10.1056/NEJM199001043220103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2294415">Sadeghi-Nejad and Senior (1990)</a> looked for signs of adrenomyeloneuropathy, a biochemically identical but milder and more slowly progressive variant of adrenoleukodystrophy, in 8 male patients with childhood-onset Addison disease. In 5 of the patients, elevated plasma hexacosanoic acid concentrations were found, confirming the diagnosis, and in all 5, magnetic resonance imaging showed evidence of brain involvement. Reexploration of the family histories showed additional missed cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2294415" 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 the family reported by <a href="#22" class="mim-tip-reference" title="O'Neill, B. P., Moser, H. W., Saxena, K. M. <strong>Familial X-linked Addison disease as an expression of adrenoleukodystrophy (ALD): elevated C26 fatty acid in cultured skin fibroblasts.</strong> Neurology 32: 543-547, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6280107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6280107</a>] [<a href="https://doi.org/10.1212/wnl.32.5.543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6280107">O'Neill et al. (1982)</a>, clinically apparent Addison disease without neurologic involvement was the expression of adrenoleukodystrophy in males, and spastic paraplegia and sphincter disturbances occurred in female carriers. Again, Addison disease in young males should prompt consideration of ALD as the underlying abnormality. The achalasia-Addisonian syndrome (<a href="/entry/231550">231550</a>), which appears to be autosomal recessive, is another example of combined adrenal and neurologic (autonomic) involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6280107" 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>Like ALD, glycerol kinase deficiency (GKD; <a href="/entry/307030">307030</a>) is an X-linked systemic disorder with adrenal insufficiency.</p>
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<p><a href="#4" class="mim-tip-reference" title="Cohen, H. N., Hay, I. D., Beastall, G. H., Thomson, J. A. <strong>Failure of adrenal androgen to induce puberty in familial cytomegalic adrenocortical hypoplasia. (Letter)</strong> Lancet 320: 1471-1472, 1982. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6129550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6129550</a>] [<a href="https://doi.org/10.1016/s0140-6736(82)91380-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6129550">Cohen et al. (1982)</a> reported treatment failure in a 19-year-old male with familial cytomegalic adrenocortical hypoplasia and associated hypogonadotropism with the adrenal androgen dehydroepiandrosterone sulfate. A 1-year course did not induce puberty. <a href="#12" class="mim-tip-reference" title="Kikuchi, K., Kaji, M., Momoi, T., Mikawa, H., Shigematsu, Y., Sudo, M. <strong>Failure to induce puberty in a man with X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism by pulsatile administration of low-dose gonadotropin-releasing hormone.</strong> Acta Endocr. 114: 153-160, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3101337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3101337</a>] [<a href="https://doi.org/10.1530/acta.0.1140153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3101337">Kikuchi et al. (1987)</a> reported failure to induce puberty in an 18-year-old patient by pulsatile administration of low-dose gonadotropin-releasing hormone (GNRH; <a href="/entry/152760">152760</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6129550+3101337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Hammond, J., Howard, N. J., Brookwell, R., Purvis-Smith, S., Wilcken, B., Hoogenraad, N. <strong>Proposed assignment of loci for X-linked adrenal hypoplasia and glycerol kinase genes. (Letter)</strong> Lancet 325: 54 only, 1985. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2856983/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2856983</a>] [<a href="https://doi.org/10.1016/s0140-6736(85)91009-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2856983">Hammond et al. (1985)</a> suggested that the locus for glycerol kinase and that for X-linked adrenal hypoplasia are in the segment Xp21-p11.2. The suggestion was based on the finding of an interstitial Xp deletion with breakpoints at p11.2 and p21 in the phenotypically normal mother of a male infant who died at 36 hrs of cytomegalic adrenal hypoplasia with glyceroluria (indicating glycerol kinase deficiency) and deficiency of ornithine carbamoyltransferase (OTC; 300461) in the liver (see Xp21 deletion syndrome, <a href="/entry/300679">300679</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2856983" 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="#37" class="mim-tip-reference" title="Yates, J. R. W., Gillard, E. F., Cooke, A., Colgan, J. M., Evans, T. J., Ferguson-Smith, M. A. <strong>A deletion of Xp21 maps congenital adrenal hypoplasia distal to glycerol kinase deficiency. (Abstract)</strong> Cytogenet. Cell Genet. 46: 723-724, 1987."None>Yates et al. (1987)</a> found a deletion of Xp21 causing congenital adrenal hypoplasia without glycerol kinase deficiency. This indicated that the AHC locus is situated distal to GK. The studies using DNA markers were performed on a patient with adrenal hypoplasia but no excess glycerol in the urine and no evidence of Duchenne muscular dystrophy.</p>
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<p><a href="#21" class="mim-tip-reference" title="Muscatelli, F., Strom, T. M., Walker, A. P., Zanaria, E., Recan, D., Meindl, A., Bardoni, B., Guioli, S., Zehetner, G., Rabl, W., Schwarz, H. P., Kaplan, J.-C., Camerino, G., Meitinger, T., Monaco, A. P. <strong>Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism.</strong> Nature 372: 672-676, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7990958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7990958</a>] [<a href="https://doi.org/10.1038/372672a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7990958">Muscatelli et al. (1994)</a> demonstrated that mutations in the DAX1 gene give rise to X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism. In 14 patients with AHC, AHC and glycerol kinase deficiency, and AHC-GKD-DMD, DAX1 was deleted. In 11 AHC families, and 1 sporadic case, point mutations were found in the coding region of the DAX1 gene (see, e.g., <a href="/entry/300473#0001">300473.0001</a>-<a href="/entry/300473#0005">300473.0005</a>). All AHC patients over 14 years of age and with only point mutations in DAX1 were also found to have hypogonadotropic hypogonadism. However, in 4 sporadic cases and a single familial case of AHC, no point mutations were found, suggesting genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7990958" 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="#40" class="mim-tip-reference" title="Zhang, Y.