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Entry
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- #150800 - HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER; HLRCC
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- OMIM
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<p>
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<span class="h4">#150800</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="/clinicalSynopsis/150800"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div 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=HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER" 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=8649&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/NBK1252/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/4161" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/hereditary-leiomyomatosis-and-renal-cell-cancer" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=150800[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=523" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1162799008<br />
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<strong>ORPHA:</strong> 523<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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150800
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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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HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER; HLRCC
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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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MULTIPLE CUTANEOUS AND UTERINE LEIOMYOMATA 1, WITH OR WITHOUT RENAL CELL CARCINOMA; MCUL1<br />
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LEIOMYOMATOSIS AND RENAL CELL CANCER, HEREDITARY; LRCC<br />
|
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LEIOMYOMA, MULTIPLE CUTANEOUS; MCL
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<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/1/1836?start=-3&limit=10&highlight=1836">
|
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1q43
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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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Leiomyomatosis and renal cell cancer
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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/150800"> 150800 </a>
|
|
</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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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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FH
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/136850"> 136850 </a>
|
|
</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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<div>
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<div class="btn-group ">
|
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<a href="/clinicalSynopsis/150800" 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/150800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/150800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<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">
|
|
<strong> INHERITANCE </strong>
|
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</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
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<div>
|
|
<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> GENITOURINARY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
|
<div>
|
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<span class="h5 mim-font">
|
|
<em> Internal Genitalia (Female) </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Uterine leiomyomata <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/146801000119103" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">146801000119103</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95315005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95315005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D25.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D25.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D25" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D25</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/218.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">218.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">218</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042133&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042133</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000131" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000131</a>]</span><br /> -
|
|
Uterine leiomyosarcoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/447389009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">447389009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/770559003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">770559003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0280631&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0280631</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002891</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002891</a>]</span><br /> -
|
|
Uterine fibroids <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/146801000119103" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">146801000119103</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95315005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95315005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D25.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D25.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D25" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D25</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/218.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">218.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">218</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042133&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042133</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000131" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000131</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Kidneys </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Renal cell carcinoma, papillary type 2 (about 20% of patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1336840&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1336840</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006732" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006732</a>]</span><br /> -
