2946 lines
231 KiB
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Entry
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- #278850 - 46,XX SEX REVERSAL 2; SRXX2
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- OMIM
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<p>
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<span class="h4">#278850</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/278850"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<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 style="display: table-cell;">External Links</div>
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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 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,XX 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=5546&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/NBK1416/" 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.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=393" 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 class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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</span>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:278850" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<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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<a id="title" class="mim-anchor"></a>
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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> 393<br />
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<strong>DO:</strong> 0111763<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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278850
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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,XX SEX REVERSAL 2; SRXX2
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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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CHROMOSOME 17q24 DUPLICATION SYNDROME
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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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<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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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/17/894?start=-3&limit=10&highlight=894">
|
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17q24.3
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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46XX sex reversal 2
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/278850"> 278850 </a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<td>
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<span class="mim-font">
|
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SOX9
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/608160"> 608160 </a>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<div class="btn-group ">
|
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<a href="/clinicalSynopsis/278850" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/278850" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/278850" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </strong>
|
|
</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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|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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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> CHEST </strong>
|
|
</span>
|
|
</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Breasts </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Mild gynecomastia (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4230987&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4230987</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/4754008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">4754008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N62" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N62</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000771" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000771</a>]</span><br />
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|
</span>
|
|
</div>
|
|
</div>
|
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|
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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> GENITOURINARY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<em> External Genitalia (Male) </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Phenotypically normal male (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4230996&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4230996</a>]</span><br /> -
|
|
Perineal hypospadias <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204890004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204890004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q54.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q54.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0452148&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0452148</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000051" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000051</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000051" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000051</a>]</span><br /> -
|
|
Small penis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/34911001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">34911001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/276333003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">276333003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q55.62" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q55.62</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/752.64" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">752.64</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240701&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240701</a>, <a href="https://bioportal.bioontology.org/search?q=C4551492&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551492</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030260" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030260</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000054" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000054</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000054" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000054</a>]</span><br /> -
|
|
Asymmetric scrotum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4230995&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4230995</a>]</span><br /> -
|
|
Hypoplastic scrotum <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204912007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204912007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/276332008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">276332008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0455792&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0455792</a>, <a href="https://bioportal.bioontology.org/search?q=C0431659&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0431659</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000046" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000046</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000046" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000046</a>]</span><br /> -
|
|
Bifid scrotum <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/236780002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">236780002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0341787&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0341787</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000048" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000048</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000048" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000048</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">
|
|
|
|
- Normal to small testes (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4230994&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4230994</a>]</span><br /> -
|
|
Ovotestis (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1017223006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1017223006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q56.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q56.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0266361&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0266361</a>, <a href="https://bioportal.bioontology.org/search?q=C4551490&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551490</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012861" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012861</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0010459" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010459</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012861" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012861</a>]</span><br /> -
|
|
Azoospermia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/425558002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">425558002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48188009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48188009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N46.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N46.01</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N46.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N46.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/606.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">606.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004509&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004509</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000027</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000027</a>]</span><br /> -
|
|
Leydig cells present <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4230992&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4230992</a>]</span><br /> -
|
|
Sertoli cells present <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4230991&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4230991</a>]</span><br /> -
|
|
Atrophic seminiferous tubules <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1968705&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1968705</a>]</span><br /> -
|
|
No spermatogenesis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4230990&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4230990</a>]</span><br /> -
|
|
Epididymal structures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/87644002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">87644002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0014533&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014533</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">
|
|
|
|
- Fallopian tube structures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/31435000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">31435000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015560&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015560</a>]</span><br /> -