-H., Guo, W., Wagner, R. L., Huang, B.-L., McCabe, L., Vilain, E., Burris, T. P., Anyane-Yeboa, K., Burghes, A. H. M., Chitayat, D., Chudley, A. E., Genel, M., and 12 others. <strong>DAX1 mutations map to putative structural domains in a deduced three-dimensional model.</strong> Am. J. Hum. Genet. 62: 855-864, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529340</a>] [<a href="https://doi.org/10.1086/301782" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529340">Zhang et al. (1998)</a> identified 14 new mutations in 17 families with AHC, bringing the total number of families with AHC studied to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529340" 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 patient who presented at 28 years of age with hypogonadotropic hypogonadism but no clinical evidence of adrenal dysfunction and who was shown to have compensated primary adrenal failure by biochemical testing, <a href="#16" class="mim-tip-reference" title="Mantovani, G., Ozisik, G., Achermann, J. C., Romoli, R., Borretta, G., Persani, L., Spada, A., Jameson, J. L., Beck-Peccoz, P. <strong>Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenital.</strong> J. Clin. Endocr. Metab. 87: 44-48, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11788621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11788621</a>] [<a href="https://doi.org/10.1210/jcem.87.1.8163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11788621">Mantovani et al. (2002)</a> identified a missense mutation in the NR0B1 gene (Y380D; <a href="/entry/300473#0025">300473.0025</a>), which caused partial loss of function in transient gene expression assays. The authors concluded that partial loss-of-function mutations in DAX1 can present with HHG and covert adrenal failure in adulthood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11788621" 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 20-year-old male with an unusual form of AHC manifest as late-onset adrenal insufficiency and gonadal failure, <a href="#23" class="mim-tip-reference" title="Ozisik, G., Mantovani, G., Achermann, J. C., Persani, L., Spada, A., Weiss, J., Beck-Peccoz, P., Jameson, J. L. <strong>An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita.</strong> J. Clin. Endocr. Metab. 88: 417-423, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519885</a>] [<a href="https://doi.org/10.1210/jc.2002-021034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12519885">Ozisik et al. (2003)</a> identified a nonsense mutation in the NR0B1 gene (Q37X; <a href="/entry/300473#0029">300473.0029</a>). Using a combination of in vitro translation assays and transfection studies, the authors demonstrated that the mutation, which was predicted to cause severe truncation of the protein, was associated with a milder phenotype due to the expression of a partially functional DAX1 protein generated from an alternate in-frame translation start site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12519885" 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 family in which 3 affected male relatives had variable adrenal-related phenotypes, <a href="#27" class="mim-tip-reference" title="Raffin-Sanson, M.-L., Oudet, B., Salenave, S., Brailly-Tabard, S., Pehuet, M., Christin-Maitre, S., Morel, Y., Young, J. <strong>A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic-pituitary-gonadal axis but deteriorating oligospermia during long-term follow-up.</strong> Europ. J. Endocr. 168: K45-K50, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23384712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23384712</a>] [<a href="https://doi.org/10.1530/EJE-12-1055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23384712">Raffin-Sanson et al. (2013)</a> identified hemizygosity for a nonsense mutation in the NR0B1 gene (W39X; <a href="/entry/300473#0031">300473.0031</a>). The proband was diagnosed with adrenal insufficiency at 19 years of age and with oligospermia at age 23, and his brother had azoospermia and mild asymptomatic adrenal insufficiency diagnosed at 36 years of age. In contrast, their nephew underwent adrenal crisis during the second week of life. <a href="#27" class="mim-tip-reference" title="Raffin-Sanson, M.-L., Oudet, B., Salenave, S., Brailly-Tabard, S., Pehuet, M., Christin-Maitre, S., Morel, Y., Young, J. <strong>A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic-pituitary-gonadal axis but deteriorating oligospermia during long-term follow-up.</strong> Europ. J. Endocr. 168: K45-K50, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23384712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23384712</a>] [<a href="https://doi.org/10.1530/EJE-12-1055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23384712">Raffin-Sanson et al. (2013)</a> stated that this was the first report of an NR0B1 mutation in a patient with documented normal gonadotrope function, and noted that the association between a normal gonadotrope axis and severe testicular dysfunction suggested that NR0B1 deficiency could cause progressive alteration of the testicular germinal epithelium, independently of gonadotropin and testosterone production. The authors also stated that W39X was a recurrent NR0B1 mutation that had been previously associated with mild phenotypes, as had the nearby Q37X amino-terminal nonsense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23384712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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In an 11-year-old prepubertal Dutch boy with a mild form of congenital adrenal hypoplasia involving prominent hypoaldosteronism without clear evidence of glucocorticoid insufficiency, <a href="#35" class="mim-tip-reference" title="Verrijn Stuart, A. A., Ozisik, G., de Vroede, M. A., Giltay, J. C., Sinke, R. J., Peterson, T. J., Harris, R. M., Weiss, J., Jameson, J. L. <strong>An amino-terminal DAX1 (NR0B1) missense mutation associated with isolated mineralocorticoid deficiency.</strong> J. Clin. Endocr. Metab. 