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Entry
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- #400044 - 46,XY SEX REVERSAL 1; SRXY1
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- OMIM
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<p>
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<span class="h4">#400044</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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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/400044"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
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<a href="/phenotypicSeries/PS400044"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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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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<li role="presentation">
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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 id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</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 id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=46,XY SEX REVERSAL" 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=1044&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/NBK1547/" 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/7612" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=400044[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=242" 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>
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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:0111778" 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/400044" 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/OMIA001230/" 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><a href="https://wormbase.org/resources/disease/DOID:0111778" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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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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</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>ORPHA:</strong> 242<br />
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<strong>DO:</strong> 0111778<br />
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">ICD+</a>
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</div>
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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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400044
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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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46,XY SEX REVERSAL 1; SRXY1
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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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</span>
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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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46,XY SEX REVERSAL, SRY-RELATED<br />
|
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46,XY GONADAL DYSGENESIS, COMPLETE, SRY-RELATED
|
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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="includedTitles" 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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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
|
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<span class="h3 mim-font">
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46,XY TRUE HERMAPHRODITISM, SRY-RELATED, INCLUDED
|
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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TESTIS-DETERMINING FACTOR, X-CHROMOSOMAL, FORMERLY, INCLUDED; TDFX, FORMERLY, INCLUDED<br />
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SEX-REVERSING LOCUS ON X, FORMERLY, INCLUDED; SRVX, FORMERLY, INCLUDED
|
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</span>
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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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<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">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/Y/13?start=-3&limit=10&highlight=13">
|
|
Yp11.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
46XY sex reversal 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/400044"> 400044 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Y-linked">YL</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">
|
|
SRY
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/480000"> 480000 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/400044" 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>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS400044" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<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/400044" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/400044" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Y-linked <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0814045&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0814045</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001450" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001450</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001450" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001450</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> Height </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Tall stature <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248328003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248328003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241240&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241240</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000098" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000098</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000098" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000098</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CHEST </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Breasts </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Normal-appearing breast development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194316&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194316</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">
|
|
|
|
- Ambiguous genitalia, severe (1 patient) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194303&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194303</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/21321009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">21321009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q56.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q56.4</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000062" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000062</a>]</span><br /> -
|
|
Urogenital sinus (1 patient) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/50961009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">50961009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0231057&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0231057</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> External Genitalia (Female) </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Infantile or normal female external genitalia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194305&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194305</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">
|
|
|
|
- No testicular components in gonads <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194306&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194306</a>]</span><br /> -
|
|
Immature testicular tissue in gonads (1 patient) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194307&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194307</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Internal Genitalia (Female) </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Primary amenorrhea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/156035004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">156035004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8913004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8913004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N91.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N91.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0232939&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232939</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000786" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000786</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000786" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000786</a>]</span><br /> -
|
|
Normal-appearing vagina <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194308&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194308</a>]</span><br /> -
|
|
Cervix present <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/289755002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">289755002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/314372002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">314372002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1277639&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1277639</a>]</span><br /> -
|
|
Small to normal uterus <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4231214&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4231214</a>]</span><br /> -
|
|
Fallopian tubes present (normal or filiform) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194309&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194309</a>]</span><br /> -
|
|
Streak or absent gonads (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194310&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194310</a>]</span><br /> -
|
|
No ovarian components in gonads <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194311&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194311</a>]</span><br /> -
|
|
Gonads consisting of fibroadipose tissue <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194312&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194312</a>]</span><br /> -
|
|
Ovarian sarcomatoid stroma in gonads <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194313&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194313</a>]</span><br /> -
|
|
Ovarian-type cortical stroma in gonad <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194314&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194314</a>]</span><br /> -
|
|
Mixed ovarian and testicular tissue in gonads (1 patient) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194315&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194315</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ENDOCRINE FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Elevated luteinizing hormone (LH) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4229939&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4229939</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011969" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011969</a>]</span><br /> -
|
|
Elevated follicle-stimulating hormone (FSH) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1864571&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1864571</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008232" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008232</a>]</span><br /> -
|
|
No elevation of androgens <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194302&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194302</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</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> NEOPLASIA </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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- Gonadoblastoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1162858007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1162858007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74751003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74751003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0206661&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0206661</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000150" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000150</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000150" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000150</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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- Highly variable intrafamilial penetrance, with many 46,XY carriers developing into normal fertile males<br /> -
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Some patients exhibit stigmata of Turner syndrome<br /> -
|
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Includes report of 1 patient designated as having true hermaphroditism<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">
|
|
<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>
|
|
<span class="mim-font">
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|
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- Caused by mutation in the sex-determining region gene (SRY, <a href="/entry/480000#0001">480000.0001</a>)<br />
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|
|
</span>
|
|
</div>
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|
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</div>
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</div>
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<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
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|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
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|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
46,XY sex reversal
|
|
- <a href="/phenotypicSeries/PS400044">PS400044</a>
|
|
- 12 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/5/179?start=-3&limit=10&highlight=179"> 5q11.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613762"> 46XY sex reversal 6 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613762"> 613762 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600982"> MAP3K1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600982"> 600982 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/8/473?start=-3&limit=10&highlight=473"> 8q23.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616067"> 46XY sex reversal 9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616067"> 616067 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603693"> ZFPM2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603693"> 603693 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/9/2?start=-3&limit=10&highlight=2"> 9p24.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/154230"> 46XY sex reversal 4 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Isolated cases">IC</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved"> 4 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/154230"> 154230 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/154230"> DEL9p24.3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/154230"> 154230 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/9/489?start=-3&limit=10&highlight=489"> 9q33.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612965"> 46XY sex reversal 3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612965"> 612965 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/184757"> NR5A1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/184757"> 184757 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/10/21?start=-3&limit=10&highlight=21"> 10p15.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614279"> 46XY sex reversal 8 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614279"> 614279 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600450"> AKR1C2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600450"> 600450 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/10/23?start=-3&limit=10&highlight=23"> 10p15.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614279"> {46XY sex reversal 8, modifier of} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614279"> 614279 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600451"> AKR1C4 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600451"> 600451 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/12/349?start=-3&limit=10&highlight=349"> 12q13.12 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/233420"> 46XY sex reversal 7 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/233420"> 233420 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605423"> DHH </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605423"> 605423 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/12/942?start=-3&limit=10&highlight=942"> 12q24.31 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/273250"> 46XY sex reversal 11 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/273250"> 273250 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617362"> DHX37 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617362"> 617362 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/17/894?start=-3&limit=10&highlight=894"> 17q24.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616425"> 46XY sex reversal 10 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616425"> 616425 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608160"> SOX9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608160"> 608160 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/17/1009?start=-3&limit=10&highlight=1009"> 17q25.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613080"> ?46XY sex reversal 5 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