|
|
Streak gonad <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/84814009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">84814009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0266360&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0266360</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025733</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025733</a>]</span><br /> -
|
|
Ovarian remnant <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4230989&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4230989</a>]</span><br /> -
|
|
Primordial oocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4230988&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4230988</a>]</span><br /> -
|
|
Primordial follicles <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1514441&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1514441</a>]</span><br /> -
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Rudimentary vagina <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1442988&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1442988</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008726</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008726</a>]</span><br /> -
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Rudimentary uterus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35850006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35850006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q51.811" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q51.811</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/752.32" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">752.32</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0266399&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0266399</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000013</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000013</a>]</span><br />
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<strong> SKELETAL </strong>
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- Normal skeletal development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4230986&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4230986</a>]</span><br />
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<span class="h5 mim-font">
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<strong> ENDOCRINE FEATURES </strong>
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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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- Low serum testosterone levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4073137&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4073137</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0040171" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0040171</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0040171" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0040171</a>]</span><br /> -
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Elevated follicle-stimulating hormone (FSH) levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4013507&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4013507</a>]</span><br /> -
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Elevated luteinizing hormone (LH) levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4013508&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4013508</a>]</span><br /> -
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Low anti-Mullerian hormone (AMH) levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4013510&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4013510</a>]</span><br />
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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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<div style="margin-left: 2em;">
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- 46,XY carriers are unaffected<br />
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Caused by duplication or triplication of a 68-kb regulatory region (XXSR) -584 to -516 kb upstream of the SRY-box-9 gene (SOX9, <a href="/entry/608160#0014">608160.0014</a>)<br />
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</h4>
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<p>A number sign (#) is used with this entry because of evidence that familial 46,XX sex reversal is caused by heterozygous duplication or triplication of a 68-kb regulatory region (XXSR) -584 to -516 kb upstream of the SOX9 gene (<a href="/entry/608160">608160</a>) on chromosome 17q24.</p><p>For a discussion of genetic heterogeneity of 46,XX sex reversal, see SRXX1 (<a href="/entry/400045">400045</a>).</p>
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<br />
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<strong>Clinical Features</strong>
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<p><a href="#12" class="mim-tip-reference" title="Kuhnle, U., Schwarz, H. P., Lohrs, U., Stengel-Ruthkowski, S., Cleve, H., Braun, A. <strong>Familial true hermaphroditism: paternal and maternal transmission of true hermaphroditism (46,XX) and XX maleness in the absence of Y-chromosomal sequences.</strong> Hum. Genet. 92: 571-576, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8262517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8262517</a>] [<a href="https://doi.org/10.1007/BF00420941" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8262517">Kuhnle et al. (1993)</a> described a family with a 46,XX male and a 46,XX true hermaphrodite sib. An offspring of a maternal uncle had 46,XX true hermaphroditism. The maternal as well as paternal transmission of the disorder allows the possibility of either autosomal dominant or X-chromosomal dominant inheritance. Since molecular genetic analysis showed that both hermaphrodites as well as the 46,XX male were negative for Y-chromosomal sequences, testicular determination seemed to be due to varying expression of the same genetic defect, which presumably was incompletely penetrant. A mutation in an autosomal or X-chromosomal gene downstream from SRY (<a href="/entry/480000">480000</a>) could have turned itself or another gene into a testis-determining factor (TDF)-like gene. In the case of the mutation of an X-chromosomal gene, a different X inactivation pattern could explain the different phenotypes: random inactivation in XX true hermaphrodites and nonrandom in XX males. They pointed out that the 46,XX male could in fact have been a true hermaphrodite with unambiguous male external genitalia, since no surgical biopsy of both gonads to exclude the presence of ovarian parts was performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8262517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Slaney, S. F., Chalmers, I. J., Affara, N. A., Chitty, L. S. <strong>An autosomal or X linked mutation results in true hermaphrodites and 46,XX males in the same family.</strong> J. Med. Genet. 35: 17-22, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9475089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9475089</a>] [<a href="https://doi.org/10.1136/jmg.35.1.17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9475089">Slaney et al. (1998)</a> reported a family in which 4 related 46,XX individuals with no evidence of Y chromosome DNA sequences underwent variable degrees of male sexual differentiation. One 46,XX male had apparently normal male external genitalia, whereas his brother and 2 cousins had various degrees of sexual ambiguity and were found to be 46,XX true hermaphrodites. <a href="#16" class="mim-tip-reference" title="Slaney, S. F., Chalmers, I. J., Affara, N. A., Chitty, L. S. <strong>An autosomal or X linked mutation results in true hermaphrodites and 46,XX males in the same family.</strong> J. Med. Genet. 35: 17-22, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9475089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9475089</a>] [<a href="https://doi.org/10.1136/jmg.35.1.17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9475089">Slaney et al. (1998)</a> stated that the presence of male sexual development in genetic females with transmission through normal male and female parents indicated that the critical genetic defect was most likely an autosomal dominant mutation, with the different phenotypic effects arising from variable penetrance. They proposed that there might be an 'activating' mutation in this family, mimicking the initiating role of the SRY gene in 46,XX individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9475089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Cox, J. J., Willatt, L., Homfray, T., Woods, C. G. <strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong> New Eng. J. Med. 364: 91-93, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21208124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21208124</a>] [<a href="https://doi.org/10.1056/NEJMc1010311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21208124">Cox et al. (2011)</a> identified a family with 46,XX testicular disorder of sex development in which 3 adult males, 2 brothers and a paternal uncle, were determined to be female according to karyotype (46,XX) and were negative for the SRY gene. The secondary sexual characteristics, behavior, growth and development, and skeletal development in these men were all those of normal males. Their general health and intelligence were normal. Affected individuals were infertile with azoospermia. In 2 men the testes had been removed and prostheses placed during their 20s because of testicular pain secondary to testosterone replacement. Histologic exams showed the presence of Leydig and Sertoli cells, severely diminished and atrophied seminiferous tubules, and no spermatogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21208124" 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="#17" class="mim-tip-reference" title="Vetro, A., Ciccone, R., Giorda, R., Patricelli, M. G., Della Mina, E., Forlino, A., Zuffardi, O. <strong>XX males SRY negative: a confirmed cause of infertility.</strong> J. Med. Genet. 48: 710-712, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21653197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21653197</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21653197">Vetro et al. (2011)</a> studied two 46,XX SRY-negative Italian brothers, phenotypically normal males with bilaterally hypotrophic testes, azoospermia, low serum testosterone levels, and elevated follicle-stimulating hormone (FSH; see <a href="/entry/136530">136530</a>) and luteinizing hormone (LH; see <a href="/entry/152780">152780</a>) levels. Both brothers, aged 47 years and 46 years, reported normal libido, and the older brother requested evaluation after 10 years of infertility. One brother exhibited bilateral mild gynecomastia, and testicular biopsy revealed germinal cell aplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21653197" 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="#1" class="mim-tip-reference" title="Benko, S., Gordon, C. T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., and 12 others. <strong>Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.</strong> J. Med. Genet. 