92: 755-761, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17164309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17164309</a>] [<a href="https://doi.org/10.1210/jc.2005-2429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17164309">Verrijn Stuart et al. (2007)</a> identified a missense mutation in the NR0B1 gene (W105C; <a href="/entry/300473#0030">300473.0030</a>) that was also detected in 3 asymptomatic male relatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17164309" 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="Mou, L., Xie, N., Yang, L., Liu, Y., Diao, R., Cai, Z., Li, H., Gui, Y. <strong>A novel mutation of DAX-1 associated with secretory azoospermia.</strong> PLoS One 10: e0133997, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26207377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26207377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26207377[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pone.0133997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26207377">Mou et al. (2015)</a> screened for NR0B1 mutations in 776 Han Chinese men with nonobstructive azoospermia and identified 1 man with a missense mutation (V385L) that showed reduced inhibition of the androgen receptor (AR; <a href="/entry/313700">313700</a>) compared to wildtype and was not found in 709 ethnically matched controls. The patient had a low-normal testosterone level with normal LH and FSH values and normal testicular volume; testicular histology showed arrest of spermatogenesis at the spermatocyte stage. Adrenocortical hormone analysis was not reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26207377" 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 href="#Bartley1982" class="mim-tip-reference" title="Bartley, J. A., Miller, D. K., Hayford, J. T., McCabe, E. R. B. <strong>Concordance of X-linked glycerol kinase deficiency with X-linked congenital adrenal hypoplasia.</strong> Lancet 320: 733-736, 1982. Note: Originally Volume II.">Bartley et al. (1982)</a>; <a href="#Hensleigh1978" class="mim-tip-reference" title="Hensleigh, P. A., Moore, W. V., Wilson, K., Tulchinsky, D. <strong>Congenital X-linked adrenal hypoplasia.</strong> Obstet. Gynec. 52: 228-232, 1978.">Hensleigh et al. (1978)</a>; <a href="#Mamelle1975" class="mim-tip-reference" title="Mamelle, J.-C., David, M., Riou, D., Gilly, J., Trouillas, J., Dutruge, J., Gilly, R. <strong>Hypoplasie surrenalienne congenitale de type cytomegalique; forme recessive liee au sexe.</strong> Arch. Franc. Pediat. 32: 139-159, 1975.">Mamelle et al.
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(1975)</a>; <a href="#Pakravan1974" class="mim-tip-reference" title="Pakravan, P., Kenny, F. M., Depp, R., Allen, A. C. <strong>Familial congenital absence of adrenal glands; evaluation of glucocorticoid, mineralocorticoid, and estrogen metabolism in the perinatal period.</strong> J. Pediat. 84: 74-78, 1974.">Pakravan et al. (1974)</a>
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Bartley, J. A., Miller, D. K., Hayford, J. T., McCabe, E. R. B.
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<strong>Concordance of X-linked glycerol kinase deficiency with X-linked congenital adrenal hypoplasia.</strong>
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Lancet 320: 733-736, 1982. Note: Originally Volume II.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6125810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6125810</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6125810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(82)90921-7" target="_blank">Full Text</a>]
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Boyd, J. F., MacDonald, A. M.
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<strong>Adrenal cortical hypoplasia in siblings.</strong>
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Arch. Dis. Child. 35: 561-568, 1960.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21032374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21032374</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21032374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/adc.35.184.561" target="_blank">Full Text</a>]
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Brochner-Mortensen, K.
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<strong>Familial occurrence of Addison's disease.</strong>
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Acta Med. Scand. 156: 205-209, 1956.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13381433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13381433</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13381433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.0954-6820.1956.tb00077.x" target="_blank">Full Text</a>]
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Cohen, H. N., Hay, I. D., Beastall, G. H., Thomson, J. A.
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<strong>Failure of adrenal androgen to induce puberty in familial cytomegalic adrenocortical hypoplasia. (Letter)</strong>
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Lancet 320: 1471-1472, 1982. Note: Originally Volume II.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6129550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6129550</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6129550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(82)91380-0" target="_blank">Full Text</a>]
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Domenice, S., Latronico, A. C., Brito, V. N., Arnhold, I. J. P., Kok, F., Mendonca, B. B.
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<strong>Adrenocorticotropin-dependent precocious puberty of testicular origin in a boy with X-linked adrenal hypoplasia congenita due to a novel mutation in the DAX1 gene.</strong>
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J. Clin. Endocr. Metab. 86: 4068-4071, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549627</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Golden, M. P., Lippe, B. M., Kaplan, S. A.
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<strong>Congenital adrenal hypoplasia and hypogonadotropic hypogonadism.</strong>
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Am. J. Dis. Child. 131: 1117-1118, 1977.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/910763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">910763</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=910763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archpedi.1977.02120230063010" target="_blank">Full Text</a>]
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Hammond, J., Howard, N. J., Brookwell, R., Purvis-Smith, S., Wilcken, B., Hoogenraad, N.