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<p>A number sign (#) is used with this entry because this form of 46,XY sex reversal is caused by point mutations or deletions in the SRY gene (<a href="/entry/480000">480000</a>) on chromosome Yp11.3.</p>
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<p>Individuals with 46,XY complete gonadal dysgenesis are phenotypically female; however, they do not develop secondary sexual characteristics at puberty and do not menstruate. They have bilateral 'streak gonads,' which typically consist of fibrous tissue and variable amounts of wavy ovarian stroma. A uterus and fallopian tube are present and external genitalia are female (reviewed by <a href="#5" class="mim-tip-reference" title="Berkovitz, G. D., Fechner, P. Y., Zacur, H. W., Rock, J. A., Snyder, H. M., III, Migeon, C. J., Perlman, E. J. <strong>Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation.</strong> Medicine 70: 375-383, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1956279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1956279</a>] [<a href="https://doi.org/10.1097/00005792-199111000-00003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1956279">Berkovitz et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1956279" 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>Genetic Heterogeneity of 46,XY Sex Reversal</em></strong></p><p>
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Male sexual determination is initiated by Y-chromosomal SRY, which activates a cascade of genes that lead the embryonic gonad to develop into a testis. Fetal testicular Sertoli cells then produce mullerian inhibitory substance (<a href="/entry/600957">600957</a>), which is responsible for the involution of the mullerian ducts, which would otherwise develop into the uterus, fallopian tubes, and cervix. Fetal testicular Leydig cells produce testosterone from cholesterol by the sequential action of a series of enzymes. Subsequent differentiation of male external genitalia also requires the action of dihydrotestosterone, produced from testicular testosterone. Perturbations in the enzymes in this classic pathway or in an alternative pathway of testicular androgen biosynthesis can result in genetic males with disordered sexual development and incompletely developed ('ambiguous') external genitalia (summary by <a href="#16" class="mim-tip-reference" title="Fluck, C. E., Meyer-Boni, M., Pandey, A. V., Kempna, P., Miller, W. L., Schoenle, E. J., Biason-Lauber, A. <strong>Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation.</strong> Am. J. Hum. Genet. 89: 201-218, 2011. Note: Erratum: Am. J. Hum. Genet. 89: 347 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21802064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21802064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21802064[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/10.1016/j.ajhg.2011.06.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21802064">Fluck et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21802064" 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>Disorders of male development for which a genetic cause has been found include 46,XY sex reversal-2 (SRXY2; <a href="/entry/300018">300018</a>), which is caused by duplication of the NR0B1 gene (<a href="/entry/300473">300473</a>) on chromosome Xp21.3-p21.2; SRXY3 (<a href="/entry/612965">612965</a>), caused by mutation in the NR5A1 gene (<a href="/entry/184757">184757</a>) on chromosome 9q33; SRXY4 (<a href="/entry/154230">154230</a>), caused by deletion on chromosome 9p24.3; SRXY5 (<a href="/entry/613080">613080</a>), caused by mutation in the CBX2 gene (<a href="/entry/602770">602770</a>) on chromosome 17q25; SRXY6 (<a href="/entry/613762">613762</a>), caused by mutation in the MAP3K1 gene (<a href="/entry/600982">600982</a>) on chromosome 5q11.2; SRXY7 (<a href="/entry/233420">233420</a>), caused by mutation in the DHH gene (<a href="/entry/605423">605423</a>) on chromosome 12q13; SRXY8 (<a href="/entry/614279">614279</a>), caused by mutation in the AKR1C2 gene (<a href="/entry/600450">600450</a>) on chromosome 10p15, with a possible contribution from the closely linked AKR1C4 gene (<a href="/entry/600451">600451</a>); SRXY9 (<a href="/entry/616067">616067</a>), caused by mutation in the ZFPM2 gene (<a href="/entry/603693">603693</a>) on chromosome 8q23; and SRXY10 (<a href="/entry/616425">616425</a>), caused by deletion of the XYSR regulatory region -640 kb upstream of the SOX9 gene (<a href="/entry/608160">608160</a>) on chromosome 17q24.</p><p><a href="#51" class="mim-tip-reference" title="Wilhelm, D., Koopman, P. <strong>The makings of maleness: towards an integrated view of male sexual development.</strong> Nature Rev. Genet. 7: 620-631, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16832429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16832429</a>] [<a href="https://doi.org/10.1038/nrg1903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16832429">Wilhelm and Koopman (2006)</a> reviewed male sexual development and the genetics of disorders of human sexual development, noting that most cases of XY sex reversal, SRY-negative XX sex reversal, and true hermaphroditism remained unexplained at the molecular level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16832429" 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>The designation 'Swyer syndrome' refers to 46,XY complete gonadal dysgenesis. The disorder is caused not only by mutations in the SRY gene but by genes on the autosome and the X chromosome.</p><p>As a result of discussions at the International Consensus Conference on Intersex, <a href="#27" class="mim-tip-reference" title="Lee, P. A., Houk, C. P., Ahmed, S. F., Hughes, I. A. <strong>Consensus statement on management of intersex disorders.</strong> Pediatrics 118: e488-e500, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882788</a>] [<a href="https://doi.org/10.1542/peds.2006-0738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16882788">Lee et al. (2006)</a> proposed the term 'disorder(s) of sex development' (DSD) to replace the previously used terms 'pseudohermaphroditism,' 'intersex,' and 'sex reversal.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16882788" 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>As defined by <a href="#27" class="mim-tip-reference" title="Lee, P. A., Houk, C. P., Ahmed, S. F., Hughes, I. A. <strong>Consensus statement on management of intersex disorders.</strong> Pediatrics 118: e488-e500, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882788</a>] [<a href="https://doi.org/10.1542/peds.2006-0738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16882788">Lee et al. (2006)</a>, disorders of sex development (DSD) are 'congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical.' 46,XY DSD is a disorder of gonadal (testicular) development, which may be complete or partial (<a href="#27" class="mim-tip-reference" title="Lee, P. A., Houk, C. P., Ahmed, S. F., Hughes, I. A. <strong>Consensus statement on management of intersex disorders.</strong> Pediatrics 118: e488-e500, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882788</a>] [<a href="https://doi.org/10.1542/peds.2006-0738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16882788">Lee et al., 2006</a>). The complete form includes streak gonads, normal mullerian structures, and normal female external genitalia. The partial form includes ambiguous external genitalia and partial development of mullerian and wolffian structures (<a href="#5" class="mim-tip-reference" title="Berkovitz, G. D., Fechner, P. Y., Zacur, H. W., Rock, J. A., Snyder, H. M., III, Migeon, C. J., Perlman, E. J. <strong>Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation.</strong> Medicine 70: 375-383, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1956279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1956279</a>] [<a href="https://doi.org/10.1097/00005792-199111000-00003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1956279">Berkovitz et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1956279+16882788" 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="#43" class="mim-tip-reference" title="Swyer, G. I. <strong>Male pseudohermaphroditism: a hitherto undescribed form.</strong> Brit. Med. J. 2: 709-712, 1955.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13250193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13250193</a>] [<a href="https://doi.org/10.1136/bmj.2.4941.709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13250193">Swyer (1955)</a> described 2 46,XY women with primary amenorrhea, tall stature, female external genitalia (one with enlarged clitoris), and normal, but hypoestrogenized, vagina and cervix. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13250193" 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>Affected sisters were reported by <a href="#11" class="mim-tip-reference" title="Cohen, M. M., Shaw, M. W. <strong>Two XY siblings with gonadal dysgenesis and a female phenotype.</strong> New Eng. J. Med. 272: 1083-1088, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14281549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14281549</a>] [<a href="https://doi.org/10.1056/NEJM196505272722101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14281549">Cohen and Shaw (1965)</a>, and affected twins by <a href="#17" class="mim-tip-reference" title="Frasier, S. D., Bashore, R. A., Mosier, H. D. <strong>Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins.</strong> J. Pediat. 64: 740-745, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14149008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14149008</a>] [<a href="https://doi.org/10.1016/s0022-3476(64)80622-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14149008">Frasier et al. (1964)</a>. The sisters reported by <a href="#11" class="mim-tip-reference" title="Cohen, M. M., Shaw, M. W. <strong>Two XY siblings with gonadal dysgenesis and a female phenotype.</strong> New Eng. J. Med. 272: 1083-1088, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14281549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14281549</a>] [<a href="https://doi.org/10.1056/NEJM196505272722101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14281549">Cohen and Shaw (1965)</a> had a marker autosome, which was present also in the mother. They referred to another instance of XY 'sisters' with an abnormal autosome. One of their 2 patients had gonadoblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14281549+14149008" 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="#44" class="mim-tip-reference" title="Taylor, H., Barter, R. H., Jacobson, C. B. <strong>Neoplasms of dysgenetic gonads.</strong> Am. J. Obstet. Gynec. 96: 816-823, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5951402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5951402</a>] [<a href="https://doi.org/10.1016/0002-9378(66)90677-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5951402">Taylor et al. (1966)</a> stated there is a high incidence of neoplasia (gonadoblastomas and germinomas) in streak gonads of patients with Swyer syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5951402" 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>Two sisters reported by <a href="#15" class="mim-tip-reference" title="Fine, G., Mellinger, R. C., Canton, J. N. <strong>Gonadoblastoma occurring in a patient with familial gonadal dysgenesis.</strong> Am. J. Clin. Path. 38: 615-629, 1962."None>Fine et al. (1962)</a> were of normal stature but were chromatin negative. One of these cases and 1 of those reported by <a href="#3" class="mim-tip-reference" title="Baron, J., Rucki, T., Simm, S. <strong>Familial gonadal malformations.</strong> Gynaecologia 153: 298-308, 1962."None>Baron et al. (1962)</a> had gonadoblastoma. In the last family, 2 'females' and a male were affected, the male showing no testes. All 3 sibs were sex-chromatin negative.</p><p><a href="#4" class="mim-tip-reference" title="Barr, M. L., Carr, D. H., Plunkett, E. R., Soltan, H. C., Wiens, R. G. <strong>Male pseudohermaphroditism and pure gonadal dysgenesis in sisters.</strong> Am. J. Obstet. Gynec. 99: 1047-1055, 1967.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6070891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6070891</a>] [<a href="https://doi.org/10.1016/0002-9378(67)90342-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6070891">Barr et al. (1967)</a> reported on a sibship containing 2 genetic males. The first, who had male pseudohermaphroditism, was reared as a female; he developed signs of masculinization at puberty and had undescended but otherwise normal testes and small fallopian tubes. The second genetic male (180 cm tall) had pure gonadal dysgenesis with small uterus and streak gonads. This patient was at first thought to have the testicular feminization syndrome (<a href="/entry/300068">300068</a>). An unaffected sister had a son with perineal hypospadias (urethral orifice at the base of the penis). The sibship reported by <a href="#9" class="mim-tip-reference" title="Chemke, J., Carmichael, R., Stewart, J. M., Geer, R. H., Robinson, A. <strong>Familial XY gonadal dysgenesis.</strong> J. Med. Genet. 7: 105-111, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5519594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5519594</a>] [<a href="https://doi.org/10.1136/jmg.7.2.105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5519594">Chemke et al. (1970)</a> was similar to that of <a href="#4" class="mim-tip-reference" title="Barr, M. L., Carr, D. H., Plunkett, E. R., Soltan, H. C., Wiens, R. G. <strong>Male pseudohermaphroditism and pure gonadal dysgenesis in sisters.</strong> Am. J. Obstet. Gynec. 99: 1047-1055, 1967.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6070891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6070891</a>] [<a href="https://doi.org/10.1016/0002-9378(67)90342-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6070891">Barr et al. (1967)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5519594+6070891" 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="#39" class="mim-tip-reference" title="Rushton, D. I. <strong>XY gonadal dysgenesis. (Letter)</strong> Lancet 313: 209 only, 1979. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/84224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">84224</a>] [<a href="https://doi.org/10.1016/s0140-6736(79)90601-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="84224">Rushton (1979)</a> pointed out that the streak gonads of this disorder differ from those of the 45,X Turner syndrome in the presence of calcification and the increased hazard of gonadoblastoma. Comparative studies of the frequency of gonadoblastoma in Turner mosaics with normal or rearranged Y chromosomes have suggested that the integrity of the Y chromosome, and in particular the presence of the distal fluorescent band Yqh, is required in these mosaics for the tumor to develop; no cases with distal deletions of the fluorescent band on Yq had been reported (<a href="#29" class="mim-tip-reference" title="Lukusa, T., Fryns, J. P., van den Berghe, H. <strong>Gonadoblastoma and Y chromosome fluorescence.</strong> Clin. Genet. 29: 311-316, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3720008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3720008</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1986.tb01259.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3720008">Lukusa et al., 1986</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3720008+84224" 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="Dumic, M., Lin-Su, K., Leibel, N. I., Ciglar, S., Vinci, G., Lasan, R., Nimkarn, S., Wilson, J. D., McElreavey, K., New, M. I. <strong>Report of fertility in a woman with a predominantly 46,XY karyotype in a family with multiple disorders of sexual development.</strong> J. Clin. Endocr. Metab. 93: 182-189, 2008. Note: Erratum: J. Clin. Endocr. Metab. 93: 1083 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000096</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18000096[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/10.1210/jc.2007-2155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000096">Dumic et al. (2008)</a> reported a fertile woman with normal ovaries and a predominantly 46,XY ovarian karyotype who gave birth to a 46,XY female with complete gonadal dysgenesis. The karyotype of the phenotypically normal mother was 100% 46,XY in blood, 80% 46,XY and 20% 45,X in cultured skin fibroblasts, and 93% 46,XY, 6% 45,X, and less than 1% 46,XX in the ovary. The 52-year-old mother had normal pubertal development with spontaneous menarche at 11 years of age. She had 2 unassisted pregnancies, the first of which ended in miscarriage. She had regular menses until menopause at age 49 years. Physical examination revealed a feminine-appearing woman with a normal body habitus; there was no receding hairline or balding of the scalp and no acne or facial hair. Breasts and pubic hair were Tanner stage V, and external genitalia were normal with no clitoromegaly or labial fusion. The vaginal introitus was normal, and pelvic examination revealed a uterus in retroverted position with no adnexal masses; hormonal findings were compatible with a normal menopausal woman. The daughter born of her second pregnancy presented at 17 years of age due to lack of breast development and primary amenorrhea. Examination showed mild facial acne but no facial hair, with Tanner stage I breasts and stage IV pubic hair. External female genitalia were normal, without clitoromegaly or labial fusion, and the vaginal introitus was normal. Pelvic examination revealed a hypoplastic uterus with no palpable gonads; ultrasound showed a small left gonad, but no gonad was seen on the right. On karyotyping, the daughter was 100% 46,XY in blood, 100% 46,XY in skin, and 99.25% 46,XY and 0.75% 45,X in gonadal tissue. The family pedigree on the mother's side was notable for the presence of 7 individuals over 4 generations, both phenotypic males and females, who had sexual ambiguity, infertility, or failure to menstruate, including 1 individual with documented 45,X/46,XY mixed gonadal dysgenesis. The mode of inheritance in the family was strongly suggestive of X-linkage. <a href="#14" class="mim-tip-reference" title="Dumic, M., Lin-Su, K., Leibel, N. I., Ciglar, S., Vinci, G., Lasan, R., Nimkarn, S., Wilson, J. D., McElreavey, K., New, M. I. <strong>Report of fertility in a woman with a predominantly 46,XY karyotype in a family with multiple disorders of sexual development.</strong> J. Clin. Endocr. Metab. 93: 182-189, 2008. Note: Erratum: J. Clin. Endocr. Metab. 93: 1083 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000096</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18000096[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/10.1210/jc.2007-2155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000096">Dumic et al. (2008)</a> stated that this was the first report of fertility in a woman with a predominantly 46,XY karyotype in the ovary, and suggested that perhaps all mothers of 46,XY(SRY+) females with complete gonadal dysgenesis should be carefully examined for an XY karyotype as well. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18000096" 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>46,XY True Hermaphroditism</em></strong></p><p>
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A 'true hermaphrodite' must have both mature ovarian and mature testicular tissue with histologic evidence of follicles and tubules, respectively (<a href="#45" class="mim-tip-reference" title="van Niekerk, W. A., Retief, A. E. <strong>The gonads of human true hermaphrodites.</strong> Hum. Genet. 58: 117-122, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6895206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6895206</a>] [<a href="https://doi.org/10.1007/BF00284158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6895206">van Niekerk and Retief, 1981</a>). It is a genetically heterogeneous condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6895206" 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="#45" class="mim-tip-reference" title="van Niekerk, W. A., Retief, A. E. <strong>The gonads of human true hermaphrodites.</strong> Hum. Genet. 58: 117-122, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6895206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6895206</a>] [<a href="https://doi.org/10.1007/BF00284158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6895206">Van Niekerk and Retief (1981)</a> found that the ovotestis was the most common gonad of the true hermaphrodite, found in 44.3% of 406 cases. The genotype of most affected individuals was 46,XX (see <a href="/entry/400045">400045</a>), but many had 46,XY or a mosaic of 46,XX/46,XY. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6895206" 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="#32" class="mim-tip-reference" title="Milner, W. A., Garlick, W. B., Fink, A. J., Stein, A. A. <strong>True hermaphrodite siblings.</strong> J. Urol. 79: 1003-1009, 1958.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13540002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13540002</a>] [<a href="https://doi.org/10.1016/S0022-5347(17)66383-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13540002">Milner et al. (1958)</a> reported 2 brothers who had hypospadias and both testicular and ovarian tissue bilaterally. <a href="#28" class="mim-tip-reference" title="Lowry, R. B., Honore, L. H., Arnold, W. J. D., Johnson, H. W., Kliman, M. R., Marshall, R. H. <strong>Familial true hermaphroditism. In: Bergsma, D.: Genetic Forms of Hypogonadism.</strong> New York: National Foundation-March of Dimes (pub.) 1975. Pp. 105-113."None>Lowry et al. (1975)</a> determined that the brothers reported by <a href="#32" class="mim-tip-reference" title="Milner, W. A., Garlick, W. B., Fink, A. J., Stein, A. A. <strong>True hermaphrodite siblings.</strong> J. Urol. 79: 1003-1009, 1958.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13540002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13540002</a>] [<a href="https://doi.org/10.1016/S0022-5347(17)66383-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13540002">Milner et al. (1958)</a> lacked Barr bodies (were 'chromatin negative'), indicating an XY genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13540002" 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="Lowry, R. B., Honore, L. H., Arnold, W. J. D., Johnson, H. W., Kliman, M. R., Marshall, R. H. <strong>Familial true hermaphroditism. In: Bergsma, D.: Genetic Forms of Hypogonadism.</strong> New York: National Foundation-March of Dimes (pub.) 1975. Pp. 105-113."None>Lowry et al. (1975)</a> described affected first cousins whose fathers were brothers. Both had a normal male (XY) karyotype.</p>
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<p>Small deletions in the short arm of the Y chromosome can result in 46,XY females (<a href="#13" class="mim-tip-reference" title="Disteche, C. M., Casanova, M., Saal, H., Friedman, C., Sybert, V., Graham, J., Thuline, H., Page, D., Fellous, M. <strong>Small deletions of the short arm of the Y chromosome in 46,XY females.</strong> Proc. Nat. Acad. Sci. 83: 7841-7844, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3464001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3464001</a>] [<a href="https://doi.org/10.1073/pnas.83.20.7841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3464001">Disteche et al., 1986</a>). The 2 patients reported by <a href="#13" class="mim-tip-reference" title="Disteche, C. M., Casanova, M., Saal, H., Friedman, C., Sybert, V., Graham, J., Thuline, H., Page, D., Fellous, M. <strong>Small deletions of the short arm of the Y chromosome in 46,XY females.</strong> Proc. Nat. Acad. Sci. 83: 7841-7844, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3464001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3464001</a>] [<a href="https://doi.org/10.1073/pnas.83.20.7841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3464001">Disteche et al. (1986)</a> had some signs of Turner syndrome, including congenital lymphedema and primary amenorrhea with streak gonads, but were of normal height. One of the patients had bilateral gonadoblastoma. Several Y-chromosome-specific DNA probes were found to be deleted in the 2 patients. DNA analysis showed that the 2 deletions were different, but included a common overlapping region likely to contain the testis-determining factor (TDF) gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3464001" 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>Cytogenetic duplication of the X chromosome in males is a rare event usually characterized by a significant degree of phenotypic abnormality, which can include sex reversal despite an apparently normal Y chromosome. <a href="#2" class="mim-tip-reference" title="Arn, P., Chen, H., Tuck-Muller, C. M., Mankinen, C., Wachtel, G., Li, S., Shen, C. C., Wachtel, S. S. <strong>SRVX, a sex reversing locus in Xp21.2-p22.11.</strong> Hum. Genet. 93: 389-393, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8168809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8168809</a>] [<a href="https://doi.org/10.1007/BF00201663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8168809">Arn et al. (1994)</a> reported 2 half brothers with maternally inherited cytogenetic duplications of Xp and sex reversal; the absence of dysmorphic features in mother and children was thought to be because of the relatively small extent of the duplication. Comparison with previous reports allowed a putative sex-reversing locus (SRVX) to be assigned to a 5- to 10-Mb segment between Xp22.11 and Xp21.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8168809" 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="#26" class="mim-tip-reference" title="Lange, J., Skaletsky, H., van Daalen, S. K. M., Embry, S. L., Korver, C. M., Brown, L. G., Oates, R. D., Silber, S., Repping, S., Page, D. C. <strong>Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes.</strong> Cell 138: 855-869, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19737515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19737515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19737515[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/10.1016/j.cell.2009.07.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19737515">Lange et al. (2009)</a> identified 60 unrelated individuals with isodicentric (idic) or isocentromeric (iso) Y chromosomes, 51 of which apparently arose via a palindromic mechanism, yielding an idicYp in 49 cases and an idicYq in 2 cases, whereas the remaining 9 arose via recombination in heterochromatic sequences, yielding an idicYp in 2 cases and an isoYp in 7 cases. As expected, the 2 individuals carrying the idicYq chromosomes lacked the SRY gene and were phenotypic females; however, 18 of the 58 idicYp and isoYp individuals, who had 2 copies of SRY, were also 'sex-reversed' and raised as females or found in childhood to have 1 degenerate ovary and 1 testis. <a href="#26" class="mim-tip-reference" title="Lange, J., Skaletsky, H., van Daalen, S. K. M., Embry, S. L., Korver, C. M., Brown, L. G., Oates, R. D., Silber, S., Repping, S., Page, D. C. <strong>Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes.</strong> Cell 138: 855-869, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19737515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19737515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19737515[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/10.1016/j.cell.2009.07.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19737515">Lange et al. (2009)</a> observed that the average intercentromeric distance in the feminized individuals was twice that in the males (p less than 10(-6)), supporting the hypothesis that mitotic instability and resultant XO mosaicism may cause sex reversal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19737515" 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><strong><em>46,XY Gonadal Dysgenesis, Complete</em></strong></p><p>