48: 825-830, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22051515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22051515</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22051515">Benko et al. (2011)</a> reported three 46,XX SRY-negative patients who exhibited isolated female-to-male ovotesticular disorders of sex development (DSD). Examination of the first patient at birth showed bifid scrotum with 2 palpable gonads, incurved short penis, and hypospadias. Pelvic MRI revealed epididymal structures; no pelvic formations resembling uterine structures were present. Hormonal data collected when the patient was 3 weeks of age suggested some degree of testicular dysgenesis. Macroscopic examination during genitoplasty revealed bilateral fallopian tubes associated with a gonadal structure, consistent with ovotestes. The second patient was born with perineal hypospadias and an asymmetric scrotum, with a normal testis on one side and an ovarian remnant with fallopian tube structures on the other. The patient also had small and rudimentary anlagen for a vagina and uterus that were surgically removed. The third patient had perineal hypospadias, ventrally curved small phallus, and hypoplastic and asymmetric scrotum with unilateral palpable gonad. Hormonal analysis in the patient at 1 year of age supported a diagnosis of gonadal dysgenesis, and genitography revealed the presence of a vaginal pouch and uterus. The patient underwent feminizing genitoplasty at 15 months with bilateral gonadectomy; histologic examination showed a streak gonad on the right that was partially differentiated toward an ovary, with dispersed primordial oocytes and rare follicles. The left gonad was a typical ovotestis, with a testicular portion having numerous seminiferous tubules lined only with Sertoli cells, and a small ovarian portion with abundant primordial follicles. An epididymal structure and a fallopian tube were both present. In a subsequent pregnancy in the third family, a 46,XX fetus was shown by ultrasound to have male external genitalia, and the pregnancy was terminated. None of the patients exhibited any skeletal abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22051515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<strong>Inheritance</strong>
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<p><a href="#3" class="mim-tip-reference" title="Blecher, S. R., Erickson, R. P. <strong>Genetics of sexual development: a new paradigm.</strong> Am. J. Med. Genet. 143A: 3054-3068, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000910</a>] [<a href="https://doi.org/10.1002/ajmg.a.32037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000910">Blecher and Erickson (2007)</a> reviewed knowledge of sexual development and proposed a new paradigm, namely, that sexual dimorphism precedes gonadal development, in a so-called 'pregonadal stage.' Noting that absence of testicular hormones does not produce a normal female phenotype, they stated that contrary to the classic paradigm, female development does not occur by default. <a href="#3" class="mim-tip-reference" title="Blecher, S. R., Erickson, R. P. <strong>Genetics of sexual development: a new paradigm.</strong> Am. J. Med. Genet. 143A: 3054-3068, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000910</a>] [<a href="https://doi.org/10.1002/ajmg.a.32037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000910">Blecher and Erickson (2007)</a> suggested that proximate gonad-determining genes are probably on the autosomes, with indirect and complex interactions between these and the primary factors on sex chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18000910" 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>In a newborn infant with severe penile/scrotal hypospadias, bifid scrotum, palpable gonads, and no uterus by ultrasound examination, <a href="#9" class="mim-tip-reference" title="Huang, B., Wang, S., Ning, Y., Lamb, A. N., Bartley, J. <strong>Autosomal XX sex reversal caused by duplication of SOX9.</strong> Am. J. Med. Genet. 87: 349-353, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10588843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10588843</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19991203)87:4<349::aid-ajmg13>3.0.co;2-n" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10588843">Huang et al. (1999)</a> performed cytogenetic analysis and demonstrated a de novo mosaic 46,XX,dup(17)(q23.1q24.3)/46,XX karyotype. Fluorescence in situ hybridization studies revealed that the SOX9 gene was duplicated on the rearranged chromosome 17 and ruled out the presence of SRY. Microsatellite analysis using 13 markers on 17q23-q24 showed that the duplication was maternal in origin, with boundaries approximately 12 cM proximal and 4 cM distal to the SOX9 gene. <a href="#9" class="mim-tip-reference" title="Huang, B., Wang, S., Ning, Y., Lamb, A. N., Bartley, J. <strong>Autosomal XX sex reversal caused by duplication of SOX9.</strong> Am. J. Med. Genet. 87: 349-353, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10588843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10588843</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19991203)87:4<349::aid-ajmg13>3.0.co;2-n" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10588843">Huang et al. (1999)</a> concluded that these findings suggested that an extra dose of SOX9 is sufficient to initiate testis differentiation in the absence of SRY. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10588843" 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>In 2 brothers and their uncle with normal male phenotypes and 46,XX karyotypes, <a href="#5" class="mim-tip-reference" title="Cox, J. J., Willatt, L., Homfray, T., Woods, C. G. <strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong> New Eng. J. Med. 364: 91-93, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21208124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21208124</a>] [<a href="https://doi.org/10.1056/NEJMc1010311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21208124">Cox et al. (2011)</a> found a 178-kb duplication 600 kb upstream of SOX9 (<a href="/entry/608160#0014">608160.0014</a>). The brothers' healthy, fertile father also carried the duplication. <a href="#5" class="mim-tip-reference" title="Cox, J. J., Willatt, L., Homfray, T., Woods, C. G. <strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong> New Eng. J. Med. 364: 91-93, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21208124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21208124</a>] [<a href="https://doi.org/10.1056/NEJMc1010311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21208124">Cox et al. (2011)</a> noted that the 1.9-Mb region of chromosome 17 upstream of SOX9 contains no other genes, is evolutionarily highly conserved in mammals, and gives rise to a wide range of phenotypes when mutated. They commented that although SRY is normally needed for SOX9 activation and the male phenotype, in this family a small duplication alone seemed to be sufficient to override this fundamental genetic process. Only the sex-dependent expression of SOX9 was affected, presumably through specific enhanced promoter activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21208124" 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="#17" class="mim-tip-reference" title="Vetro, A., Ciccone, R., Giorda, R., Patricelli, M. G., Della Mina, E., Forlino, A., Zuffardi, O. <strong>XX males SRY negative: a confirmed cause of infertility.</strong> J. Med. Genet. 48: 710-712, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21653197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21653197</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21653197">Vetro et al. (2011)</a> reported 2 azoospermic 46,XX SRY-negative brothers who had a 96-kb triplication located 500 kb upstream of the SOX9 gene (<a href="/entry/608160#0016">608160.0016</a>). The mutation was not present in their 2 fertile sisters and mother. Sequencing of the SOX9 and SOX3 (<a href="/entry/313430">313430</a>) genes in the family did not reveal any pathogenic variants. Two of 3 paternal male cousins were also reported to be infertile, but the brothers' deceased father, who died of myocardial infarction at age 50 years, had been considered completely normal. The 2 brothers shared the same paternal haplotype for the SOX9 region, supporting the possibility that their apparently unaffected father was the carrier of the triplication. <a href="#17" class="mim-tip-reference" title="Vetro, A., Ciccone, R., Giorda, R., Patricelli, M. G., Della Mina, E., Forlino, A., Zuffardi, O. <strong>XX males SRY negative: a confirmed cause of infertility.</strong> J. Med. Genet. 48: 710-712, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21653197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21653197</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21653197">Vetro et al. (2011)</a> stated that this was the shortest region of amplification upstream of SOX9 reported to be associated with 46,XX SRY-negative infertile males, and noted that, like the duplication reported by <a href="#5" class="mim-tip-reference" title="Cox, J. J., Willatt, L., Homfray, T., Woods, C. G. <strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong> New Eng. J. Med. 364: 91-93, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21208124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21208124</a>] [<a href="https://doi.org/10.1056/NEJMc1010311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21208124">Cox et al. (2011)</a>, the triplication did not seem to have any effect on the XY background. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21208124+21653197" 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 cohort of 14 cases of 46,XX patients with a disorder of sex development (DSD), <a href="#1" class="mim-tip-reference" title="Benko, S., Gordon, C. T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., and 12 others. <strong>Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.</strong> J. Med. Genet. 48: 825-830, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22051515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22051515</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22051515">Benko et al. (2011)</a> used MLPA and quantitative PCR to screen for copy number variation (CNV) in the SOX9 proximal gene desert and identified 3 different duplications in 3 unrelated SRY-negative patients (see, e.g., <a href="/entry/608160#0017">608160.0017</a>) who were negative for mutation in the WNT4 (<a href="/entry/603490">603490</a>) and RSPO1 (<a href="/entry/609595">609595</a>) genes. DNA from a 46,XX fetus with male external genitalia in the third family showed the same duplication as in the older affected sib. <a href="#1" class="mim-tip-reference" title="Benko, S., Gordon, C. T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., and 12 others. <strong>Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.</strong> J. Med. Genet. 