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[<a href="https://doi.org/10.1016/s0022-3476(75)80978-4" target="_blank">Full Text</a>]
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<strong>A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic-pituitary-gonadal axis but deteriorating oligospermia during long-term follow-up.</strong>
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[<a href="https://doi.org/10.1530/EJE-12-1055" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.84.2.5468" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199001043220103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2001-011930" target="_blank">Full Text</a>]
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<strong>X-linked adrenal hypoplasia in a large Greenlandic family. Detection of a missense mutation (N4401) in the DAX-1 gene; implication for genetic counselling and carrier diagnosis.</strong>
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[<a href="https://doi.org/10.1007/s004390050316" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI7212" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/adc.43.232.724" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2005-2429" target="_blank">Full Text</a>]
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<a id="Weiss1970" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1136/jmg.7.1.27" target="_blank">Full Text</a>]
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<a id="Yates1987" class="mim-anchor"></a>
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<a id="Zachmann1992" class="mim-anchor"></a>
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Zachmann, M., Fuchs, E., Prader, A.
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[<a href="https://doi.org/10.1007/BF01954375" target="_blank">Full Text</a>]
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Zachmann, M., Illig, R., Prader, A.
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<strong>Gonadotropin deficiency and cryptorchidism in three prepubertal brothers with congenital adrenal hypoplasia.</strong>
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[<a href="https://doi.org/10.1016/s0022-3476(80)80486-0" target="_blank">Full Text</a>]
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Zhang, Y.-H., Guo, W., Wagner, R. L., Huang, B.-L., McCabe, L., Vilain, E., Burris, T. P., Anyane-Yeboa, K., Burghes, A. H. M., Chitayat, D., Chudley, A. E., Genel, M., and 12 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529340</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/301782" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 08/09/2016
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 6/29/2010<br>Marla J. F. O'Neill - updated : 9/16/2009<br>Marla J. F. O'Neill - updated : 7/26/2006<br>Cassandra L. Kniffin - reorganized : 2/23/2004<br>Victor A. McKusick - updated : 4/14/2003<br>John A. Phillips, III - updated : 1/8/2003<br>John A. Phillips, III - updated : 8/8/2002<br>Victor A. McKusick - updated : 7/3/2002<br>John A. Phillips, III - updated : 3/21/2002<br>Victor A. McKusick - updated : 12/27/2001<br>Deborah L. Stone - updated : 9/10/2001<br>John A. Phillips, III - updated : 7/13/2001<br>John A. Phillips, III - updated : 11/16/2000<br>Paul J. Converse - updated : 8/21/2000<br>John A. Phillips, III - updated : 3/31/2000<br>Victor A. McKusick - updated : 2/18/2000<br>John A. Phillips, III - updated : 10/6/1999<br>Victor A. McKusick - updated : 8/4/1999<br>Victor A. McKusick - updated : 4/27/1999<br>John A. Phillips, III - updated : 3/2/1999<br>John A. Phillips, III - updated : 1/8/1999<br>Victor A. McKusick - updated : 11/24/1998<br>Victor A. McKusick - updated : 5/13/1998<br>John A. Phillips, III - updated : 3/19/1998<br>John A. Phillips, III - updated : 3/17/1998<br>Victor A. McKusick - updated : 3/13/1998<br>Victor A. McKusick - updated : 2/20/1998<br>Jennifer P. Macke - updated : 9/24/1997<br>John A. Phillips, III - updated : 1/8/1997<br>John A. Phillips, III - updated : 11/14/1996<br>John A. Phillips, III - updated : 9/19/1996<br>John A. Phillips, III - updated : 2/28/1996
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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alopez : 08/09/2016
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carol : 06/23/2016<br>carol : 2/19/2016<br>carol : 6/29/2010<br>carol : 10/5/2009<br>terry : 9/16/2009<br>terry : 3/27/2009<br>wwang : 10/15/2008<br>carol : 7/26/2006<br>terry : 7/26/2006<br>terry : 4/21/2005<br>carol : 3/4/2004<br>carol : 2/23/2004<br>ckniffin : 2/5/2004<br>cwells : 11/7/2003<br>tkritzer : 9/17/2003<br>alopez : 7/3/2003<br>alopez : 4/30/2003<br>alopez : 4/14/2003<br>terry : 4/14/2003<br>alopez : 1/8/2003<br>cwells : 8/8/2002<br>cwells : 7/18/2002<br>terry : 7/3/2002<br>alopez : 3/21/2002<br>carol : 1/9/2002<br>mcapotos : 1/2/2002<br>terry : 12/27/2001<br>carol : 9/10/2001<br>carol : 8/24/2001<br>cwells : 7/19/2001<br>cwells : 7/13/2001<br>terry : 1/24/2001<br>alopez : 1/24/2001<br>terry : 11/16/2000<br>mgross : 8/21/2000<br>mgross : 4/27/2000<br>terry : 3/31/2000<br>mcapotos : 3/24/2000<br>mcapotos : 3/23/2000<br>terry : 2/18/2000<br>mgross : 10/22/1999<br>alopez : 10/6/1999<br>alopez : 10/6/1999<br>mgross : 9/24/1999<br>carol : 8/13/1999<br>terry : 8/4/1999<br>terry : 5/25/1999<br>terry : 4/27/1999<br>mgross : 3/2/1999<br>alopez : 1/8/1999<br>alopez : 11/30/1998<br>terry : 11/24/1998<br>dkim : 9/11/1998<br>alopez : 5/20/1998<br>alopez : 5/20/1998<br>alopez : 5/19/1998<br>terry : 5/13/1998<br>psherman : 3/19/1998<br>psherman : 3/17/1998<br>alopez : 3/13/1998<br>terry : 3/10/1998<br>alopez : 2/26/1998<br>alopez : 2/20/1998<br>terry : 2/20/1998<br>alopez : 9/24/1997<br>alopez : 9/23/1997<br>mark : 7/8/1997<br>jenny : 5/28/1997<br>jenny : 5/27/1997<br>jenny : 5/21/1997<br>jenny : 5/13/1997<br>alopez : 4/4/1997<br>alopez : 4/2/1997<br>jenny : 2/25/1997<br>mark : 1/11/1997<br>jenny : 1/10/1997<br>terry : 12/26/1996<br>terry : 11/20/1996<br>terry : 11/20/1996<br>mark : 10/16/1996<br>terry : 10/10/1996<br>carol : 9/19/1996<br>mark : 4/17/1996<br>mark : 4/17/1996<br>joanna : 4/16/1996<br>joanna : 4/16/1996<br>joanna : 2/28/1996<br>joanna : 2/4/1996<br>mark : 10/12/1995<br>carol : 1/6/1995<br>warfield : 3/22/1994<br>mimadm : 2/27/1994<br>carol : 5/22/1992<br>carol : 5/12/1992