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<a href="#37" class="mim-tip-reference" title="Page, D. C., Mosher, R., Simpson, E. M., Fisher, E. M. C., Mardon, G., Pollack, J., McGillivray, B., de la Chapelle, A., Brown, L. G. <strong>The sex-determining region of the human Y chromosome encodes a finger protein.</strong> Cell 51: 1091-1104, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3690661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3690661</a>] [<a href="https://doi.org/10.1016/0092-8674(87)90595-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3690661">Page et al. (1987)</a> cloned a 230-kb segment of the human Y chromosome thought to contain some or all of the TDF (SRY) gene. The cloned region spanned the deletion in a female who carried all but 160 kb of the Y. Homologous sequences were found within the sex-determining region of the mouse Y chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3690661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Jager, R. J., Anvret, M., Hall, K., Scherer, G. <strong>A human XY female with a frame shift mutation in the candidate testis-determining gene SRY.</strong> Nature 348: 452-454, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2247151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2247151</a>] [<a href="https://doi.org/10.1038/348452a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2247151">Jager et al. (1990)</a> demonstrated a mutation in SRY in 1 out of 12 sex-reversed XY females with gonadal dysgenesis who had no large deletions of the short arm of the Y chromosome. They found a 4-nucleotide deletion in the part of the SRY gene that encodes a conserved DNA-binding motif. A frameshift presumably led to a nonfunctional protein. Mutation occurred de novo, because the father had a normal SRY sequence. This is strong evidence that SRY is TDF. The de novo G-to-A mutation led to a change from methionine to isoleucine at a residue that lies within the putative DNA-binding motif of SRY and is identical in all SRY and SRY-related genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2247151" 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="#46" class="mim-tip-reference" title="Vilain, E., McElreavey, K., Jaubert, F., Raymond, J.-P., Richaud, F., Fellous, M. <strong>Familial case with sequence variant in the testis-determining region associated with two sex phenotypes.</strong> Am. J. Hum. Genet. 50: 1008-1011, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570829</a>]" pmid="1570829">Vilain et al. (1992)</a> described a family in which all 5 XY individuals in 2 generations had a single basepair substitution resulting in an amino acid change in the conserved domain of the SRY open reading frame (<a href="/entry/480000#0004">480000.0004</a>). A G-to-C change at nucleotide 588 resulted in substitution of leucine for valine. Three of the individuals were XY sex-reversed females and 2 were XY males. One of the males had 8 children; all were phenotypic females, 2 of whom were sex-reversed XY females carrying the mutation mentioned. Several models were proposed to explain association between a sequence variant in SRY and 2 alternative sex phenotypes. These included the existence of alleles at an unlinked locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1570829" 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="#31" class="mim-tip-reference" title="McElreavey, K. D., Vilain, E., Boucekkine, C., Vidaud, M., Jaubert, F., Richaud, F., Fellous, M. <strong>XY sex reversal associated with a nonsense mutation in SRY.</strong> Genomics 13: 838-840, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1639410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1639410</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90164-n" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1639410">McElreavey et al. (1992)</a> described an XY sex-reversed female with pure gonadal dysgenesis who harbored a de novo nonsense mutation in SRY, which resulted directly in the formation of a stop codon in the putative DNA-binding motif. A C-to-T transition at nucleotide 687 changed a glutamine codon (CAG) to a termination codon (TAG); see <a href="/entry/480000#0005">480000.0005</a>. The patient, referred to as the 'propositus,' was a phenotypic female who presented at age 20 years for primary amenorrhea. Treatment with estrogen induced menstruation and slight enlargement of the breasts which were underdeveloped. Laparotomy showed 2 streak gonads without germ cells or remnants of tubes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1639410" 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="Harley, V. R., Jackson, D. I., Hextall, P. J., Hawkins, J. R., Berkovitz, G. D., Sockanathan, S., Lovell-Badge, R., Goodfellow, P. N. <strong>DNA binding activity of recombinant SRY from normal males and XY females.</strong> Science 255: 453-456, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1734522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1734522</a>] [<a href="https://doi.org/10.1126/science.1734522" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1734522">Harley et al. (1992)</a> found point mutations in the region of the SRY gene encoding the high mobility group (HMG) box in 5 XY females. (The HMG box is related to that present in the T-cell-specific, DNA binding protein TCF1 (<a href="/entry/142410">142410</a>).) In 4 cases, the binding activity of mutant SRY protein for the AACAAAG core sequence was negligible; in the fifth case, DNA binding was reduced. In the SRY gene in a 46,XY female, <a href="#34" class="mim-tip-reference" title="Muller, J., Schwartz, M., Skakkebaek, N. E. <strong>Analysis of the sex-determining region of the Y chromosome (SRY) in sex reversed patients: point-mutation in SRY causing sex-reversion in a 46,XY female.</strong> J. Clin. Endocr. Metab. 75: 331-333, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1619028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1619028</a>] [<a href="https://doi.org/10.1210/jcem.75.1.1619028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1619028">Muller et al. (1992)</a> demonstrated an A-to-T transversion of nucleotide 684 in the open reading frame, resulting in a change of lysine (AAG) to a stop codon (UAG). The patient had gonadoblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1619028+1734522" 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>46,XY True Hermaphroditism</em></strong></p><p>
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<a href="#30" class="mim-tip-reference" title="Maier, E. M., Leitner, C., Lohrs, U., Kuhnle, U. <strong>True hermaphroditism in an XY individual due to a familial point mutation of the SRY gene.</strong> J. Pediat. Endocr. Metab. 16: 575-580, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12793612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12793612</a>] [<a href="https://doi.org/10.1515/jpem.2003.16.4.575" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12793612">Maier et al. (2003)</a> reported a 46,XY true hermaphrodite who had a mutation in the SRY gene (<a href="/entry/480000#0006">480000.0006</a>). The father, his 3 brothers, and his first-born son carried the identical mutation without phenotypic effects. <a href="#30" class="mim-tip-reference" title="Maier, E. M., Leitner, C., Lohrs, U., Kuhnle, U. <strong>True hermaphroditism in an XY individual due to a familial point mutation of the SRY gene.</strong> J. Pediat. Endocr. Metab. 16: 575-580, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12793612/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12793612</a>] [<a href="https://doi.org/10.1515/jpem.2003.16.4.575" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12793612">Maier et al. (2003)</a> concluded that the mutated protein retained enough activity to allow normal development in some individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12793612" 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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<a href="#36" class="mim-tip-reference" title="Norling, A., Linden Hirschberg, A., Iwarsson, E., Persson, B., Wedell, A., Barbaro, M. <strong>Novel candidate genes for 46,XY gonadal dysgenesis identified by a customized 1 M array-CGH platform.</strong> Europ. J. Med. Genet. 56: 661-668, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24055526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24055526</a>] [<a href="https://doi.org/10.1016/j.ejmg.2013.09.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24055526">Norling et al. (2013)</a> performed array CGH in 9 unrelated patients with 46,XY gonadal dysgenesis in whom sequence analysis of known gonadal dysgenesis-associated genes was negative, and identified 3 candidate regions: in a pair of affected sibs, a 217-kb interstitial duplication of exons 5 to 12 of the SUPT3H gene (<a href="/entry/602947">602947</a>) on chromosome 6p21, and a 22-kb deletion involving 8 of the 9 exons of the C2ORF80 gene (<a href="/entry/615536">615536</a>) on 2q34, both inherited from their unaffected mother; and in another patient, a 454-kb duplication at chromosome 9q21.11 involving the candidate genes PIP5K1B (<a href="/entry/602745">602745</a>), PRKACG (<a href="/entry/176893">176893</a>), and FAM189A2 (<a href="/entry/607710">607710</a>). <a href="#36" class="mim-tip-reference" title="Norling, A., Linden Hirschberg, A., Iwarsson, E., Persson, B., Wedell, A., Barbaro, M. <strong>Novel candidate genes for 46,XY gonadal dysgenesis identified by a customized 1 M array-CGH platform.</strong> Europ. J. Med. Genet. 56: 661-668, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24055526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24055526</a>] [<a href="https://doi.org/10.1016/j.ejmg.2013.09.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24055526">Norling et al. (2013)</a> noted that all 5 candidate genes are expressed in testicular tissues, but that detailed functional information was lacking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24055526" 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 46,XY infant with ambiguous genitalia, who was negative for mutation in the SRY and NR5A1 genes and in whom microarray analysis did not reveal deletions or duplications in any known DSD-associated genes, <a href="#50" class="mim-tip-reference" title="White, S., Hewitt, J., Turbitt, E., van der Zwan, Y., Hersmus, R., Drop, S., Koopman, P., Harley, V., Cools, M., Looijenga, L., Sinclair, A. <strong>A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development.</strong> Europ. J. Hum. Genet. 20: 348-351, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22071891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22071891</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22071891[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/10.1038/ejhg.2011.204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22071891">White et al. (2012)</a> identified heterozygosity for a maternally inherited 767-kb deletion on chromosome 16 (chr16:76,956,767-77,723,905, NCBI36), located within the WWOX gene (<a href="/entry/605131">605131</a>). The deletion removed exons 6 through 8 and was predicted to generate an alternative in-frame mRNA product with exon 5 spliced directly onto exon 9; this alternative transcript was verified by sequencing cDNA derived from matched lymphocytes. Examination at 10 days of age showed unfused labioscrotal folds, impalpable gonads, 20-mm clitoral hypertrophy, and a perineal urogenital sinus. Genitography demonstrated the presence of a vagina and underdeveloped uterus. Small dysgenic gonads were removed from the abdomen at age 2 years; histologic analysis showed bilateral undifferentiated gonadal tissue and immature testis, both containing malignant germ cells. The heterozygous mother had relatively late menarche at age 16 years with irregular menstruation up to her first pregnancy. The proband had 2 brothers and 2 sisters, all unaffected, none of whom inherited the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22071891" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For discussion of a possible association between disorders of sex development and variation in the ESR2 gene, see <a href="/entry/601663">601663</a>.</p><p>For discussion of a possible association between 46,XY sex reversal and variation in the STARD8 gene, see <a href="/entry/300689#0001">300689.0001</a>.</p><p><strong><em>Exclusion Studies</em></strong></p><p>
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<a href="#14" class="mim-tip-reference" title="Dumic, M., Lin-Su, K., Leibel, N. I., Ciglar, S., Vinci, G., Lasan, R., Nimkarn, S., Wilson, J. D., McElreavey, K., New, M. I. <strong>Report of fertility in a woman with a predominantly 46,XY karyotype in a family with multiple disorders of sexual development.</strong> J. Clin. Endocr. Metab. 93: 182-189, 2008. Note: Erratum: J. Clin. Endocr. Metab. 93: 1083 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000096</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18000096[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/10.1210/jc.2007-2155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000096">Dumic et al. (2008)</a> evaluated the Y chromosome in a 46,XY girl and her 46,XY mother and normal father, and confirmed that the girl inherited her Y chromosome from her father. Analysis of multiple candidate genes, including SOX9 (<a href="/entry/608160">608160</a>), SF1 (<a href="/entry/184757">184757</a>), DMRT1 (<a href="/entry/602424">602424</a>), DMRT3 (<a href="/entry/614754">614754</a>), TSPYL (<a href="/entry/604714">604714</a>), BPESC1 (<a href="/entry/618995">618995</a>), DHH (<a href="/entry/605423">605423</a>), WNT4 (<a href="/entry/603490">603490</a>), SRY (<a href="/entry/480000">480000</a>), and DAX1 (<a href="/entry/300473">300473</a>), revealed normal male coding sequences in both the mother and daughter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18000096" 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="Berta, P., Hawkins, J. R., Sinclair, A. H., Taylor, A., Griffiths, B. L., Goodfellow, P. N., Fellous, M. <strong>Genetic evidence equating SRY and the testis-determining factor.</strong> Nature 348: 448-450, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2247149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2247149</a>] [<a href="https://doi.org/10.1038/348448A0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2247149">Berta et al. (1990)</a> and <a href="#22" class="mim-tip-reference" title="Jager, R. J., Anvret, M., Hall, K., Scherer, G. <strong>A human XY female with a frame shift mutation in the candidate testis-determining gene SRY.</strong> Nature 348: 452-454, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2247151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2247151</a>] [<a href="https://doi.org/10.1038/348452a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2247151">Jager et al. (1990)</a> presented compelling evidence that the mutation in one type of XY female gonadal dysgenesis is not on the X but on the Y chromosome. In the human sex-determining region in a 35-kb interval near the pseudoautosomal boundary of the Y chromosome, there is a candidate gene for testis-determining factor, termed SRY ('sex-reversed, Y,' from mouse terminology), which is conserved and specific to the Y chromosome in all mammals tested (<a href="#42" class="mim-tip-reference" title="Sinclair, A. H., Berta, P., Palmer, M. S., Hawkins, J. R., Griffiths, B. L., Smith, M. J., Foster, J. W., Frischauf, A.-M., Lovell-Badge, R., Goodfellow, P. N. <strong>A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif.</strong> Nature 346: 240-244, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1695712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1695712</a>] [<a href="https://doi.org/10.1038/346240a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1695712">Sinclair et al., 1990</a>); see <a href="/entry/480000">480000</a>. <a href="#10" class="mim-tip-reference" title="Cherfas, J. <strong>Sex and the single gene.</strong> Science 252: 782 only, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2028253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2028253</a>] [<a href="https://doi.org/10.1126/science.2028253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2028253">Cherfas (1991)</a> stated that SRY stands for 'sex-determining region Y.' This is a nice presumption and perhaps in its present usage should be so considered, but it does not indicate the true historical derivation (VAM). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2247151+1695712+2247149+2028253" 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="#1" class="mim-tip-reference" title="Allard, S., Cadotte, M., Boivin, Y. <strong>Dysgenesie gonadique pure familiare et gonadoblastome.</strong> Un. Med. Canada 101: 448-452, 1972.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5013462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5013462</a>]" pmid="5013462">Allard et al. (1972)</a> observed transmission of XY sex reversal through a normal male, arguing for autosomal inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5013462" 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="#35" class="mim-tip-reference" title="Nazareth, H. R. S., Moreira-Filho, C. A., Cunha, A. J. B., Vieira-Filho, J. P. B., Lengyel, A. M. J., Lima, M. C. <strong>H-Y antigens in 46,XY pure testicular dysgenesis.</strong> Am. J. Med. Genet. 3: 149-154, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/474628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">474628</a>] [<a href="https://doi.org/10.1002/ajmg.1320030206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="474628">Nazareth et al. (1979)</a> found H-Y positivity in a sporadic case occurring in an offspring of first-cousin parents. They favored recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=474628" 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="#41" class="mim-tip-reference" title="Simpson, J. L., Blagowidow, N., Martin, A. O. <strong>XY gonadal dysgenesis: genetic heterogeneity based upon clinical observations, H-Y antigen status, and segregation analysis.