48: 825-830, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22051515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22051515</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22051515">Benko et al. (2011)</a> stated that the region of overlap between these genomic alterations and previously reported 46,XX and 46,XY DSD-related deletions and duplications at the SOX9 locus revealed a minimal noncoding 78-kb sex-determining region (RevSex) located in a gene desert approximately 517 to 595 kb upstream of the SOX9 promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22051515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By performing CNV analysis in a cohort of 19 cases of SRY-negative 46,XX testicular or ovotesticular DSD, <a href="#11" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> identified 3 unrelated individuals with heterozygous duplications upstream of the SOX9 gene, shown to be paternally inherited in 1 case. The 3 duplications and previously reported SOX9 upstream duplication/triplication cases shared a common 68-kb duplicated region, located 516 to 584 kb upstream of SOX9, which <a href="#11" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> designated XXSR for 'XX sex-reversal region,' noting that it was largely identical with the 78-kb RevSex region. The authors also defined a distinct 32.5-kb XY sex-reversal region (XYSR) upstream of the SOX9 gene, based on 46,XY patients with deletions (see SRXY10, <a href="/entry/616425">616425</a>). <a href="#11" class="mim-tip-reference" title="Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others. <strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong> J. Med. Genet. 52: 240-247, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25604083">Kim et al. (2015)</a> stated that the XYSR and XXSR intervals do not overlap, being separated by 23 kb, and proposed that each harbors a differently-acting gonad-specific regulatory element. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25604083" 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="Xia, X.-Y., Zhang, C., Li, T.-F., Wu, Q.-Y., Li, N., Li, W.-W., Cui, Y.-X., Li, X.-J., Shi, Y.-C. <strong>A duplication upstream of SOX9 was not positively correlated with the SRY-negative 46,XX testicular disorder of sex development: a case report and literature review.</strong> Molec. Med. Rep. 12: 5659-5664, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26260363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26260363</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26260363[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/10.3892/mmr.2015.4202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26260363">Xia et al. (2015)</a> reported a 46,XX male in whom duplication upstream of SOX9 appeared to be a polymorphism. The patient presented at age 19 with gynecomastia and at age 29 with infertility and azoospermia. Testicular biopsy showed hypoplastic seminiferous tubules with interstitial fibrosis and few Sertoli cells, and the patient had low testosterone with elevated FSH and LH. Brain and adrenals appeared normal on CT scan, and no uterus or ovary was detected. Karyotype analysis revealed a 46,XX inv(9)(p11q13) karyotype; the chromosome 9 inversion was determined to have been inherited from his healthy mother. FISH analysis showed that he was SRY-negative, and no Y chromosome sequences were detected by PCR. Sequencing of 8 candidate genes, including SOX9, showed no mutation; however, SNP array analysis revealed an approximately 88-kb duplication in a region upstream of SOX9 (chr17:67,024,087-67,112,435; GRCh37). Because the duplication was also present in his unaffected mother, <a href="#18" class="mim-tip-reference" title="Xia, X.-Y., Zhang, C., Li, T.-F., Wu, Q.-Y., Li, N., Li, W.-W., Cui, Y.-X., Li, X.-J., Shi, Y.-C. <strong>A duplication upstream of SOX9 was not positively correlated with the SRY-negative 46,XX testicular disorder of sex development: a case report and literature review.</strong> Molec. Med. Rep. 12: 5659-5664, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26260363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26260363</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26260363[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/10.3892/mmr.2015.4202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26260363">Xia et al. (2015)</a> suggested that it represented a polymorphism and was not a direct cause of the 46,XX testicular disorder of sex development (DSD). The authors concluded that other genetic or environmental factors are significant in the regulation of DSD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26260363" 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>Sex reversal mutations have been observed in the goat (<a href="#8" class="mim-tip-reference" title="Hamerton, J. L., Dickson, J. M., Pollard, C. E., Grieves, S. A., Short, R. V. <strong>Genetic intersexuality in goats.</strong> J. Reprod. Fertil. 7 (suppl.): 25-51, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5272213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5272213</a>]" pmid="5272213">Hamerton et al., 1969</a>) and in the mouse (<a href="#4" class="mim-tip-reference" title="Cattanach, B. M., Pollard, C. E., Hawkes, S. G. <strong>Sex-reversed mice: XX and XO males.</strong> Cytogenetics 10: 318-337, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5156366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5156366</a>] [<a href="https://doi.org/10.1159/000130151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5156366">Cattanach et al., 1971</a>). The disorder is recessive in the goat, but dominant in the mouse. In these cases the autosomal gene apparently causes the indifferent gonad of genetic females to differentiate partially or completely into a testis. <a href="#14" class="mim-tip-reference" title="Selden, J. R., Wachtel, S. S., Koo, G. C., Haskins, M. E., Patterson, D. F. <strong>Genetic basis of XX male syndrome and XX true hermaphroditism: evidence in the dog.</strong> Science 201: 644-646, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/675252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">675252</a>] [<a href="https://doi.org/10.1126/science.675252" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="675252">Selden et al. (1978)</a> studied an instructive family of American cocker spaniels which suggested that abnormality of sexual development (development of testes or ovotestes) in animals with an XX karyotype was caused by anomalous transmission of H-Y genes. The observations suggested a common basis for the XX male syndrome and for XX true hermaphroditism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5156366+5272213+675252" 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="#10" class="mim-tip-reference" title="Kasdan, R., Nankin, H. R., Troen, P., Wald, N., Pan, S., Yanaihara, T. <strong>Paternal transmission of maleness in XX human beings.</strong> New Eng. J. Med. 288: 539-545, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4685451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4685451</a>] [<a href="https://doi.org/10.1056/NEJM197303152881102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4685451">Kasdan et al. (1973)</a> described a family in which a paternally transmitted, non-Y, male-determining autosomal gene was postulated as the only plausible explanation for sex reversal. The phenotype resembled that of the Klinefelter syndrome. Translocation of Y-chromosome material to an autosome could be excluded as the cause in at least some cases. With the discovery of the SRY ('sex region on the Y') gene (<a href="/entry/480000">480000</a>) and its equating to the TDF (testis-determining factor) gene, it became possible to demonstrate Y-chromosome material on one X chromosome in XX males (see <a href="/entry/400045">400045</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4685451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Like <a href="#10" class="mim-tip-reference" title="Kasdan, R., Nankin, H. R., Troen, P., Wald, N., Pan, S., Yanaihara, T. <strong>Paternal transmission of maleness in XX human beings.</strong> New Eng. J. Med. 288: 539-545, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4685451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4685451</a>] [<a href="https://doi.org/10.1056/NEJM197303152881102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4685451">Kasdan et al. (1973)</a> and <a href="#2" class="mim-tip-reference" title="Berger, R., Abonyi, D., Nadot, A., Vialatte, J., Lejeune, J. <strong>Hermaphrodisme vrai et 'garcon XX' dans une fratrie.</strong> Rev. Europ. Etud. Clin. Biol. 15: 330-333, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5447060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5447060</a>]" pmid="5447060">Berger et al. (1970)</a>, <a href="#15" class="mim-tip-reference" title="Skordis, N. A., Stetka, D. G., MacGillivray, M. H., Greenfield, S. P. <strong>Familial 46,XX males coexisting with familial 46,XX true hermaphrodites in same pedigree.</strong> J. Pediat. 110: 244-248, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3806296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3806296</a>] [<a href="https://doi.org/10.1016/s0022-3476(87)80162-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3806296">Skordis et al. (1987)</a> described XX true hermaphrodites and XX males in the same family. In the report of <a href="#15" class="mim-tip-reference" title="Skordis, N. A., Stetka, D. G., MacGillivray, M. H., Greenfield, S. P. <strong>Familial 46,XX males coexisting with familial 46,XX true hermaphrodites in same pedigree.</strong> J. Pediat. 110: 244-248, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3806296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3806296</a>] [<a href="https://doi.org/10.1016/s0022-3476(87)80162-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3806296">Skordis et al. (1987)</a>, the propositus was a paternal uncle with 46,XX true hermaphroditism. One of his brothers fathered a 46,XX daughter with true hermaphroditism; a second brother fathered two 46,XX males. Both fathers had normal male karyotypes and phenotypes. <a href="#15" class="mim-tip-reference" title="Skordis, N. A., Stetka, D. G., MacGillivray, M. H., Greenfield, S. P. <strong>Familial 46,XX males coexisting with familial 46,XX true hermaphrodites in same pedigree.</strong> J. Pediat. 110: 244-248, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3806296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3806296</a>] [<a href="https://doi.org/10.1016/s0022-3476(87)80162-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3806296">Skordis et al. (1987)</a> concluded that XX true hermaphrodites and XX males represent alternative manifestations of the same genetic defect and that the abnormality occurs via paternal transmission of an autosomal testis-determining factor. It was pointed out by <a href="#7" class="mim-tip-reference" title="de la Chapelle, A. <strong>The Y-chromosomal and autosomal testis-determining genes.</strong> Development 101 (suppl.): 33-38, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3503720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3503720</a>]" pmid="3503720">de la Chapelle (1987)</a> that in the several instances of familial XX maleness and XX true hermaphroditism, most affected persons are true hermaphrodites or XX males with ambiguous genitalia, whereas XX males without genital ambiguity are rare in such families. No Y-chromosome DNA has been found in familial cases. Typical autosomal dominant inheritance of XX testicular differentiation occurs in informative pedigrees. <a href="#7" class="mim-tip-reference" title="de la Chapelle, A. <strong>The Y-chromosomal and autosomal testis-determining genes.