|
|
Collecting duct carcinoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128669006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128669006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/733470002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">733470002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1266044&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1266044</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
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|
|
|
</div>
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|
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|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Cutaneous piloleiomyomas (may be single or multiple) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3549863&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3549863</a>]</span><br /> -
|
|
Leiomyomas are sensitive to light touch <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3549864&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3549864</a>]</span><br /> -
|
|
Cutaneous leiomyosarcoma (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254771006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254771006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0346067&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0346067</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006755" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006755</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006755" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006755</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
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|
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|
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|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEOPLASIA </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Uterine leiomyosarcoma (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/447389009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">447389009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/770559003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">770559003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0280631&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0280631</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002891</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002891</a>]</span><br /> -
|
|
Cutaneous leiomyosarcoma (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254771006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254771006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0346067&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0346067</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006755" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006755</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006755" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006755</a>]</span><br /> -
|
|
Renal cell carcinoma, solitary papillary type 2 (about 20% of patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3549862&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3549862</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
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|
|
</div>
|
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|
|
</div>
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Decreased fumarate hydratase activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853903&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853903</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003536" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003536</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003536" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003536</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Highly variable phenotype <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839039&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839039</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span><br /> -
|
|
Cutaneous leiomyomas increase in number over time<br /> -
|
|
Mean age of diagnosis of uterine leiomyomas is 30 years<br /> -
|
|
Mean age of diagnosis of renal cell carcinoma is 46 years<br /> -
|
|
Incomplete penetrance <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836598&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836598</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the fumarate hydratase gene (FH, <a href="/entry/136850#0003">136850.0003</a>)<br />
|
|
|
|
</span>
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<p>A number sign (#) is used with this entry because multiple cutaneous and uterine leiomyomatosis with or without renal cell carcinoma, also referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC), is caused by heterozygous mutation in the gene encoding fumarate hydratase (FH; <a href="/entry/136850">136850</a>) on chromosome 1q43.</p><p>Homozygous mutation in the FH gene causes fumarase deficiency (FMRD; <a href="/entry/606812">606812</a>).</p>
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<p>Hereditary leiomyomatosis and renal cell cancer is an autosomal dominant tumor predisposition syndrome characterized by the variable development of 3 tumors: cutaneous piloleiomyomata that develop in essentially all patients by age 40 years; leiomyomata (fibroids) of the uterus, and rarely leiomyosarcomas, at a mean age of 30 years (range, 18 to 52 years); and type 2 papillary renal cell carcinoma at a mean age of 46 years (range, 17 to 75 years), which occurs in about 20% of patients. Type 2 papillary renal cell carcinoma is a pathologic subtype characterized by large tumor cells with eosinophilic cytoplasm and pseudostratified nuclei; it shows an aggressive clinical course. Some patients with FH mutations may develop collecting duct renal cell carcinoma. The main focus of management in HLRCC is prevention of disease and death due to renal cancer (summary by <a href="#6" class="mim-tip-reference" title="Gardie, B., Remenieras, A., Kattygnarath, D., Bombled, J., Lefevre, S., Perrier-Trudova, V., Rustin, P., Barrois, M., Slama, A., Avril, M.-F., Bessis, D., Caron, O., and 41 others. <strong>Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.</strong> J. Med. Genet. 