</strong> Hum. Genet. 58: 91-97, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7286997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7286997</a>] [<a href="https://doi.org/10.1007/BF00284155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7286997">Simpson et al. (1981)</a> reported 3 pedigrees of XY gonadal dysgenesis consistent with X-linked inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7286997" 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="#33" class="mim-tip-reference" title="Moreira-Filho, C. A., Toledo, S. P. A., Bagnolli, V. R., Frota-Pessoa, O., Bisi, H., Wajntal, A. <strong>H-Y antigen in Swyer syndrome and the genetics of XY gonadal dysgenesis.</strong> Hum. Genet. 53: 51-56, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/535902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">535902</a>] [<a href="https://doi.org/10.1007/BF00289451" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="535902">Moreira-Filho et al. (1979)</a> suggested that there are 3 forms of Swyer syndrome (defined as streak gonads without other somatic features of the Turner syndrome and with a normal 46,XY karyotype). (1) Sporadic testicular agenesis syndrome (STAS) corresponds to H-Y negative Swyer syndrome. (2) Familial testicular agenesis syndrome (FTAS) is H-Y negative Swyer syndrome showing an X-linked recessive pedigree pattern. The mutation is probably homologous to that of the wood lemming. The phenotype of STAS and FTAS is identical even though the mutation is probably on the Y in STAS and on the X in FTAS. (3) In familial testicular dysgenesis syndrome (FTDS), the patients are H-Y positive and have a female phenotype and streak gonads; the streak gonads may contain testis-like tumoral structures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=535902" 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="#48" class="mim-tip-reference" title="Wachtel, S. S. <strong>The genetics of intersexuality: clinical and theoretic perspectives.</strong> Obstet. Gynec. 54: 671-685, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/390460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">390460</a>]" pmid="390460">Wachtel (1979)</a> and <a href="#47" class="mim-tip-reference" title="Wachtel, S. S., Koo, G. C., de la Chapelle, A., Kallio, H., Heyman, J. M., Miller, O. J. <strong>H-Y antigen in 46,XY gonadal dysgenesis.</strong> Hum. Genet. 54: 25-30, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7390478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7390478</a>] [<a href="https://doi.org/10.1007/BF00279045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7390478">Wachtel et al. (1980)</a> suggested the existence of 4 'causes' of XY gonadal dysgenesis: (1) mutational suppression of H-Y structural genes by regulatory elements of the X chromosome or failure of an X-linked structural gene (in association with H-Y negative somatic cell phenotype); (2) failure of H-Y antigen to engage its gonadal receptor (in association with the H-Y positive somatic cell phenotype); (3) loss of the critical moiety of H-Y genes in deleted or translocated Y chromosome (in association with H-Y negative or intermediate somatic cell phenotype); and (4) presence of XY-XO mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7390478+390460" 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="#38" class="mim-tip-reference" title="Passarge, E., Wolf, U. <strong>Genetic heterogeneity of XY gonadal dysgenesis (Swyer syndrome): H-Y antigen-negative XY gonadal dysgenesis associated with inflammatory bowel disease.</strong> Am. J. Med. Genet. 8: 437-441, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7246614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7246614</a>] [<a href="https://doi.org/10.1002/ajmg.1320080409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7246614">Passarge and Wolf (1981)</a> pointed out that there are 2 groups of patients with XY gonadal dysgenesis (Swyer syndrome) and that each of these may be heterogeneous. One group is the H-Y antigen-positive form, which may represent a 'receptor disease.' The second is the H-Y antigen-negative form, which may be due to mutation in the H-Y generating system, either of the structural gene (presumably autosomal) or of a controlling gene (on the sex chromosomes). It may be only the H-Y antigen-positive cases that are at risk for gonadoblastoma or dysgerminoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7246614" 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="Page, D. C., Mosher, R., Simpson, E. M., Fisher, E. M. C., Mardon, G., Pollack, J., McGillivray, B., de la Chapelle, A., Brown, L. G. <strong>The sex-determining region of the human Y chromosome encodes a finger protein.</strong> Cell 51: 1091-1104, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3690661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3690661</a>] [<a href="https://doi.org/10.1016/0092-8674(87)90595-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3690661">Page et al. (1987)</a> advanced several hypotheses to explain the existence of an X-linked locus. One hypothesis was inconsistent with the prevailing notion of a dominantly acting sex-determining factor unique to the Y chromosome and suggested that the X and Y loci are functionally interchangeable, that both are testis determining, and that the X locus is subject to X-chromosome inactivation. According to this model, sex is determined by the total number of expressed X and Y loci: a single dose is female determining, while a double (or greater) dose is male determining. The addition of an X-derived transgene to the genome of an XX embryo should result in testis differentiation, as long as that transgene is not subject to X inactivation. Increased expression of the X-chromosomal locus could explain the presence of testicular tissue in XX hermaphrodites and the rare Y-negative XX males, who lack the TDF locus of the Y chromosome. Although some XY females lack TDF as judged by Y-DNA analysis, others do not have discernible deletions. These unexplained XY females may have point mutations in TDF or in genes that function in conjunction with or downstream of TDF. The model mentioned above suggests that mutation in the X-chromosomal locus (at Xp22.3-p21) could cause XY embryos to develop as females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3690661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="De Arce, M. A., Costigan, C., Gosden, J. R., Lawler, M., Humphries, P. <strong>Further evidence consistent with Yqh as an indicator of risk of gonadal blastoma in Y-bearing mosaic Turner syndrome.</strong> Clin. Genet. 41: 28-32, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1633643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1633643</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1992.tb03624.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1633643">De Arce et al. (1992)</a> demonstrated lack of gonadoblastoma in a 14-year-old girl who was a mosaic for 45X/46X-isodicentric Y. The anomalous Y chromosome showed no fluorescent distal Yq. In another patient, an 8-year-old girl with 45X/46XY karyotype, bilateral gonadoblastoma developed in her rudimentary ovaries at the age of 8. Her normal Y chromosome showed the characteristic distal fluorescence seen in her father's Y chromosome. Using Y chromosome probes, <a href="#12" class="mim-tip-reference" title="De Arce, M. A., Costigan, C., Gosden, J. R., Lawler, M., Humphries, P. <strong>Further evidence consistent with Yqh as an indicator of risk of gonadal blastoma in Y-bearing mosaic Turner syndrome.</strong> Clin. Genet. 41: 28-32, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1633643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1633643</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1992.tb03624.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1633643">De Arce et al. (1992)</a> demonstrated the Y chromosome in the paraffin blocks of the ovarian tissue of both girls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1633643" 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="#18" class="mim-tip-reference" title="German, J., Simpson, J. L., Chaganti, R. S. K. <strong>Genetically determined sex-reversal in 46,XY humans.</strong> Science 202: 53-56, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/567843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">567843</a>] [<a href="https://doi.org/10.1126/science.567843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="567843">German et al. (1978)</a> suggested that there is a gene on the X chromosome that blocks the testis-determining function of H-Y (which was then a leading candidate for TDF, testis-determining factor). However, it was later shown that TDF and H-Y antigen map to different parts of the Y chromosome with TDF being absent and H-Y antigen being present in XY females with Y short arm deletions (<a href="#40" class="mim-tip-reference" title="Simpson, E., Chandler, P., Goulmy, E., Disteche, C. M., Ferguson-Smith, M. A., Page, D. C. <strong>Separation of the genetic loci for the H-Y antigen and for testis determination on human Y chromosome.</strong> Nature 326: 876-878, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3494951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3494951</a>] [<a href="https://doi.org/10.1038/326876a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3494951">Simpson et al., 1987</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=567843+3494951" 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>Mapping studies by hybridization to DNA from somatic cell hybrids containing various fragments of the X chromosome suggested that a sequence related to Swyer syndrome on the X chromosome maps to region Xp22.3-p21 (<a href="#37" class="mim-tip-reference" title="Page, D. C., Mosher, R., Simpson, E. M., Fisher, E. M. C., Mardon, G., Pollack, J., McGillivray, B., de la Chapelle, A., Brown, L. G. <strong>The sex-determining region of the human Y chromosome encodes a finger protein.</strong> Cell 51: 1091-1104, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3690661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3690661</a>] [<a href="https://doi.org/10.1016/0092-8674(87)90595-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3690661">Page et al., 1987</a>). <a href="#2" class="mim-tip-reference" title="Arn, P., Chen, H., Tuck-Muller, C. M., Mankinen, C., Wachtel, G., Li, S., Shen, C. C., Wachtel, S. S. <strong>SRVX, a sex reversing locus in Xp21.2-p22.11.</strong> Hum. Genet. 93: 389-393, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8168809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8168809</a>] [<a href="https://doi.org/10.1007/BF00201663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8168809">Arn et al. (1994)</a> mapped the SRVX gene to a 5- to 10-Mb segment between Xp22.11 and Xp21.2, which includes the DMD locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3690661+8168809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Bernstein, R., Koo, G. C., Wachtel, S. S. <strong>Abnormalities of the X-chromosome in 46,XY female sibs with ovaries.</strong> Science 207: 768-769, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7352285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7352285</a>] [<a href="https://doi.org/10.1126/science.7352285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7352285">Bernstein et al. (1980)</a> observed an abnormal band on Xp in a 46,XY female and her 46,XY female fetal sib. Despite the presence of an intact Y chromosome, neither had testicular differentiation and both were H-Y negative. Giemsa banding suggested duplication of p21 and p22. The maternal grandmother, mother and a younger sister, all phenotypically normal, had a karyotype 46,XXp+. The proband had profound psychomotor retardation, and both sibs had multiple congenital malformations. (The second sib was ascertained by amniocentesis for prenatal diagnosis followed by elective abortion.) Multiple congenital anomalies in the proband included ventricular septal defect, cleft palate, asymmetric skull and facies, prognathic jaw, low-set ears, and clinodactyly V. When the girl died at 5 year of age, postmortem studies showed hypoplastic uterus and fallopian tubes. Histologic examination of the uterine adnexa revealed an area of ovarian stroma with scattered degenerative follicles. There was no testicular morphology, and the external genitalia were those of a normal 5-year-old female. The second affected sib, the product of a pregnancy terminated at 20 weeks, showed ovaries containing numerous follicles and germ cells. As in the proband, there was no evidence of testicular morphology. <a href="#49" class="mim-tip-reference" title="Wachtel, S. S. <strong>X-linked sex-reversing genes.</strong> Cytogenet. Cell Genet. 80: 222-225, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9678362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9678362</a>] [<a href="https://doi.org/10.1159/000014984" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9678362">Wachtel (1998)</a> referred to other cases of XY sex reversal in subjects with Xp duplication and chromosomal abnormalities resembling those in the family reported by <a href="#6" class="mim-tip-reference" title="Bernstein, R., Koo, G. C., Wachtel, S. S. <strong>Abnormalities of the X-chromosome in 46,XY female sibs with ovaries.</strong> Science 207: 768-769, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7352285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7352285</a>] [<a href="https://doi.org/10.1126/science.7352285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7352285">Bernstein et al. (1980)</a>. This suggested occurrence of a gene on Xp, duplication of which can block development of the testis in an XY fetus. The gonads begin to develop as ovaries, but in the absence of the second X chromosome, the germ cells die, the follicles become atretic, and the ovaries degenerate. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9678362+7352285" 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="#Boczkowski1976" class="mim-tip-reference" title="Boczkowski, K. <strong>Familial occurrence of gonadal tumors in XY females with breast development.</strong> Hum. Genet. 33: 289-294, 1976.">Boczkowski (1976)</a>; <a href="#Ghosh1978" class="mim-tip-reference" title="Ghosh, S. N., Shah, P. M., Gharpure, H. M. <strong>Absence of H-Y antigen in XY females with dysgenetic gonads.</strong> Nature 276: 180-181, 1978.">Ghosh et al. (1978)</a>; <a href="#Herbst1978" class="mim-tip-reference" title="Herbst, E. W., Fredga, K., Frank, F., Winking, H., Gropp, A. <strong>Cytological identification of two X-chromosome types in the wood lemming (Myopus schisticolor).</strong> Chromosoma 69: 185-191, 1978.">Herbst et al. (1978)</a>; <a href="#Judd1970" class="mim-tip-reference" title="Judd, H. L., Scully, R. E., Atkins, L., Neer, R. M., Kliman, B. <strong>Pure gonadal dysgenesis with progressive hirsutism: demonstration of testosterone production by gonadal streaks.</strong> New Eng. J. Med. 282: 881-885, 1970.">Judd et
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al. (1970)</a>; <a href="#Koopman1991" class="mim-tip-reference" title="Koopman, P., Gubbay, J., Vivian, N., Goodfellow, P., Lovell-Badge, R. <strong>Male development of chromosomally female mice transgenic for Sry.</strong> Nature 351: 117-121, 1991.">Koopman et al. (1991)</a>; <a href="#Koopman1990" class="mim-tip-reference" title="Koopman, P., Munsterberg, A., Capel, B., Vivian, N., Lovell-Badge, R. <strong>Expression of a candidate sex-determining gene during mouse testis differentiation.</strong> Nature 348: 450-452, 1990.">Koopman et al. (1990)</a>; <a href="#Wolf1980" class="mim-tip-reference" title="Wolf, U., Fraccaro, M., Mayerova, A., Hecht, T., Maraschio, P., Hameister, H. <strong>A gene controlling H-Y antigen on the X chromosome: tentative assignment by deletion mapping to Xp223.</strong> Hum. Genet. 54: 149-154, 1980.">Wolf et al.