</strong> Development 101 (suppl.): 33-38, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3503720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3503720</a>]" pmid="3503720">De la Chapelle (1987)</a> hypothesized that an autosomal dominant testis-determining factor, TDFA, exists. They suggested that TDFA shows somewhat variable expression in XX persons, often causing genital ambiguity or true hermaphroditism, but has no phenotypic effect in XY persons. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3806296+5447060+3503720+4685451" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Pierella, P., Craig, I., Bobrow, M., de la Chapelle, A. <strong>Steroid sulphatase levels in XX males, including observations on two affected cousins.</strong> Hum. Genet. 59: 87-88, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10819031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10819031</a>] [<a href="https://doi.org/10.1007/BF00278863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10819031">Pierella et al. (1981)</a> suggested the existence, at least in some cases, of an autosomal mutation that causes inactivation of a subterminal portion of Xp which normally escapes inactivation. The suggestion was based on the demonstration of male levels of steroid sulfatase in 2 affected cousins who could not share the same X chromosome because they were related through their fathers and their paternal grandfathers. An autosomal factor influencing sex determination, H-Y antigen (<a href="/entry/426000">426000</a>) production, Xg (<a href="/entry/314700">314700</a>) expression, and steroid sulfatase (<a href="/entry/300747">300747</a>) levels can be understood if its effects are mediated via autosomal control of inactivation of a distal segment of Xp. Autosomal control of X inactivation may be suggested by the presence of more than one active X per cell in tetraploids and some triploids. There is probably pathogenetic heterogeneity in the category of XX males. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10819031" 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="#de1972" class="mim-tip-reference" title="de la Chapelle, A. <strong>Nature and origin of males with XX sex chromosomes.</strong> Am. J. Hum. Genet. 24: 71-105, 1972.">de la Chapelle (1972)</a>
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Benko, S., Gordon, C. T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., and 12 others.
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<strong>Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.</strong>
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J. Med. Genet. 48: 825-830, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22051515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22051515</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22051515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2011-100255" target="_blank">Full Text</a>]
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Berger, R., Abonyi, D., Nadot, A., Vialatte, J., Lejeune, J.
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<strong>Hermaphrodisme vrai et 'garcon XX' dans une fratrie.</strong>
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Rev. Europ. Etud. Clin. Biol. 15: 330-333, 1970.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5447060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5447060</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5447060" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Blecher, S. R., Erickson, R. P.
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<strong>Genetics of sexual development: a new paradigm.</strong>
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Am. J. Med. Genet. 143A: 3054-3068, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000910</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18000910" 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/10.1002/ajmg.a.32037" target="_blank">Full Text</a>]
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Cattanach, B. M., Pollard, C. E., Hawkes, S. G.
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<strong>Sex-reversed mice: XX and XO males.</strong>
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Cytogenetics 10: 318-337, 1971.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5156366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5156366</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5156366" 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/10.1159/000130151" target="_blank">Full Text</a>]
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Cox, J. J., Willatt, L., Homfray, T., Woods, C. G.
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<strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong>
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New Eng. J. Med. 364: 91-93, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21208124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21208124</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21208124" 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/10.1056/NEJMc1010311" target="_blank">Full Text</a>]
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<strong>Nature and origin of males with XX sex chromosomes.</strong>
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Am. J. Hum. Genet. 24: 71-105, 1972.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4622299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4622299</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4622299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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de la Chapelle, A.
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<strong>The Y-chromosomal and autosomal testis-determining genes.</strong>
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Development 101 (suppl.): 33-38, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3503720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3503720</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3503720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Hamerton, J. L., Dickson, J. M., Pollard, C. E., Grieves, S. A., Short, R. V.
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<strong>Genetic intersexuality in goats.</strong>
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J. Reprod. Fertil. 7 (suppl.): 25-51, 1969.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5272213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5272213</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5272213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Huang1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Huang, B., Wang, S., Ning, Y., Lamb, A. N., Bartley, J.
|
|
<strong>Autosomal XX sex reversal caused by duplication of SOX9.</strong>
|
|
Am. J. Med. Genet. 87: 349-353, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10588843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10588843</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10588843" 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/10.1002/(sici)1096-8628(19991203)87:4<349::aid-ajmg13>3.0.co;2-n" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Kasdan1973" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Kasdan, R., Nankin, H. R., Troen, P., Wald, N., Pan, S., Yanaihara, T.
|
|
<strong>Paternal transmission of maleness in XX human beings.</strong>
|
|
New Eng. J. Med. 288: 539-545, 1973.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4685451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4685451</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4685451" 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/10.1056/NEJM197303152881102" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Kim2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others.
|
|
<strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong>
|
|
J. Med. Genet. 52: 240-247, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25604083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25604083</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25604083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2014-102864" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Kuhnle1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Kuhnle, U., Schwarz, H. P., Lohrs, U., Stengel-Ruthkowski, S., Cleve, H., Braun, A.
|
|
<strong>Familial true hermaphroditism: paternal and maternal transmission of true hermaphroditism (46,XX) and XX maleness in the absence of Y-chromosomal sequences.</strong>
|
|
Hum. Genet. 92: 571-576, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8262517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8262517</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8262517" 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/BF00420941" target="_blank">Full Text</a>]
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Pierella1981" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pierella, P., Craig, I., Bobrow, M., de la Chapelle, A.
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<strong>Steroid sulphatase levels in XX males, including observations on two affected cousins.</strong>
|
|
Hum. Genet. 59: 87-88, 1981.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10819031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10819031</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10819031" 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/BF00278863" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Selden1978" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Selden, J. R., Wachtel, S. S., Koo, G. C., Haskins, M. E., Patterson, D. F.
|
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<strong>Genetic basis of XX male syndrome and XX true hermaphroditism: evidence in the dog.</strong>
|
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Science 201: 644-646, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/675252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">675252</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=675252" 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/10.1126/science.675252" target="_blank">Full Text</a>]
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Skordis1987" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Skordis, N. A., Stetka, D. G., MacGillivray, M. H., Greenfield, S. P.
|
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<strong>Familial 46,XX males coexisting with familial 46,XX true hermaphrodites in same pedigree.</strong>
|
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J. Pediat. 110: 244-248, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3806296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3806296</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3806296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(87)80162-2" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Slaney1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Slaney, S. F., Chalmers, I. J., Affara, N. A., Chitty, L. S.