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<strong>#</strong> 300200
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ADRENAL HYPOPLASIA, CONGENITAL; AHC
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<em>Alternative titles; symbols</em>
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ADRENAL HYPOPLASIA, CONGENITAL, WITH HYPOGONADOTROPIC HYPOGONADISM; AHCH<br />
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ADDISON DISEASE, X-LINKED; AHX<br />
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AHC WITH HHG<br />
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CYTOMEGALIC ADRENOCORTICAL HYPOPLASIA<br />
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AHC WITH ISOLATED GONADOTROPIN DEFICIENCY
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<strong>SNOMEDCT:</strong> 237764004;
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<strong>ORPHA:</strong> 95702;
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<strong>DO:</strong> 0080156;
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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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Xp21.2
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Adrenal hypoplasia, congenital
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300200
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X-linked recessive
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3
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NR0B1
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300473
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism is caused by mutation in the NR0B1 gene (300473).</p>
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<strong>Description</strong>
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<p>Congenital adrenal hypoplasia (AHC) is a rare disorder that can be inherited in an X-linked or autosomal recessive (see 240200) pattern. In X-linked AHC, primary adrenocortical failure occurs because the adrenal glands lack the permanent adult cortical zone. The remaining cells are termed 'cytomegalic' because they are larger than typical fetal adrenal cells (Hay et al., 1981; Reutens et al., 1999). </p><p>Patients with AHC usually present in early infancy with primary adrenal failure. Hypogonadotropic hypogonadism (HHG) is a hallmark of the disorder, and is recognized during adolescence because of the absence or interruption of normal pubertal development. Abnormal spermatogenesis has also been observed in these patients. Milder forms of the disease have been described, with adrenal insufficiency sometimes occurring in childhood or even early adulthood. A few cases of partial HHG have been reported (summary by Raffin-Sanson et al., 2013). Transient precocious sexual development in infancy or early childhood can be a prominent feature of AHC (Landau et al., 2010). </p><p>A contiguous gene syndrome involving a combination of congenital adrenal hypoplasia, glycerol kinase deficiency (307030), and Duchenne muscular dystrophy (DMD; 310200) is caused by deletion of multiple genes on chromosome Xp21 (see 300679).</p>
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<strong>Clinical Features</strong>
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<p>Weiss and Mellinger (1970) described an X-linked form of congenital adrenal hypoplasia in 3 of 4 brothers, each of whom had a different father. Histologically, there was hypoplasia of the adrenal cortex and lack of organization of the cortex into cords, as well as clumps of large pale-staining cells. Several other families consistent with X-linked inheritance had been reported (e.g., Boyd and MacDonald, 1960; Uttley, 1968; Stempfel and Engel, 1960). Brochner-Mortensen (1956) described Addison disease in 2 brothers and 2 of their maternal uncles. Three of the patients had died at ages 19, 26, and 33 years. In brothers reported by Meakin et al. (1959), the diagnosis was made in the elder at 9 years of age and in the second at 6 years of age. </p><p>Congenital adrenal hypoplasia with hypogonadotropic hypogonadism (HHG) was observed by Hay (1977), who suggested that hypogonadism might be a consequence of absence of adrenal androgen secretion. Hay et al. (1981) described 5 boys with cytomegalic adrenocortical hypoplasia who had been followed for many years. Despite treatment with replacement corticosteroids, all 5 failed to show a spontaneous onset of puberty, and when assessed at ages 13 to 19 years, all had both sexual infantilism and skeletal immaturity. Hypogonadism was confirmed by low levels of plasma testosterone and inadequate pituitary reserve of gonadotropin. Treatment with either testosterone or gonadotropin resulted in advances in pubertal staging in all 5 patients. </p><p>Hay et al. (1981) noted that the association of hypogonadotrophic hypogonadism with familial cytomegalic adrenocortical hypoplasia is a common finding. Prader et al. (1975), Golden et al. (1977), and Zachmann et al. (1980) also described this association. Martin (1971) described a pair of brothers in whom the signs of Addison disease developed at age 5. Gonadotropin deficiency was later demonstrated in both brothers (Martin, 1980). </p><p>An extensive Greenlandic pedigree was reported by Petersen et al. (1982). Over 5 generations, 11 boys had died with a