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(1980)</a>; <a href="#Wolf1979" class="mim-tip-reference" title="Wolf, U. <strong>XY gonadal dysgenesis and the H-Y antigen.</strong> Hum. Genet. 47: 269-277, 1979.">Wolf (1979)</a>
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[<a href="https://doi.org/10.1016/0002-9378(67)90342-0" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1956279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1956279</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1956279" 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/10.1210/jcem.75.1.1619028" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320030206" target="_blank">Full Text</a>]
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Wolf, U., Fraccaro, M., Mayerova, A., Hecht, T., Maraschio, P., Hameister, H.
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<strong>A gene controlling H-Y antigen on the X chromosome: tentative assignment by deletion mapping to Xp223.</strong>
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Hum. Genet. 54: 149-154, 1980.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7390489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7390489</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7390489" 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/10.1007/BF00278963" target="_blank">Full Text</a>]
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Wolf, U.
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<strong>XY gonadal dysgenesis and the H-Y antigen.</strong>
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Hum. Genet. 47: 269-277, 1979.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/110669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">110669</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=110669" 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/10.1007/BF00321019" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 05/20/2016
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Marla J. F. O'Neill - updated : 3/17/2016<br>Marla J. F. O'Neill - updated : 10/27/2014<br>Marla J. F. O'Neill - updated : 12/6/2013<br>Marla J. F. O'Neill - updated : 8/6/2012<br>Marla J. F. O'Neill - updated : 9/27/2011<br>Marla J. F. O'Neill - updated : 2/16/2011<br>Marla J. F. O'Neill - updated : 10/7/2009
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Carol A. Bocchini : 8/18/2009
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alopez : 08/11/2023
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alopez : 12/07/2022<br>mgross : 08/24/2020<br>carol : 08/20/2019<br>alopez : 11/16/2018<br>alopez : 07/19/2016<br>alopez : 07/19/2016<br>alopez : 05/20/2016<br>alopez : 3/17/2016<br>alopez : 6/22/2015<br>alopez : 6/22/2015<br>alopez : 6/22/2015<br>mcolton : 6/17/2015<br>alopez : 10/29/2014<br>alopez : 10/28/2014<br>mcolton : 10/27/2014<br>carol : 12/6/2013<br>carol : 8/8/2012<br>terry : 8/6/2012<br>alopez : 10/6/2011<br>terry : 9/27/2011<br>alopez : 2/28/2011<br>alopez : 2/28/2011<br>alopez : 2/28/2011<br>wwang : 2/22/2011<br>terry : 2/16/2011<br>wwang : 10/22/2009<br>terry : 10/7/2009<br>carol : 8/20/2009<br>carol : 8/18/2009
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<span class="mim-font">
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<strong>#</strong> 400044
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46,XY SEX REVERSAL 1; SRXY1
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<em>Alternative titles; symbols</em>
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46,XY SEX REVERSAL, SRY-RELATED<br />
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46,XY GONADAL DYSGENESIS, COMPLETE, SRY-RELATED
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Other entities represented in this entry:
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<span class="h3 mim-font">
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46,XY TRUE HERMAPHRODITISM, SRY-RELATED, INCLUDED
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TESTIS-DETERMINING FACTOR, X-CHROMOSOMAL, FORMERLY, INCLUDED; TDFX, FORMERLY, INCLUDED<br />
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SEX-REVERSING LOCUS ON X, FORMERLY, INCLUDED; SRVX, FORMERLY, INCLUDED
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<strong>ORPHA:</strong> 242;
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<strong>DO:</strong> 0111778;
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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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<span class="mim-font">
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Yp11.2
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<span class="mim-font">
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46XY sex reversal 1
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<span class="mim-font">
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400044
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<span class="mim-font">
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Y-linked
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<span class="mim-font">
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3
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SRY
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<span class="mim-font">
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480000
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because this form of 46,XY sex reversal is caused by point mutations or deletions in the SRY gene (480000) on chromosome Yp11.3.</p>
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<strong>Description</strong>
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<p>Individuals with 46,XY complete gonadal dysgenesis are phenotypically female; however, they do not develop secondary sexual characteristics at puberty and do not menstruate. They have bilateral 'streak gonads,' which typically consist of fibrous tissue and variable amounts of wavy ovarian stroma. A uterus and fallopian tube are present and external genitalia are female (reviewed by Berkovitz et al., 1991). </p><p><strong><em>Genetic Heterogeneity of 46,XY Sex Reversal</em></strong></p><p>
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Male sexual determination is initiated by Y-chromosomal SRY, which activates a cascade of genes that lead the embryonic gonad to develop into a testis. Fetal testicular Sertoli cells then produce mullerian inhibitory substance (600957), which is responsible for the involution of the mullerian ducts, which would otherwise develop into the uterus, fallopian tubes, and cervix. Fetal testicular Leydig cells produce testosterone from cholesterol by the sequential action of a series of enzymes. Subsequent differentiation of male external genitalia also requires the action of dihydrotestosterone, produced from testicular testosterone. Perturbations in the enzymes in this classic pathway or in an alternative pathway of testicular androgen biosynthesis can result in genetic males with disordered sexual development and incompletely developed ('ambiguous') external genitalia (summary by Fluck et al., 2011). </p><p>Disorders of male development for which a genetic cause has been found include 46,XY sex reversal-2 (SRXY2; 300018), which is caused by duplication of the NR0B1 gene (300473) on chromosome Xp21.3-p21.2; SRXY3 (612965), caused by mutation in the NR5A1 gene (184757) on chromosome 9q33; SRXY4 (154230), caused by deletion on chromosome 9p24.3; SRXY5 (613080), caused by mutation in the CBX2 gene (602770) on chromosome 17q25; SRXY6 (613762), caused by mutation in the MAP3K1 gene (600982) on chromosome 5q11.2; SRXY7 (233420), caused by mutation in the DHH gene (605423) on chromosome 12q13; SRXY8 (614279), caused by mutation in the AKR1C2 gene (600450) on chromosome 10p15, with a possible contribution from the closely linked AKR1C4 gene (600451); SRXY9 (616067), caused by mutation in the ZFPM2 gene (603693) on chromosome 8q23; and SRXY10 (616425), caused by deletion of the XYSR regulatory region -640 kb upstream of the SOX9 gene (608160) on chromosome 17q24.</p><p>Wilhelm and Koopman (2006) reviewed male sexual development and the genetics of disorders of human sexual development, noting that most cases of XY sex reversal, SRY-negative XX sex reversal, and true hermaphroditism remained unexplained at the molecular level. </p>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</strong>
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<p>The designation 'Swyer syndrome' refers to 46,XY complete gonadal dysgenesis. The disorder is caused not only by mutations in the SRY gene but by genes on the autosome and the X chromosome.</p><p>As a result of discussions at the International Consensus Conference on Intersex, Lee et al. (2006) proposed the term 'disorder(s) of sex development' (DSD) to replace the previously used terms 'pseudohermaphroditism,' 'intersex,' and 'sex reversal.' </p><p>As defined by Lee et al. (2006), disorders of sex development (DSD) are 'congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical.' 46,XY DSD is a disorder of gonadal (testicular) development, which may be complete or partial (Lee et al., 2006). The complete form includes streak gonads, normal mullerian structures, and normal female external genitalia. The partial form includes ambiguous external genitalia and partial development of mullerian and wolffian structures (Berkovitz et al., 1991). </p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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<p>Swyer (1955) described 2 46,XY women with primary amenorrhea, tall stature, female external genitalia (one with enlarged clitoris), and normal, but hypoestrogenized, vagina and cervix. </p><p>Affected sisters were reported by Cohen and Shaw (1965), and affected twins by Frasier et al. (1964). The sisters reported by Cohen and Shaw (1965) had a marker autosome, which was present also in the mother. They referred to another instance of XY 'sisters' with an abnormal autosome. One of their 2 patients had gonadoblastoma. </p><p>Taylor et al. (1966) stated there is a high incidence of neoplasia (gonadoblastomas and germinomas) in streak gonads of patients with Swyer syndrome. </p><p>Two sisters reported by Fine et al. (1962) were of normal stature but were chromatin negative. One of these cases and 1 of those reported by Baron et al. (1962) had gonadoblastoma. In the last family, 2 'females' and a male were affected, the male showing no testes. All 3 sibs were sex-chromatin negative.</p><p>Barr et al. (1967) reported on a sibship containing 2 genetic males. The first, who had male pseudohermaphroditism, was reared as a female; he developed signs of masculinization at puberty and had undescended but otherwise normal testes and small fallopian tubes. The second genetic male (180 cm tall) had pure gonadal dysgenesis with small uterus and streak gonads. This patient was at first thought to have the testicular feminization syndrome (300068). An unaffected sister had a son with perineal hypospadias (urethral orifice at the base of the penis). The sibship reported by Chemke et al. (1970) was similar to that of Barr et al. (1967). </p><p>Rushton (1979) pointed out that the streak gonads of this disorder differ from those of the 45,X Turner syndrome in the presence of calcification and the increased hazard of gonadoblastoma. Comparative studies of the frequency of gonadoblastoma in Turner mosaics with normal or rearranged Y chromosomes have suggested that the integrity of the Y chromosome, and in particular the presence of the distal fluorescent band Yqh, is required in these mosaics for the tumor to develop; no cases with distal deletions of the fluorescent band on Yq had been reported (Lukusa et al., 1986). </p><p>Dumic et al. (2008) reported a fertile woman with normal ovaries and a predominantly 46,XY ovarian karyotype who gave birth to a 46,XY female with complete gonadal dysgenesis. The karyotype of the phenotypically normal mother was 100% 46,XY in blood, 80% 46,XY and 20% 45,X in cultured skin fibroblasts, and 93% 46,XY, 6% 45,X, and less than 1% 46,XX in the ovary. The 52-year-old mother had normal pubertal development with spontaneous menarche at 11 years of age. She had 2 unassisted pregnancies, the first of which ended in miscarriage. She had regular menses until menopause at age 49 years. Physical examination revealed a feminine-appearing woman with a normal body habitus; there was no receding hairline or balding of the scalp and no acne or facial hair. Breasts and pubic hair were Tanner stage V, and external genitalia were normal with no clitoromegaly or labial fusion. The vaginal introitus was normal, and pelvic examination revealed a uterus in retroverted position with no adnexal masses; hormonal findings were compatible with a normal menopausal woman. The daughter born of her second pregnancy presented at 17 years of age due to lack of breast development and primary amenorrhea. Examination showed mild facial acne but no facial hair, with Tanner stage I breasts and stage IV pubic hair. External female genitalia were normal, without clitoromegaly or labial fusion, and the vaginal introitus was normal. Pelvic examination revealed a hypoplastic uterus with no palpable gonads; ultrasound showed a small left gonad, but no gonad was seen on the right. On karyotyping, the daughter was 100% 46,XY in blood, 100% 46,XY in skin, and 99.25% 46,XY and 0.75% 45,X in gonadal tissue. The family pedigree on the mother's side was notable for the presence of 7 individuals over 4 generations, both phenotypic males and females, who had sexual ambiguity, infertility, or failure to menstruate, including 1 individual with documented 45,X/46,XY mixed gonadal dysgenesis. The mode of inheritance in the family was strongly suggestive of X-linkage. Dumic et al. (2008) stated that this was the first report of fertility in a woman with a predominantly 46,XY karyotype in the ovary, and suggested that perhaps all mothers of 46,XY(SRY+) females with complete gonadal dysgenesis should be carefully examined for an XY karyotype as well. </p><p><strong><em>46,XY True Hermaphroditism</em></strong></p><p>