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<strong>An autosomal or X linked mutation results in true hermaphrodites and 46,XX males in the same family.</strong>
|
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J. Med. Genet. 35: 17-22, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9475089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9475089</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9475089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.35.1.17" target="_blank">Full Text</a>]
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Vetro2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vetro, A., Ciccone, R., Giorda, R., Patricelli, M. G., Della Mina, E., Forlino, A., Zuffardi, O.
|
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<strong>XX males SRY negative: a confirmed cause of infertility.</strong>
|
|
J. Med. Genet. 48: 710-712, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21653197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21653197</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21653197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2011-100036" target="_blank">Full Text</a>]
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Xia2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xia, X.-Y., Zhang, C., Li, T.-F., Wu, Q.-Y., Li, N., Li, W.-W., Cui, Y.-X., Li, X.-J., Shi, Y.-C.
|
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<strong>A duplication upstream of SOX9 was not positively correlated with the SRY-negative 46,XX testicular disorder of sex development: a case report and literature review.</strong>
|
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Molec. Med. Rep. 12: 5659-5664, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26260363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26260363</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26260363[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26260363" 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/10.3892/mmr.2015.4202" target="_blank">Full Text</a>]
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</p>
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</ol>
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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="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 08/03/2016
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 6/16/2015<br>Marla J. F. O'Neill - updated : 9/26/2011<br>Ada Hamosh - updated : 1/19/2011<br>John A. Phillips, III - updated : 5/15/2009<br>John A. Phillips, III - updated : 1/23/2008
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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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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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</span>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/08/2021
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 08/03/2016<br>alopez : 06/22/2015<br>mcolton : 6/16/2015<br>alopez : 5/18/2015<br>alopez : 9/26/2011<br>alopez : 9/26/2011<br>carol : 4/26/2011<br>alopez : 2/28/2011<br>alopez : 2/24/2011<br>alopez : 1/31/2011<br>terry : 1/19/2011<br>carol : 8/20/2009<br>alopez : 5/15/2009<br>terry : 3/26/2009<br>carol : 1/23/2008<br>mark : 1/13/1998<br>mimadm : 3/12/1994<br>supermim : 3/17/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988<br>carol : 5/21/1987
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</span>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 278850
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<div>
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<h3>
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<span class="mim-font">
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46,XX SEX REVERSAL 2; SRXX2
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<div>
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<br />
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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CHROMOSOME 17q24 DUPLICATION SYNDROME
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</h4>
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<p>
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<span class="mim-text-font">
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<strong>ORPHA:</strong> 393;
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<strong>DO:</strong> 0111763;
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</span>
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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 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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</th>
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<tbody>
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<td>
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<span class="mim-font">
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17q24.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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46XX sex reversal 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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278850
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
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SOX9
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</span>
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</td>
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<td>
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<span class="mim-font">
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608160
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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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>TEXT</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>A number sign (#) is used with this entry because of evidence that familial 46,XX sex reversal is caused by heterozygous duplication or triplication of a 68-kb regulatory region (XXSR) -584 to -516 kb upstream of the SOX9 gene (608160) on chromosome 17q24.</p><p>For a discussion of genetic heterogeneity of 46,XX sex reversal, see SRXX1 (400045).</p>
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</span>
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<div>
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<br />
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<div>
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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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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Kuhnle et al. (1993) described a family with a 46,XX male and a 46,XX true hermaphrodite sib. An offspring of a maternal uncle had 46,XX true hermaphroditism. The maternal as well as paternal transmission of the disorder allows the possibility of either autosomal dominant or X-chromosomal dominant inheritance. Since molecular genetic analysis showed that both hermaphrodites as well as the 46,XX male were negative for Y-chromosomal sequences, testicular determination seemed to be due to varying expression of the same genetic defect, which presumably was incompletely penetrant. A mutation in an autosomal or X-chromosomal gene downstream from SRY (480000) could have turned itself or another gene into a testis-determining factor (TDF)-like gene. In the case of the mutation of an X-chromosomal gene, a different X inactivation pattern could explain the different phenotypes: random inactivation in XX true hermaphrodites and nonrandom in XX males. They pointed out that the 46,XX male could in fact have been a true hermaphrodite with unambiguous male external genitalia, since no surgical biopsy of both gonads to exclude the presence of ovarian parts was performed. </p><p>Slaney et al. (1998) reported a family in which 4 related 46,XX individuals with no evidence of Y chromosome DNA sequences underwent variable degrees of male sexual differentiation. One 46,XX male had apparently normal male external genitalia, whereas his brother and 2 cousins had various degrees of sexual ambiguity and were found to be 46,XX true hermaphrodites. Slaney et al. (1998) stated that the presence of male sexual development in genetic females with transmission through normal male and female parents indicated that the critical genetic defect was most likely an autosomal dominant mutation, with the different phenotypic effects arising from variable penetrance. They proposed that there might be an 'activating' mutation in this family, mimicking the initiating role of the SRY gene in 46,XX individuals. </p><p>Cox et al. (2011) identified a family with 46,XX testicular disorder of sex development in which 3 adult males, 2 brothers and a paternal uncle, were determined to be female according to karyotype (46,XX) and were negative for the SRY gene. The secondary sexual characteristics, behavior, growth and development, and skeletal development in these men were all those of normal males. Their general health and intelligence were normal. Affected individuals were infertile with azoospermia. In 2 men the testes had been removed and prostheses placed during their 20s because of testicular pain secondary to testosterone replacement. Histologic exams showed the presence of Leydig and Sertoli cells, severely diminished and atrophied seminiferous tubules, and no spermatogenesis. </p><p>Vetro et al. (2011) studied two 46,XX SRY-negative Italian brothers, phenotypically normal males with bilaterally hypotrophic testes, azoospermia, low serum testosterone levels, and elevated follicle-stimulating hormone (FSH; see 136530) and luteinizing hormone (LH; see 152780) levels. Both brothers, aged 47 years and 46 years, reported normal libido, and the older brother requested evaluation after 10 years of infertility. One brother exhibited bilateral mild gynecomastia, and testicular biopsy revealed germinal cell aplasia. </p><p>Benko et al. (2011) reported three 46,XX SRY-negative patients who exhibited isolated female-to-male ovotesticular disorders of sex development (DSD). Examination