48: 226-234, 2011. Note: Erratum: J. Med. Genet. 48: 576 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21398687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21398687</a>] [<a href="https://doi.org/10.1136/jmg.2010.085068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21398687">Gardie et al., 2011</a>; <a href="#19" class="mim-tip-reference" title="Smit, D. L., Mensenkamp, A. R., Badeloe, S., Breuning, M. H., Simon, M. E. H., van Spaendonck, K. Y., Aalfs, C. M., Post, J. G., Shanley, S., Krapels, I. P. C., Hoefsloot, L. H., van Moorselaar, R. J. A., Starink, T. M., Bayley, J.-P., Frank, J., van Steensel, M. A. M., Menko, F. H. <strong>Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis.</strong> Clin. Genet. 79: 49-59, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20618355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20618355</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01486.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20618355">Smit et al., 2011</a>; and <a href="#12" class="mim-tip-reference" title="Lehtonen, H. J. <strong>Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics.</strong> Familial Cancer 10: 397-411, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21404119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21404119</a>] [<a href="https://doi.org/10.1007/s10689-011-9428-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21404119">Lehtonen, 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20618355+21398687+21404119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a general discussion of papillary renal cell carcinoma, see RCCP1 (<a href="/entry/605074">605074</a>).</p>
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<p><a href="#10" class="mim-tip-reference" title="Kloepfer, H. W., Krafchuk, J., Derbes, V., Burks, J. <strong>Hereditary multiple leiomyoma of the skin.</strong> Am. J. Hum. Genet. 10: 48-52, 1958.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13520698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13520698</a>]" pmid="13520698">Kloepfer et al. (1958)</a> described 3 Italian half first cousins with multiple leiomyomata of the skin. The parents and common grandparent were not known to be affected, but all critical individuals were not examined. The skin tumors were composed of smooth muscle fibers and were thought to arise from the erector pilorum muscles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13520698" 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="Rudner, E. J., Schwartz, O. D., Grekin, J. N. <strong>Multiple cutaneous leiomyoma in identical twins.</strong> Arch. Derm. 90: 81-82, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14149729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14149729</a>] [<a href="https://doi.org/10.1001/archderm.1964.01600010087018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14149729">Rudner et al. (1964)</a> described identical twins with multiple cutaneous leiomyomata and a history of hysterectomy for uterine leiomyomata. <a href="#13" class="mim-tip-reference" title="Mezzadra, G. <strong>Leiomioma cutaneo multiplo ereditario. Studio di un caso sistematizzato in soggetto maschile appartenente a famiglia portatrice di leiomiomatosi cutanea e fibromiomatosi uterina.</strong> Minerva Derm. 40: 388-393, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5855898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5855898</a>]" pmid="5855898">Mezzadra (1965)</a> described 3 generations of an Italian family with cutaneous leiomyomata associated with uterine myomata. <a href="#15" class="mim-tip-reference" title="Reed, W. B., Walker, R., Horowitz, R. <strong>Cutaneous leiomyomata with uterine leiomyomata.</strong> Acta Derm. Venerol. 53: 409-416, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4127477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4127477</a>]" pmid="4127477">Reed et al. (1973)</a> also emphasized the association of uterine myomata. <a href="#4" class="mim-tip-reference" title="Engelke, H., Christophers, E. <strong>Leiomyomatosis cutis et uteri.</strong> Acta Derm. Venerol. 59 (suppl. 85): 51-54, 1979."None>Engelke and Christophers (1979)</a> commented on the unusually early age of onset of uterine myofibromas. <a href="#7" class="mim-tip-reference" title="Guillet, G., Grau, P., Sassolas, B., Zagnoli, A., Leroy, J. P., Labouche, F. <strong>Leiomyomes cutanes multiples et fibromes uterins: a propos d'une observation d'un cas non familial.</strong> Semin. Hop. Paris 63: 65-67, 1987."None>Guillet et al. (1987)</a> described a nonfamilial case of associated multiple cutaneous leiomyomas and uterine fibromas. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5855898+14149729+4127477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Launonen, V., Vierimaa, O., Kiuru, M., Isola, J., Roth, S., Pukkala, E., Sistonen, P., Herva, R., Aaltonen, L. A. <strong>Inherited susceptibility to uterine leiomyomas and renal cell cancer.</strong> Proc. Nat. Acad. Sci. 98: 3387-3392, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11248088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11248088</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11248088[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/10.1073/pnas.051633798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11248088">Launonen et al. (2001)</a> reported the clinical, histopathologic, and molecular features of a cancer syndrome with predisposition to uterine leiomyomas and papillary renal cell carcinoma. In the Finnish family they studied, 11 members had uterine leiomyomas and 2 had uterine leiomyosarcoma. Seven individuals had a history of cutaneous nodules, 2 of which were confirmed to be cutaneous leiomyomatosis. The 4 kidney cancer cases occurred in young (33- to 48-year-old) females and displayed a unique natural history. All these kidney cancers displayed a distinct papillary histology and presented as unilateral solitary lesions that had metastasized at the time of diagnosis. A second, smaller family was also studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11248088" 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 55-year-old man with HLRCC and an N64T mutation in the FH gene (<a href="/entry/136850#0004">136850.0004</a>), <a href="#3" class="mim-tip-reference" title="Carvajal-Carmona, L. G., Alam, N. A., Pollard, P. J., Jones, A. M., Barclay, E., Wortham, N., Pignatelli, M., Freeman, A., Pomplun, S., Ellis, I., Poulsom, R., El-Bahrawy, M. A., Berney, D. M., Tomlinson, I. P. M. <strong>Adult Leydig cell tumors of the testis caused by germline fumarate hydratase mutations.