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A 'true hermaphrodite' must have both mature ovarian and mature testicular tissue with histologic evidence of follicles and tubules, respectively (van Niekerk and Retief, 1981). It is a genetically heterogeneous condition. </p><p>Van Niekerk and Retief (1981) found that the ovotestis was the most common gonad of the true hermaphrodite, found in 44.3% of 406 cases. The genotype of most affected individuals was 46,XX (see 400045), but many had 46,XY or a mosaic of 46,XX/46,XY. </p><p>Milner et al. (1958) reported 2 brothers who had hypospadias and both testicular and ovarian tissue bilaterally. Lowry et al. (1975) determined that the brothers reported by Milner et al. (1958) lacked Barr bodies (were 'chromatin negative'), indicating an XY genotype. </p><p>Lowry et al. (1975) described affected first cousins whose fathers were brothers. Both had a normal male (XY) karyotype.</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>Cytogenetics</strong>
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<p>Small deletions in the short arm of the Y chromosome can result in 46,XY females (Disteche et al., 1986). The 2 patients reported by Disteche et al. (1986) had some signs of Turner syndrome, including congenital lymphedema and primary amenorrhea with streak gonads, but were of normal height. One of the patients had bilateral gonadoblastoma. Several Y-chromosome-specific DNA probes were found to be deleted in the 2 patients. DNA analysis showed that the 2 deletions were different, but included a common overlapping region likely to contain the testis-determining factor (TDF) gene. </p><p>Cytogenetic duplication of the X chromosome in males is a rare event usually characterized by a significant degree of phenotypic abnormality, which can include sex reversal despite an apparently normal Y chromosome. Arn et al. (1994) reported 2 half brothers with maternally inherited cytogenetic duplications of Xp and sex reversal; the absence of dysmorphic features in mother and children was thought to be because of the relatively small extent of the duplication. Comparison with previous reports allowed a putative sex-reversing locus (SRVX) to be assigned to a 5- to 10-Mb segment between Xp22.11 and Xp21.2. </p><p>Lange et al. (2009) identified 60 unrelated individuals with isodicentric (idic) or isocentromeric (iso) Y chromosomes, 51 of which apparently arose via a palindromic mechanism, yielding an idicYp in 49 cases and an idicYq in 2 cases, whereas the remaining 9 arose via recombination in heterochromatic sequences, yielding an idicYp in 2 cases and an isoYp in 7 cases. As expected, the 2 individuals carrying the idicYq chromosomes lacked the SRY gene and were phenotypic females; however, 18 of the 58 idicYp and isoYp individuals, who had 2 copies of SRY, were also 'sex-reversed' and raised as females or found in childhood to have 1 degenerate ovary and 1 testis. Lange et al. (2009) observed that the average intercentromeric distance in the feminized individuals was twice that in the males (p less than 10(-6)), supporting the hypothesis that mitotic instability and resultant XO mosaicism may cause sex reversal. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p><strong><em>46,XY Gonadal Dysgenesis, Complete</em></strong></p><p>
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Page et al. (1987) cloned a 230-kb segment of the human Y chromosome thought to contain some or all of the TDF (SRY) gene. The cloned region spanned the deletion in a female who carried all but 160 kb of the Y. Homologous sequences were found within the sex-determining region of the mouse Y chromosome. </p><p>Jager et al. (1990) demonstrated a mutation in SRY in 1 out of 12 sex-reversed XY females with gonadal dysgenesis who had no large deletions of the short arm of the Y chromosome. They found a 4-nucleotide deletion in the part of the SRY gene that encodes a conserved DNA-binding motif. A frameshift presumably led to a nonfunctional protein. Mutation occurred de novo, because the father had a normal SRY sequence. This is strong evidence that SRY is TDF. The de novo G-to-A mutation led to a change from methionine to isoleucine at a residue that lies within the putative DNA-binding motif of SRY and is identical in all SRY and SRY-related genes. </p><p>Vilain et al. (1992) described a family in which all 5 XY individuals in 2 generations had a single basepair substitution resulting in an amino acid change in the conserved domain of the SRY open reading frame (480000.0004). A G-to-C change at nucleotide 588 resulted in substitution of leucine for valine. Three of the individuals were XY sex-reversed females and 2 were XY males. One of the males had 8 children; all were phenotypic females, 2 of whom were sex-reversed XY females carrying the mutation mentioned. Several models were proposed to explain association between a sequence variant in SRY and 2 alternative sex phenotypes. These included the existence of alleles at an unlinked locus. </p><p>McElreavey et al. (1992) described an XY sex-reversed female with pure gonadal dysgenesis who harbored a de novo nonsense mutation in SRY, which resulted directly in the formation of a stop codon in the putative DNA-binding motif. A C-to-T transition at nucleotide 687 changed a glutamine codon (CAG) to a termination codon (TAG); see 480000.0005. The patient, referred to as the 'propositus,' was a phenotypic female who presented at age 20 years for primary amenorrhea. Treatment with estrogen induced menstruation and slight enlargement of the breasts which were underdeveloped. Laparotomy showed 2 streak gonads without germ cells or remnants of tubes. </p><p>Harley et al. (1992) found point mutations in the region of the SRY gene encoding the high mobility group (HMG) box in 5 XY females. (The HMG box is related to that present in the T-cell-specific, DNA binding protein TCF1 (142410).) In 4 cases, the binding activity of mutant SRY protein for the AACAAAG core sequence was negligible; in the fifth case, DNA binding was reduced. In the SRY gene in a 46,XY female, Muller et al. (1992) demonstrated an A-to-T transversion of nucleotide 684 in the open reading frame, resulting in a change of lysine (AAG) to a stop codon (UAG). The patient had gonadoblastoma. </p><p><strong><em>46,XY True Hermaphroditism</em></strong></p><p>
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Maier et al. (2003) reported a 46,XY true hermaphrodite who had a mutation in the SRY gene (480000.0006). The father, his 3 brothers, and his first-born son carried the identical mutation without phenotypic effects. Maier et al. (2003) concluded that the mutated protein retained enough activity to allow normal development in some individuals. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Norling et al. (2013) performed array CGH in 9 unrelated patients with 46,XY gonadal dysgenesis in whom sequence analysis of known gonadal dysgenesis-associated genes was negative, and identified 3 candidate regions: in a pair of affected sibs, a 217-kb interstitial duplication of exons 5 to 12 of the SUPT3H gene (602947) on chromosome 6p21, and a 22-kb deletion involving 8 of the 9 exons of the C2ORF80 gene (615536) on 2q34, both inherited from their unaffected mother; and in another patient, a 454-kb duplication at chromosome 9q21.11 involving the candidate genes PIP5K1B (602745), PRKACG (176893), and FAM189A2 (607710). Norling et al. (2013) noted that all 5 candidate genes are expressed in testicular tissues, but that detailed functional information was lacking. </p><p>In a 46,XY infant with ambiguous genitalia, who was negative for mutation in the SRY and NR5A1 genes and in whom microarray analysis did not reveal deletions or duplications in any known DSD-associated genes, White et al. (2012) identified heterozygosity for a maternally inherited 767-kb deletion on chromosome 16 (chr16:76,956,767-77,723,905, NCBI36), located within the WWOX gene (605131). The deletion removed exons 6 through 8 and was predicted to generate an alternative in-frame mRNA product with exon 5 spliced directly onto exon 9; this alternative transcript was verified by sequencing cDNA derived from matched lymphocytes. Examination at 10 days of age showed unfused labioscrotal folds, impalpable gonads, 20-mm clitoral hypertrophy, and a perineal urogenital sinus. Genitography demonstrated the presence of a vagina and underdeveloped uterus. Small dysgenic gonads were removed from the abdomen at age 2 years; histologic analysis showed bilateral undifferentiated gonadal tissue and immature testis, both containing malignant germ cells. The heterozygous mother had relatively late menarche at age 16 years with irregular menstruation up to her first pregnancy. The proband had 2 brothers and 2 sisters, all unaffected, none of whom inherited the deletion. </p><p>For discussion of a possible association between disorders of sex development and variation in the ESR2 gene, see 601663.</p><p>For discussion of a possible association between 46,XY sex reversal and variation in the STARD8 gene, see 300689.0001.</p><p><strong><em>Exclusion Studies</em></strong></p><p>
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Dumic et al. (2008) evaluated the Y chromosome in a 46,XY girl and her 46,XY mother and normal father, and confirmed that the girl inherited her Y chromosome from her father. Analysis of multiple candidate genes, including SOX9 (608160), SF1 (184757), DMRT1 (602424), DMRT3 (614754), TSPYL (604714), BPESC1 (618995), DHH (605423), WNT4 (603490), SRY (480000), and DAX1 (300473), revealed normal male coding sequences in both the mother and daughter. </p>
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<strong>Pathogenesis</strong>
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<span class="mim-text-font">