of the first patient at birth showed bifid scrotum with 2 palpable gonads, incurved short penis, and hypospadias. Pelvic MRI revealed epididymal structures; no pelvic formations resembling uterine structures were present. Hormonal data collected when the patient was 3 weeks of age suggested some degree of testicular dysgenesis. Macroscopic examination during genitoplasty revealed bilateral fallopian tubes associated with a gonadal structure, consistent with ovotestes. The second patient was born with perineal hypospadias and an asymmetric scrotum, with a normal testis on one side and an ovarian remnant with fallopian tube structures on the other. The patient also had small and rudimentary anlagen for a vagina and uterus that were surgically removed. The third patient had perineal hypospadias, ventrally curved small phallus, and hypoplastic and asymmetric scrotum with unilateral palpable gonad. Hormonal analysis in the patient at 1 year of age supported a diagnosis of gonadal dysgenesis, and genitography revealed the presence of a vaginal pouch and uterus. The patient underwent feminizing genitoplasty at 15 months with bilateral gonadectomy; histologic examination showed a streak gonad on the right that was partially differentiated toward an ovary, with dispersed primordial oocytes and rare follicles. The left gonad was a typical ovotestis, with a testicular portion having numerous seminiferous tubules lined only with Sertoli cells, and a small ovarian portion with abundant primordial follicles. An epididymal structure and a fallopian tube were both present. In a subsequent pregnancy in the third family, a 46,XX fetus was shown by ultrasound to have male external genitalia, and the pregnancy was terminated. None of the patients exhibited any skeletal abnormalities. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Inheritance</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Blecher and Erickson (2007) reviewed knowledge of sexual development and proposed a new paradigm, namely, that sexual dimorphism precedes gonadal development, in a so-called 'pregonadal stage.' Noting that absence of testicular hormones does not produce a normal female phenotype, they stated that contrary to the classic paradigm, female development does not occur by default. Blecher and Erickson (2007) suggested that proximate gonad-determining genes are probably on the autosomes, with indirect and complex interactions between these and the primary factors on sex chromosomes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a newborn infant with severe penile/scrotal hypospadias, bifid scrotum, palpable gonads, and no uterus by ultrasound examination, Huang et al. (1999) performed cytogenetic analysis and demonstrated a de novo mosaic 46,XX,dup(17)(q23.1q24.3)/46,XX karyotype. Fluorescence in situ hybridization studies revealed that the SOX9 gene was duplicated on the rearranged chromosome 17 and ruled out the presence of SRY. Microsatellite analysis using 13 markers on 17q23-q24 showed that the duplication was maternal in origin, with boundaries approximately 12 cM proximal and 4 cM distal to the SOX9 gene. Huang et al. (1999) concluded that these findings suggested that an extra dose of SOX9 is sufficient to initiate testis differentiation in the absence of SRY. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 2 brothers and their uncle with normal male phenotypes and 46,XX karyotypes, Cox et al. (2011) found a 178-kb duplication 600 kb upstream of SOX9 (608160.0014). The brothers' healthy, fertile father also carried the duplication. Cox et al. (2011) noted that the 1.9-Mb region of chromosome 17 upstream of SOX9 contains no other genes, is evolutionarily highly conserved in mammals, and gives rise to a wide range of phenotypes when mutated. They commented that although SRY is normally needed for SOX9 activation and the male phenotype, in this family a small duplication alone seemed to be sufficient to override this fundamental genetic process. Only the sex-dependent expression of SOX9 was affected, presumably through specific enhanced promoter activity. </p><p>Vetro et al. (2011) reported 2 azoospermic 46,XX SRY-negative brothers who had a 96-kb triplication located 500 kb upstream of the SOX9 gene (608160.0016). The mutation was not present in their 2 fertile sisters and mother. Sequencing of the SOX9 and SOX3 (313430) genes in the family did not reveal any pathogenic variants. Two of 3 paternal male cousins were also reported to be infertile, but the brothers' deceased father, who died of myocardial infarction at age 50 years, had been considered completely normal. The 2 brothers shared the same paternal haplotype for the SOX9 region, supporting the possibility that their apparently unaffected father was the carrier of the triplication. Vetro et al. (2011) stated that this was the shortest region of amplification upstream of SOX9 reported to be associated with 46,XX SRY-negative infertile males, and noted that, like the duplication reported by Cox et al. (2011), the triplication did not seem to have any effect on the XY background. </p><p>In a cohort of 14 cases of 46,XX patients with a disorder of sex development (DSD), Benko et al. (2011) used MLPA and quantitative PCR to screen for copy number variation (CNV) in the SOX9 proximal gene desert and identified 3 different duplications in 3 unrelated SRY-negative patients (see, e.g., 608160.0017) who were negative for mutation in the WNT4 (603490) and RSPO1 (609595) genes. DNA from a 46,XX fetus with male external genitalia in the third family showed the same duplication as in the older affected sib. Benko et al. (2011) stated that the region of overlap between these genomic alterations and previously reported 46,XX and 46,XY DSD-related deletions and duplications at the SOX9 locus revealed a minimal noncoding 78-kb sex-determining region (RevSex) located in a gene desert approximately 517 to 595 kb upstream of the SOX9 promoter. </p><p>By performing CNV analysis in a cohort of 19 cases of SRY-negative 46,XX testicular or ovotesticular DSD, Kim et al. (2015) identified 3 unrelated individuals with heterozygous duplications upstream of the SOX9 gene, shown to be paternally inherited in 1 case. The 3 duplications and previously reported SOX9 upstream duplication/triplication cases shared a common 68-kb duplicated region, located 516 to 584 kb upstream of SOX9, which Kim et al. (2015) designated XXSR for 'XX sex-reversal region,' noting that it was largely identical with the 78-kb RevSex region. The authors also defined a distinct 32.5-kb XY sex-reversal region (XYSR) upstream of the SOX9 gene, based on 46,XY patients with deletions (see SRXY10, 616425). Kim et al. (2015) stated that the XYSR and XXSR intervals do not overlap, being separated by 23 kb, and proposed that each harbors a differently-acting gonad-specific regulatory element. </p><p>Xia et al. (2015) reported a 46,XX male in whom duplication upstream of SOX9 appeared to be a polymorphism. The patient presented at age 19 with gynecomastia and at age 29 with infertility and azoospermia. Testicular biopsy showed hypoplastic seminiferous tubules with interstitial fibrosis and few Sertoli cells, and the patient had low testosterone with elevated FSH and LH. Brain and adrenals appeared normal on CT scan, and no uterus or ovary was detected. Karyotype analysis revealed a 46,XX inv(9)(p11q13) karyotype; the chromosome 9 inversion was determined to have been inherited from his healthy mother. FISH analysis showed that he was SRY-negative, and no Y chromosome sequences were detected by PCR. Sequencing of 8 candidate genes, including SOX9, showed no mutation; however, SNP array analysis revealed an approximately 88-kb duplication in a region upstream of SOX9 (chr17:67,024,087-67,112,435; GRCh37). Because the duplication was also present in his unaffected mother, Xia et al. (2015) suggested that it represented a polymorphism and was not a direct cause of the 46,XX testicular disorder of sex development (DSD). The authors concluded that other genetic or environmental factors are significant in the regulation of DSD. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sex reversal mutations have been observed in the goat (Hamerton et al., 1969) and in the mouse (Cattanach et al., 1971). The disorder is recessive in the goat, but dominant in the mouse. In these cases the autosomal gene apparently causes the indifferent gonad of genetic females to differentiate partially or completely into a testis. Selden et al. (1978) studied an instructive family of American cocker spaniels which suggested that abnormality of sexual development (development of testes or ovotestes) in animals with an XX karyotype was caused by anomalous transmission of H-Y genes. The observations suggested a common basis for the XX male syndrome and for XX true hermaphroditism. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<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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</div>
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<span class="mim-text-font">