clinical picture of adrenocortical insufficiency within 3 weeks of birth. In 3 treated males who survived, the adrenal glands could not be identified by computed tomography. Pubertal development was delayed in 2 patients aged 14 years. Subsequently, Schwartz et al. (1997) identified a missense mutation (300473.0008) in the DAX1 gene in 3 affected members of this Greenlandic family. </p><p>Reutens et al. (1999) described the clinical features and genetic alterations in 6 families with AHC. Most patients presented within the first year of life with variable signs and symptoms, including hyperpigmentation, salt-wasting crisis, vomiting, and malaise. One patient had a delayed presentation at the age of 7 years, after a hypotensive episode and hyponatremia during an acute asthma attack. A review of the literature showed an apparent bimodal distribution for age at diagnosis. The majority of patients were diagnosed within the first 2 months of life, and another group of patients were diagnosed from 1 to 11 years. Nonsense mutations in the DAX1 gene were identified in 3 cases, and frameshift mutations resulting in a premature stop codon were found in the other 3 families. There were no obvious genotype/phenotype correlations. The authors concluded that the clinical presentation of DAX1 mutations is variable and emphasized the value of genetic testing in boys with primary adrenal insufficiency and suspected X-linked AHC. </p><p>The review of Kletter et al. (1991) suggested that gonadotropin deficiency is an integral part of X-linked cytomegalic adrenocortical hypoplasia.</p><p>Zachmann et al. (1992) found progressive high frequency hearing loss developing at about the age of 14 years in 3 brothers with X-linked congenital adrenal hypoplasia associated with gonadotropin deficiency. All 3, aged 22, 20, and 18 years, had developed progressive high frequency hearing loss at about 14 years of age. They were doing well on replacement therapy with hydrocortisone, fluorohydrocortisone, and long-acting testosterone. High resolution chromosomal analysis showed no structural anomalies. Although no statement was made concerning the sense of smell, the gonadotropin deficiency may have represented Kallmann syndrome (308700). </p><p>Jones et al. (1995) reported the case of a Hispanic boy with congenital adrenal hypoplasia who had coal-black hyperpigmentation at birth. Both parents were of light complexion. Usually hyperpigmentation in this condition appears gradually over a period of months to years. Following steroid therapy, the patient's color began to lighten, and at week 7 of life the infant had pigmentation intermediate between coal-black and the color of his Hispanic mother. By 6 months of age, the infant's skin color was similar to that of his mother. </p><p><strong><em>Clinical Variability</em></strong></p><p>
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Tabarin et al. (2000) reported an unusually mild case in a man who presented with apparently isolated adrenal insufficiency at 28 years of age. Examination revealed partial pubertal development (Tanner stage 3) and undiagnosed incomplete HHG. The patient noted that puberty had occurred at about age 16, and that he had impaired libido and infrequent erections. Severe oligospermia was detected. A mutation in the DAX1 gene (300473.0020) was found, extending the clinical spectrum of the disease to include a milder disorder with delayed onset of symptoms. </p><p>Domenice et al. (2001) reported a 2-year-old Brazilian boy with a DAX1 mutation (300473.0024). Initial clinical manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. Testosterone levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce testosterone levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and testosterone levels to the prepubertal range. The authors concluded that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations. </p><p>Salvi et al. (2002) reported a 25-year-old man with a complex rearrangement in the DAX1 gene (300473.0026) who was diagnosed with adrenal failure at 6 weeks of age, but who experienced transient recovery of adrenal function of several months' duration later in infancy. He subsequently failed to undergo puberty because of hypogonadotropic hypogonadism (HHG) that was demonstrated to be of pituitary origin, with no pituitary gonadotropin secretion upon stimulation by low-dose pulsatile GnRH or by acute administration of GnRH by intravenous bolus. The patient was also diagnosed with schizophrenia in early adulthood. Salvi et al. (2002) noted that heterogeneity both in age at diagnosis and in severity of the adrenal syndrome is a well-recognized feature of AHC, and that variability in the HHG syndrome that classically accompanies AHC has also been reported. They stated that there was evidence in the literature supporting a purely hypothalamic origin of the defect, a pituitary origin, or both, and noted that the results obtained in their patient did not exclude a hypothalamic component to the HHG. </p><p>Landau et al. (2010) studied 12 patients with AHC from 5 Israeli families. Six patients from 2 families had a contiguous gene deletion involving NR0B1, and those patients also exhibited developmental delay ranging from mild to severe. The remaining 6 patients had point mutations, resulting in a nonsense mutation, a missense mutation, and a splice site mutation, respectively. Signs of transient precocious sexual development were documented in infancy and childhood in 5 patients from 4 families, with enlarged penis in all 5 patients and increased testicular volume in 2 brothers. All 5 patients later exhibited HHG at the age of puberty. Landau et al. (2010) noted that the clinical spectrum of disease in X-linked AHC is quite variable, and that precocious sexual development can be a prominent