</strong> J. Clin. Endocr. Metab. 91: 3071-3075, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16757530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16757530</a>] [<a href="https://doi.org/10.1210/jc.2006-0183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16757530">Carvajal-Carmona et al. (2006)</a> identified a Leydig cell tumor of the testis. They suggested that this was part of the phenotypic spectrum of HLRCC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16757530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>As part of the French National Cancer Institute study, <a href="#6" class="mim-tip-reference" title="Gardie, B., Remenieras, A., Kattygnarath, D., Bombled, J., Lefevre, S., Perrier-Trudova, V., Rustin, P., Barrois, M., Slama, A., Avril, M.-F., Bessis, D., Caron, O., and 41 others. <strong>Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.</strong> J. Med. Genet. 48: 226-234, 2011. Note: Erratum: J. Med. Genet. 48: 576 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21398687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21398687</a>] [<a href="https://doi.org/10.1136/jmg.2010.085068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21398687">Gardie et al. (2011)</a> identified 44 families with genetically-confirmed HLRCC. Cutaneous leiomyomas occurred in 37 (84.1%) of 44 families and in 102 (67.5%) of 151 affected members. Uterine leiomyomas occurred in 32 families and in 76 (81.7%) of 93 female affected members; renal tumors occurred in 15 (34%) families and in 27 (17.9%) of 151 affected members. The average age at diagnosis of renal cell carcinoma was 43 years (range, 28 to 70 years). Twenty (74.1%) of 27 patient died of metastatic renal cell carcinoma. Four patients had isolated type 2 papillary renal cell carcinoma, indicating that this can be a sole manifestation of the disorder. There was significant intrafamilial variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21398687" 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 retrospective study, <a href="#19" class="mim-tip-reference" title="Smit, D. L., Mensenkamp, A. R., Badeloe, S., Breuning, M. H., Simon, M. E. H., van Spaendonck, K. Y., Aalfs, C. M., Post, J. G., Shanley, S., Krapels, I. P. C., Hoefsloot, L. H., van Moorselaar, R. J. A., Starink, T. M., Bayley, J.-P., Frank, J., van Steensel, M. A. M., Menko, F. H. <strong>Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis.</strong> Clin. Genet. 79: 49-59, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20618355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20618355</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01486.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20618355">Smit et al. (2011)</a> analyzed 14 families from the Netherlands with genetically-confirmed HLRCC. There was intrafamilial variability, but all families had at least 1 member with multiple cutaneous piloleiomyomas, which manifested between the second and fourth decade of life. These skin lesions tended to grow in size and number over time, and about 75% of patients reported pain or itching. Uterine leiomyomas occurred in 17 of 21 mutation carriers, with most (86%) occurring before 40 years of age. Renal cell cancer occurred in 1 member of 2 unrelated families: 1 patient had type 2 papillary renal cell carcinoma at age 30 years, and the other had a Wilms tumor at age 2, although it was unclear if this was related. A patient in a third family had reportedly died of metastatic renal cancer at age 21. Three mutation carriers had other malignancies: 2 with basal cell carcinoma and 1 with leukemia. One patient had an incidental adrenal adenoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20618355" 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>Based on an Italian family with multiple leiomyomata of the skin, <a href="#10" class="mim-tip-reference" title="Kloepfer, H. W., Krafchuk, J., Derbes, V., Burks, J. <strong>Hereditary multiple leiomyoma of the skin.</strong> Am. J. Hum. Genet. 10: 48-52, 1958.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13520698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13520698</a>]" pmid="13520698">Kloepfer et al. (1958)</a> suggested autosomal dominant inheritance with reduced penetrance. Dominant inheritance with incomplete penetrance was supported by the pedigree of <a href="#13" class="mim-tip-reference" title="Mezzadra, G. <strong>Leiomioma cutaneo multiplo ereditario. Studio di un caso sistematizzato in soggetto maschile appartenente a famiglia portatrice di leiomiomatosi cutanea e fibromiomatosi uterina.</strong> Minerva Derm. 40: 388-393, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5855898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5855898</a>]" pmid="5855898">Mezzadra (1965)</a>, who described cutaneous leiomyomata associated with uterine myomata in 3 generations of an Italian family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13520698+5855898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Weilbaecher, R. G. <strong>Personal Communication.</strong> New Orleans, La. 1967."None>Weilbaecher (1967)</a> observed a Swedish family with 5 affected members in 3 generations and male-to-male transmission.</p><p>Autosomal dominant skin disorders sometimes become manifest in a mosaic form, involving the body in a linear, patchy, or otherwise circumscribed arrangement. Such cases can be explained by an early postzygotic mutation. The segmental lesions usually show the same degree of severity as that found in the corresponding nonmosaic trait, which <a href="#8" class="mim-tip-reference" title="Happle, R. <strong>A rule concerning the segmental manifestation of autosomal dominant skin disorders: review of clinical examples providing evidence for dichotomous types of severity.</strong> Arch. Derm. 133: 1505-1509, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9420534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9420534</a>]" pmid="9420534">Happle (1997)</a> referred to as type 1 segmental involvement. Occasionally, however, the intensity of involvement observed in the circumscribed area is far more pronounced. <a href="#8" class="mim-tip-reference" title="Happle, R. <strong>A rule concerning the segmental manifestation of autosomal dominant skin disorders: review of clinical examples providing evidence for dichotomous types of severity.