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<p>Kasdan et al. (1973) described a family in which a paternally transmitted, non-Y, male-determining autosomal gene was postulated as the only plausible explanation for sex reversal. The phenotype resembled that of the Klinefelter syndrome. Translocation of Y-chromosome material to an autosome could be excluded as the cause in at least some cases. With the discovery of the SRY ('sex region on the Y') gene (480000) and its equating to the TDF (testis-determining factor) gene, it became possible to demonstrate Y-chromosome material on one X chromosome in XX males (see 400045). </p><p>Like Kasdan et al. (1973) and Berger et al. (1970), Skordis et al. (1987) described XX true hermaphrodites and XX males in the same family. In the report of Skordis et al. (1987), the propositus was a paternal uncle with 46,XX true hermaphroditism. One of his brothers fathered a 46,XX daughter with true hermaphroditism; a second brother fathered two 46,XX males. Both fathers had normal male karyotypes and phenotypes. Skordis et al. (1987) concluded that XX true hermaphrodites and XX males represent alternative manifestations of the same genetic defect and that the abnormality occurs via paternal transmission of an autosomal testis-determining factor. It was pointed out by de la Chapelle (1987) that in the several instances of familial XX maleness and XX true hermaphroditism, most affected persons are true hermaphrodites or XX males with ambiguous genitalia, whereas XX males without genital ambiguity are rare in such families. No Y-chromosome DNA has been found in familial cases. Typical autosomal dominant inheritance of XX testicular differentiation occurs in informative pedigrees. De la Chapelle (1987) hypothesized that an autosomal dominant testis-determining factor, TDFA, exists. They suggested that TDFA shows somewhat variable expression in XX persons, often causing genital ambiguity or true hermaphroditism, but has no phenotypic effect in XY persons. </p><p>Pierella et al. (1981) suggested the existence, at least in some cases, of an autosomal mutation that causes inactivation of a subterminal portion of Xp which normally escapes inactivation. The suggestion was based on the demonstration of male levels of steroid sulfatase in 2 affected cousins who could not share the same X chromosome because they were related through their fathers and their paternal grandfathers. An autosomal factor influencing sex determination, H-Y antigen (426000) production, Xg (314700) expression, and steroid sulfatase (300747) levels can be understood if its effects are mediated via autosomal control of inactivation of a distal segment of Xp. Autosomal control of X inactivation may be suggested by the presence of more than one active X per cell in tetraploids and some triploids. There is probably pathogenetic heterogeneity in the category of XX males. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<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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|
de la Chapelle (1972)
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</span>
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<div>
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<br />
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</div>
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</div>
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<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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<li>
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<p class="mim-text-font">
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Benko, S., Gordon, C. T., Mallet, D., Sreenivasan, R., Thauvin-Robinet, C., Brendehaug, A., Thomas, S., Bruland, O., David, M., Nicolino, M., Labalme, A., Sanlaville, D., and 12 others.
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<strong>Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.</strong>
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J. Med. Genet. 48: 825-830, 2011.
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[PubMed: 22051515]
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[Full Text: https://doi.org/10.1136/jmedgenet-2011-100255]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Berger, R., Abonyi, D., Nadot, A., Vialatte, J., Lejeune, J.
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<strong>Hermaphrodisme vrai et 'garcon XX' dans une fratrie.</strong>
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Rev. Europ. Etud. Clin. Biol. 15: 330-333, 1970.
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[PubMed: 5447060]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Blecher, S. R., Erickson, R. P.
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<strong>Genetics of sexual development: a new paradigm.</strong>
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Am. J. Med. Genet. 143A: 3054-3068, 2007.
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[PubMed: 18000910]
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[Full Text: https://doi.org/10.1002/ajmg.a.32037]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cattanach, B. M., Pollard, C. E., Hawkes, S. G.
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<strong>Sex-reversed mice: XX and XO males.</strong>
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Cytogenetics 10: 318-337, 1971.
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[PubMed: 5156366]
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[Full Text: https://doi.org/10.1159/000130151]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cox, J. J., Willatt, L., Homfray, T., Woods, C. G.
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<strong>A SOX9 duplication and familial 46,XX developmental testicular disorder. (Letter)</strong>
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New Eng. J. Med. 364: 91-93, 2011.
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[PubMed: 21208124]
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[Full Text: https://doi.org/10.1056/NEJMc1010311]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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de la Chapelle, A.
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<strong>Nature and origin of males with XX sex chromosomes.</strong>
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Am. J. Hum. Genet. 24: 71-105, 1972.
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[PubMed: 4622299]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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de la Chapelle, A.
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<strong>The Y-chromosomal and autosomal testis-determining genes.</strong>
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Development 101 (suppl.): 33-38, 1987.
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[PubMed: 3503720]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hamerton, J. L., Dickson, J. M., Pollard, C. E., Grieves, S. A., Short, R. V.
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<strong>Genetic intersexuality in goats.</strong>
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J. Reprod. Fertil. 7 (suppl.): 25-51, 1969.
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[PubMed: 5272213]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Huang, B., Wang, S., Ning, Y., Lamb, A. N., Bartley, J.
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<strong>Autosomal XX sex reversal caused by duplication of SOX9.</strong>
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Am. J. Med. Genet. 87: 349-353, 1999.
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[PubMed: 10588843]
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[Full Text: https://doi.org/10.1002/(sici)1096-8628(19991203)87:4<349::aid-ajmg13>3.0.co;2-n]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kasdan, R., Nankin, H. R., Troen, P., Wald, N., Pan, S., Yanaihara, T.
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<strong>Paternal transmission of maleness in XX human beings.</strong>
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New Eng. J. Med. 288: 539-545, 1973.
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[PubMed: 4685451]
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[Full Text: https://doi.org/10.1056/NEJM197303152881102]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kim, G.-J., Sock, E., Buchberger, A., Just, W., Denzer, F., Hoepffner, W., German, J., Cole, T., Mann, J., Seguin, J. H., Zipf, W., Costigan, C., and 17 others.
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<strong>Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.</strong>
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J. Med. Genet. 52: 240-247, 2015.
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[PubMed: 25604083]
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[Full Text: https://doi.org/10.1136/jmedgenet-2014-102864]
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</p>
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</li>
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Kuhnle, U., Schwarz, H. P., Lohrs, U., Stengel-Ruthkowski, S., Cleve, H., Braun, A.
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<strong>Familial true hermaphroditism: paternal and maternal transmission of true hermaphroditism (46,XX) and XX maleness in the absence of Y-chromosomal sequences.</strong>
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Pierella, P., Craig, I., Bobrow, M., de la Chapelle, A.
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<strong>Steroid sulphatase levels in XX males, including observations on two affected cousins.</strong>
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Hum. Genet. 59: 87-88, 1981.
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Selden, J. R., Wachtel, S. S., Koo, G. C., Haskins, M. E., Patterson, D. F.
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<strong>Genetic basis of XX male syndrome and XX true hermaphroditism: evidence in the dog.</strong>
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Skordis, N. A., Stetka, D. G., MacGillivray, M. H., Greenfield, S. P.
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<strong>Familial 46,XX males coexisting with familial 46,XX true hermaphrodites in same pedigree.</strong>
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Slaney, S. F., Chalmers, I. J., Affara, N. A., Chitty, L. S.
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<strong>An autosomal or X linked mutation results in true hermaphrodites and 46,XX males in the same family.</strong>
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Vetro, A., Ciccone, R., Giorda, R., Patricelli, M. G., Della Mina, E., Forlino, A., Zuffardi, O.
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<strong>XX males SRY negative: a confirmed cause of infertility.</strong>
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Xia, X.-Y., Zhang, C., Li, T.-F., Wu, Q.-Y., Li, N., Li, W.-W., Cui, Y.-X., Li, X.-J., Shi, Y.-C.
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