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<p>Berta et al. (1990) and Jager et al. (1990) presented compelling evidence that the mutation in one type of XY female gonadal dysgenesis is not on the X but on the Y chromosome. In the human sex-determining region in a 35-kb interval near the pseudoautosomal boundary of the Y chromosome, there is a candidate gene for testis-determining factor, termed SRY ('sex-reversed, Y,' from mouse terminology), which is conserved and specific to the Y chromosome in all mammals tested (Sinclair et al., 1990); see 480000. Cherfas (1991) stated that SRY stands for 'sex-determining region Y.' This is a nice presumption and perhaps in its present usage should be so considered, but it does not indicate the true historical derivation (VAM). </p>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Allard et al. (1972) observed transmission of XY sex reversal through a normal male, arguing for autosomal inheritance. </p><p>Nazareth et al. (1979) found H-Y positivity in a sporadic case occurring in an offspring of first-cousin parents. They favored recessive inheritance. </p><p>Simpson et al. (1981) reported 3 pedigrees of XY gonadal dysgenesis consistent with X-linked inheritance. </p><p>Moreira-Filho et al. (1979) suggested that there are 3 forms of Swyer syndrome (defined as streak gonads without other somatic features of the Turner syndrome and with a normal 46,XY karyotype). (1) Sporadic testicular agenesis syndrome (STAS) corresponds to H-Y negative Swyer syndrome. (2) Familial testicular agenesis syndrome (FTAS) is H-Y negative Swyer syndrome showing an X-linked recessive pedigree pattern. The mutation is probably homologous to that of the wood lemming. The phenotype of STAS and FTAS is identical even though the mutation is probably on the Y in STAS and on the X in FTAS. (3) In familial testicular dysgenesis syndrome (FTDS), the patients are H-Y positive and have a female phenotype and streak gonads; the streak gonads may contain testis-like tumoral structures. </p><p>Wachtel (1979) and Wachtel et al. (1980) suggested the existence of 4 'causes' of XY gonadal dysgenesis: (1) mutational suppression of H-Y structural genes by regulatory elements of the X chromosome or failure of an X-linked structural gene (in association with H-Y negative somatic cell phenotype); (2) failure of H-Y antigen to engage its gonadal receptor (in association with the H-Y positive somatic cell phenotype); (3) loss of the critical moiety of H-Y genes in deleted or translocated Y chromosome (in association with H-Y negative or intermediate somatic cell phenotype); and (4) presence of XY-XO mosaicism. </p><p>Passarge and Wolf (1981) pointed out that there are 2 groups of patients with XY gonadal dysgenesis (Swyer syndrome) and that each of these may be heterogeneous. One group is the H-Y antigen-positive form, which may represent a 'receptor disease.' The second is the H-Y antigen-negative form, which may be due to mutation in the H-Y generating system, either of the structural gene (presumably autosomal) or of a controlling gene (on the sex chromosomes). It may be only the H-Y antigen-positive cases that are at risk for gonadoblastoma or dysgerminoma. </p><p>Page et al. (1987) advanced several hypotheses to explain the existence of an X-linked locus. One hypothesis was inconsistent with the prevailing notion of a dominantly acting sex-determining factor unique to the Y chromosome and suggested that the X and Y loci are functionally interchangeable, that both are testis determining, and that the X locus is subject to X-chromosome inactivation. According to this model, sex is determined by the total number of expressed X and Y loci: a single dose is female determining, while a double (or greater) dose is male determining. The addition of an X-derived transgene to the genome of an XX embryo should result in testis differentiation, as long as that transgene is not subject to X inactivation. Increased expression of the X-chromosomal locus could explain the presence of testicular tissue in XX hermaphrodites and the rare Y-negative XX males, who lack the TDF locus of the Y chromosome. Although some XY females lack TDF as judged by Y-DNA analysis, others do not have discernible deletions. These unexplained XY females may have point mutations in TDF or in genes that function in conjunction with or downstream of TDF. The model mentioned above suggests that mutation in the X-chromosomal locus (at Xp22.3-p21) could cause XY embryos to develop as females. </p><p>De Arce et al. (1992) demonstrated lack of gonadoblastoma in a 14-year-old girl who was a mosaic for 45X/46X-isodicentric Y. The anomalous Y chromosome showed no fluorescent distal Yq. In another patient, an 8-year-old girl with 45X/46XY karyotype, bilateral gonadoblastoma developed in her rudimentary ovaries at the age of 8. Her normal Y chromosome showed the characteristic distal fluorescence seen in her father's Y chromosome. Using Y chromosome probes, De Arce et al. (1992) demonstrated the Y chromosome in the paraffin blocks of the ovarian tissue of both girls. </p><p>German et al. (1978) suggested that there is a gene on the X chromosome that blocks the testis-determining function of H-Y (which was then a leading candidate for TDF, testis-determining factor). However, it was later shown that TDF and H-Y antigen map to different parts of the Y chromosome with TDF being absent and H-Y antigen being present in XY females with Y short arm deletions (Simpson et al., 1987). </p><p>Mapping studies by hybridization to DNA from somatic cell hybrids containing various fragments of the X chromosome suggested that a sequence related to Swyer syndrome on the X chromosome maps to region Xp22.3-p21 (Page et al., 1987). Arn et al. (1994) mapped the SRVX gene to a 5- to 10-Mb segment between Xp22.11 and Xp21.2, which includes the DMD locus. </p><p>Bernstein et al. (1980) observed an abnormal band on Xp in a 46,XY female and her 46,XY female fetal sib. Despite the presence of an intact Y chromosome, neither had testicular differentiation and both were H-Y negative. Giemsa banding suggested duplication of p21 and p22. The maternal grandmother, mother and a younger sister, all phenotypically normal, had a karyotype 46,XXp+. The proband had profound psychomotor retardation, and both sibs had multiple congenital malformations. (The second sib was ascertained by amniocentesis for prenatal diagnosis followed by elective abortion.) Multiple congenital anomalies in the proband included ventricular septal defect, cleft palate, asymmetric skull and facies, prognathic jaw, low-set ears, and clinodactyly V. When the girl died at 5 year of age, postmortem studies showed hypoplastic uterus and fallopian tubes. Histologic examination of the uterine adnexa revealed an area of ovarian stroma with scattered degenerative follicles. There was no testicular morphology, and the external genitalia were those of a normal 5-year-old female. The second affected sib, the product of a pregnancy terminated at 20 weeks, showed ovaries containing numerous follicles and germ cells. As in the proband, there was no evidence of testicular morphology. Wachtel (1998) referred to other cases of XY sex reversal in subjects with Xp duplication and chromosomal abnormalities resembling those in the family reported by Bernstein et al. (1980). This suggested occurrence of a gene on Xp, duplication of which can block development of the testis in an XY fetus. The gonads begin to develop as ovaries, but in the absence of the second X chromosome, the germ cells die, the follicles become atretic, and the ovaries degenerate. </p>
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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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Boczkowski (1976); Ghosh et al. (1978); Herbst et al. (1978); Judd et
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al. (1970); Koopman et al. (1991); Koopman et al. (1990); Wolf et al.
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(1980); Wolf (1979)
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</span>
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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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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Allard, S., Cadotte, M., Boivin, Y.
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<strong>Dysgenesie gonadique pure familiare et gonadoblastome.</strong>
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Un. Med. Canada 101: 448-452, 1972.
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Arn, P., Chen, H., Tuck-Muller, C. M., Mankinen, C., Wachtel, G., Li, S., Shen, C. C., Wachtel, S. S.
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<strong>SRVX, a sex reversing locus in Xp21.2-p22.11.</strong>
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Gynaecologia 153: 298-308, 1962.
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Barr, M. L., Carr, D. H., Plunkett, E. R., Soltan, H. C., Wiens, R. G.
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Berkovitz, G. D., Fechner, P. Y., Zacur, H. W., Rock, J. A., Snyder, H. M., III, Migeon, C. J., Perlman, E. J.
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<strong>Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation.</strong>
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Medicine 70: 375-383, 1991.
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Bernstein, R., Koo, G. C., Wachtel, S. S.
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<strong>Abnormalities of the X-chromosome in 46,XY female sibs with ovaries.</strong>
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Science 207: 768-769, 1980.
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Berta, P., Hawkins, J. R., Sinclair, A. H., Taylor, A., Griffiths, B. L., Goodfellow, P. N., Fellous, M.
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<strong>Genetic evidence equating SRY and the testis-determining factor.</strong>
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Nature 348: 448-450, 1990.
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<p class="mim-text-font">
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Boczkowski, K.
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<strong>Familial occurrence of gonadal tumors in XY females with breast development.</strong>
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Hum. Genet. 33: 289-294, 1976.
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[PubMed: 987012]
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Chemke, J., Carmichael, R., Stewart, J. M., Geer, R. H., Robinson, A.
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<strong>Familial XY gonadal dysgenesis.</strong>
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J. Med. Genet. 7: 105-111, 1970.
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Cherfas, J.
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<strong>Sex and the single gene.</strong>
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Science 252: 782 only, 1991.
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[PubMed: 2028253]
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</li>
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Cohen, M. M., Shaw, M. W.
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<strong>Two XY siblings with gonadal dysgenesis and a female phenotype.</strong>
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New Eng. J. Med. 272: 1083-1088, 1965.
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De Arce, M. A., Costigan, C., Gosden, J. R., Lawler, M., Humphries, P.
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<strong>Further evidence consistent with Yqh as an indicator of risk of gonadal blastoma in Y-bearing mosaic Turner syndrome.</strong>
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Disteche, C. M., Casanova, M., Saal, H., Friedman, C., Sybert, V., Graham, J., Thuline, H., Page, D., Fellous, M.
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<strong>Small deletions of the short arm of the Y chromosome in 46,XY females.</strong>
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Proc. Nat. Acad. Sci. 83: 7841-7844, 1986.
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[PubMed: 3464001]
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Dumic, M., Lin-Su, K., Leibel, N. I., Ciglar, S., Vinci, G., Lasan, R., Nimkarn, S., Wilson, J. D., McElreavey, K., New, M. I.
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Nature Rev. Genet. 7: 620-631, 2006.
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[PubMed: 16832429]
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[Full Text: https://doi.org/10.1038/nrg1903]
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Wolf, U., Fraccaro, M., Mayerova, A., Hecht, T., Maraschio, P., Hameister, H.
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<strong>A gene controlling H-Y antigen on the X chromosome: tentative assignment by deletion mapping to Xp223.</strong>
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Hum. Genet. 54: 149-154, 1980.
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[PubMed: 7390489]
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[Full Text: https://doi.org/10.1007/BF00278963]
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Wolf, U.
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<strong>XY gonadal dysgenesis and the H-Y antigen.</strong>
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Hum. Genet. 47: 269-277, 1979.
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[PubMed: 110669]
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[Full Text: https://doi.org/10.1007/BF00321019]
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Marla J. F. O'Neill - updated : 05/20/2016<br>Marla J. F. O'Neill - updated : 3/17/2016<br>Marla J. F. O'Neill - updated : 10/27/2014<br>Marla J. F. O'Neill - updated : 12/6/2013<br>Marla J. F. O'Neill - updated : 8/6/2012<br>Marla J. F. O'Neill - updated : 9/27/2011<br>Marla J. F. O'Neill - updated : 2/16/2011<br>Marla J. F. O'Neill - updated : 10/7/2009
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Carol A. Bocchini : 8/18/2009
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