feature. </p><p>Raffin-Sanson et al. (2013) studied a family in which 3 male relatives were hemizygous for a nonsense mutation in the NR0B1 gene (W39X; see MOLECULAR GENETICS), with different adrenal consequences. The proband, 47 years old at the time of the report, had been diagnosed at age 19 years with adrenal insufficiency and with oligospermia at age 23. Evaluation at 32 years of age showed normal external genitalia, and he reported spontaneous onset of puberty at age 13, with normal virilization, growth spurt, and testicular growth. CT scan showed bilateral adrenal atrophy. Over 25 years of follow-up, his LH pulsatile secretion and testosterone level remained normal, consistent with LH-driven preservation of Leydig cell function. However, his sperm counts fell from 4 x 10(6) at age 23 to 0.05 x 10(6) by age 37, and inhibin B (see 147290) levels also decreased, indicating impaired Sertoli cell function. He fathered 1 child by in vitro fertilization at age 33 and another by spontaneous conception 2 years later. Evaluation of the proband's younger brother at age 36 years revealed complete virilization with normal penile length and testicular volume, but low testosterone level and azoospermia. He also exhibited an abnormal cortisol response to the standard-dose cortrosyn test and was diagnosed with mild asymptomatic adrenal insufficiency. In addition, their sister gave birth to a boy who underwent adrenal crisis during the second week of life. All 3 patients carried the recurrent W39X mutation, which Raffin-Sanson et al. (2013) stated had previously been reported in patients with mild phenotypes. </p>
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<strong>Diagnosis</strong>
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<p><strong><em>Differential Diagnosis</em></strong></p><p>
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Adrenoleukodystrophy (ALD; 300100) is a well-established X-linked disorder. Since adrenal insufficiency can precede neurologic symptoms by several years in ALD, and may in fact be the only manifestation in one form of the disorder, some reported cases of X-linked Addison disease may represent that disorder. For example, Sadeghi-Nejad and Senior (1990) looked for signs of adrenomyeloneuropathy, a biochemically identical but milder and more slowly progressive variant of adrenoleukodystrophy, in 8 male patients with childhood-onset Addison disease. In 5 of the patients, elevated plasma hexacosanoic acid concentrations were found, confirming the diagnosis, and in all 5, magnetic resonance imaging showed evidence of brain involvement. Reexploration of the family histories showed additional missed cases. </p><p>In the family reported by O'Neill et al. (1982), clinically apparent Addison disease without neurologic involvement was the expression of adrenoleukodystrophy in males, and spastic paraplegia and sphincter disturbances occurred in female carriers. Again, Addison disease in young males should prompt consideration of ALD as the underlying abnormality. The achalasia-Addisonian syndrome (231550), which appears to be autosomal recessive, is another example of combined adrenal and neurologic (autonomic) involvement. </p><p>Like ALD, glycerol kinase deficiency (GKD; 307030) is an X-linked systemic disorder with adrenal insufficiency.</p>
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<strong>Clinical Management</strong>
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<p>Cohen et al. (1982) reported treatment failure in a 19-year-old male with familial cytomegalic adrenocortical hypoplasia and associated hypogonadotropism with the adrenal androgen dehydroepiandrosterone sulfate. A 1-year course did not induce puberty. Kikuchi et al. (1987) reported failure to induce puberty in an 18-year-old patient by pulsatile administration of low-dose gonadotropin-releasing hormone (GNRH; 152760). </p>
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<strong>Mapping</strong>
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<p>Hammond et al. (1985) suggested that the locus for glycerol kinase and that for X-linked adrenal hypoplasia are in the segment Xp21-p11.2. The suggestion was based on the finding of an interstitial Xp deletion with breakpoints at p11.2 and p21 in the phenotypically normal mother of a male infant who died at 36 hrs of cytomegalic adrenal hypoplasia with glyceroluria (indicating glycerol kinase deficiency) and deficiency of ornithine carbamoyltransferase (OTC; 300461) in the liver (see Xp21 deletion syndrome, 300679). </p><p>Yates et al. (1987) found a deletion of Xp21 causing congenital adrenal hypoplasia without glycerol kinase deficiency. This indicated that the AHC locus is situated distal to GK. The studies using DNA markers were performed on a patient with adrenal hypoplasia but no excess glycerol in the urine and no evidence of Duchenne muscular dystrophy.</p>
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>Muscatelli et al. (1994) demonstrated that mutations in the DAX1 gene give rise to X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism. In 14 patients with AHC, AHC and glycerol kinase deficiency, and AHC-GKD-DMD, DAX1 was deleted. In 11 AHC families, and 1 sporadic case, point mutations were found in the coding region of the DAX1 gene (see, e.g., 300473.0001-300473.0005). All AHC patients over 14 years of age and with only point mutations in DAX1 were also found to have hypogonadotropic hypogonadism. However, in 4 sporadic cases and a single familial case of AHC, no point mutations were found, suggesting genetic heterogeneity. </p><p>Zhang et al. (1998) identified 14 new mutations in 17 families with AHC, bringing the total number of families with AHC studied to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. </p><p>In a patient who presented at 28 years of age with hypogonadotropic hypogonadism but no clinical evidence of adrenal dysfunction and who was shown to have compensated primary adrenal failure by biochemical testing, Mantovani et al. (2002) identified a missense mutation in the NR0B1 gene (Y380D; 300473.0025), which caused partial loss of function in transient gene expression assays. The authors concluded that partial loss-of-function mutations in DAX1 can present with HHG and covert adrenal failure in adulthood. </p><p>In a 20-year-old male with an unusual form of AHC manifest as late-onset adrenal insufficiency and gonadal failure, Ozisik et al. (2003) identified a nonsense mutation in the NR0B1 gene (Q37X; 300473.0029). Using a combination of in vitro translation assays and transfection studies, the authors demonstrated that the mutation, which was predicted to cause severe truncation of the protein, was associated with a milder phenotype due to the expression of a partially functional DAX1 protein generated from an alternate in-frame translation start site. </p><p>In a family in which 3 affected male relatives had variable adrenal-related phenotypes, Raffin-Sanson et al. (2013) identified hemizygosity for a nonsense mutation in the NR0B1 gene (W39X; 300473.0031). The proband was diagnosed with adrenal insufficiency at 19 years of age and with oligospermia at age 23, and his brother had azoospermia and mild asymptomatic adrenal insufficiency diagnosed at 36 years of age. In contrast, their nephew underwent adrenal crisis during the second week of life. Raffin-Sanson et al. (2013) stated that this was the first report of an NR0B1 mutation in a patient with documented normal gonadotrope function, and noted that the association between a normal gonadotrope axis and severe testicular dysfunction suggested that NR0B1 deficiency could cause progressive alteration of the testicular germinal epithelium, independently of gonadotropin and testosterone production. The authors also stated that W39X was a recurrent NR0B1 mutation that had been previously associated with mild phenotypes, as had the nearby Q37X amino-terminal nonsense mutation. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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In an 11-year-old prepubertal Dutch boy with a mild form of congenital adrenal hypoplasia involving prominent hypoaldosteronism without clear evidence of glucocorticoid insufficiency, Verrijn Stuart et al. (2007) identified a missense mutation in the NR0B1 gene (W105C; 300473.0030) that was also detected in 3 asymptomatic male relatives. </p><p>Mou et al. (2015) screened for NR0B1 mutations in 776 Han Chinese men with nonobstructive azoospermia and identified 1 man with a missense mutation (V385L) that showed reduced inhibition of the androgen receptor (AR; 313700) compared to wildtype and was not found in 709 ethnically matched controls. The patient had a low-normal testosterone level with normal LH and FSH values and normal testicular volume; testicular histology showed arrest of spermatogenesis at the spermatocyte stage. Adrenocortical hormone analysis was not reported. </p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Bartley et al. (1982); Hensleigh et al. (1978); Mamelle et al.
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(1975); Pakravan et al. (1974)
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<strong>REFERENCES</strong>
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Zachmann, M., Fuchs, E., Prader, A.
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Zachmann, M., Illig, R., Prader, A.
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<strong>Gonadotropin deficiency and cryptorchidism in three prepubertal brothers with congenital adrenal hypoplasia.</strong>
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Zhang, Y.-H., Guo, W., Wagner, R. L., Huang, B.-L., McCabe, L., Vilain, E., Burris, T. P., Anyane-Yeboa, K., Burghes, A. H. M., Chitayat, D., Chudley, A. E., Genel, M., and 12 others.
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<strong>DAX1 mutations map to putative structural domains in a deduced three-dimensional model.</strong>
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Marla J. F. O'Neill - updated : 08/09/2016<br>Marla J. F. O'Neill - updated : 6/29/2010<br>Marla J. F. O'Neill - updated : 9/16/2009<br>Marla J. F. O'Neill - updated : 7/26/2006<br>Cassandra L. Kniffin - reorganized : 2/23/2004<br>Victor A. McKusick - updated : 4/14/2003<br>John A. Phillips, III - updated : 1/8/2003<br>John A. Phillips, III - updated : 8/8/2002<br>Victor A. McKusick - updated : 7/3/2002<br>John A. Phillips, III - updated : 3/21/2002<br>Victor A. McKusick - updated : 12/27/2001<br>Deborah L. Stone - updated : 9/10/2001<br>John A. Phillips, III - updated : 7/13/2001<br>John A. Phillips, III - updated : 11/16/2000<br>Paul J. Converse - updated : 8/21/2000<br>John A. Phillips, III - updated : 3/31/2000<br>Victor A. McKusick - updated : 2/18/2000<br>John A. Phillips, III - updated : 10/6/1999<br>Victor A. McKusick - updated : 8/4/1999<br>Victor A. McKusick - updated : 4/27/1999<br>John A. Phillips, III - updated : 3/2/1999<br>John A. Phillips, III - updated : 1/8/1999<br>Victor A. McKusick - updated : 11/24/1998<br>Victor A. McKusick - updated : 5/13/1998<br>John A. Phillips, III - updated : 3/19/1998<br>John A. Phillips, III - updated : 3/17/1998<br>Victor A. McKusick - updated : 3/13/1998<br>Victor A. McKusick - updated : 2/20/1998<br>Jennifer P. Macke - updated : 9/24/1997<br>John A. Phillips, III - updated : 1/8/1997<br>John A. Phillips, III - updated : 11/14/1996<br>John A. Phillips, III - updated : 9/19/1996<br>John A. Phillips, III - updated : 2/28/1996
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Victor A. McKusick : 6/4/1986
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