</strong> Arch. Derm. 133: 1505-1509, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9420534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9420534</a>]" pmid="9420534">Happle (1997)</a> suggested that this phenomenon can be explained by the loss of heterozygosity (LOH) at the same locus that caused the less severe, diffuse involvement. <a href="#8" class="mim-tip-reference" title="Happle, R. <strong>A rule concerning the segmental manifestation of autosomal dominant skin disorders: review of clinical examples providing evidence for dichotomous types of severity.</strong> Arch. Derm. 133: 1505-1509, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9420534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9420534</a>]" pmid="9420534">Happle (1997)</a> pointed to cutaneous leiomyomatosis as an autosomal dominant disorder in which sporadic cases of segmental leiomyomatosis had been reported by many authors. He referred to this involvement as type 1. He pointed to several families affected with cutaneous leiomyomatosis in which there was superimposed severe segmental leiomyomatosis, providing evidence of type 2 involvement. Sporadic cases showing both severe segmental and ordinary disseminated lesions can be best explained as examples of type 2 involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9420534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The transmission pattern of uterine leiomyomas and renal cell cancer in the families studied by <a href="#11" class="mim-tip-reference" title="Launonen, V., Vierimaa, O., Kiuru, M., Isola, J., Roth, S., Pukkala, E., Sistonen, P., Herva, R., Aaltonen, L. A. <strong>Inherited susceptibility to uterine leiomyomas and renal cell cancer.</strong> Proc. Nat. Acad. Sci. 98: 3387-3392, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11248088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11248088</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11248088[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/10.1073/pnas.051633798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11248088">Launonen et al. (2001)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11248088" 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="#19" class="mim-tip-reference" title="Smit, D. L., Mensenkamp, A. R., Badeloe, S., Breuning, M. H., Simon, M. E. H., van Spaendonck, K. Y., Aalfs, C. M., Post, J. G., Shanley, S., Krapels, I. P. C., Hoefsloot, L. H., van Moorselaar, R. J. A., Starink, T. M., Bayley, J.-P., Frank, J., van Steensel, M. A. M., Menko, F. H. <strong>Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis.</strong> Clin. Genet. 79: 49-59, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20618355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20618355</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01486.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20618355">Smit et al. (2011)</a> proposed criteria for the clinical diagnosis of HLRCC. The major criterion is multiple cutaneous piloleiomyomas; minor criteria include severely symptomatic early-onset uterine leiomyomas, type 2 papillary renal carcinoma before age 40, and a first-degree relative who meets 1 of the these criteria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20618355" 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="#9" class="mim-tip-reference" title="Kiuru, M., Launonen, V., Hietala, M., Aittomaki, K., Vierimaa, O., Salovaara, R., Arola, J., Pukkala, E., Sistonen, P., Herva, R., Aaltonen, L. A. <strong>Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology.</strong> Am. J. Path. 159: 825-829, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549574</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11549574[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S0002-9440(10)61757-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11549574">Kiuru et al. (2001)</a> concluded that familial cutaneous leiomyomatosis is a 2-hit condition associated with renal cell carcinoma with characteristic histopathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549574" 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="#14" class="mim-tip-reference" title="Pithukpakorn, M., Wei, M.-H., Toure, O., Steinbach, P. J., Glenn, G. M., Zbar, B., Linehan, W. M., Toro, J. R. <strong>Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer. (Letter)</strong> J. Med. Genet. 43: 755-762, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16597677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16597677</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16597677[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/10.1136/jmg.2006.041087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16597677">Pithukpakorn et al. (2006)</a> studied FH enzyme activity in the whole cell and in cytosolic, and mitochondrial fractions in 50 lymphoblastoid and 16 fibroblast cell lines including cell lines from individuals with HLRCC with 16 different mutations. Lower FH enzyme activity was observed in cells from individuals with HLRCC than in cells from normal controls. The enzyme activity in lymphoblastoid cell lines from 3 individuals with mutations in R190 was not significantly different from individuals with other missense mutations. Cell lines from other hereditary renal cancer syndromes showed FH enzyme levels not significantly different from those of control cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16597677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Alam, N. A., Bevan, S., Churchman, M., Barclay, E., Barker, K., Jaeger, E. E. M., Nelson, H. M., Healy, E., Pembroke, A. C., Friedmann, P. S., Dalziel, K., Calonje, E., and 12 others. <strong>Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43.</strong> Am. J. Hum. Genet. 68: 1264-1269, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11283798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11283798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11283798[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/10.1086/320124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11283798">Alam et al. (2001)</a> performed a genomewide screen of 11 families with this disorder and found linkage to 1q42.3-q43 (maximum multipoint lod score of 5.40). By haplotype construction and analysis of recombinations, they refined the minimal interval containing the locus, which they designated MCUL1 (multiple cutaneous and uterine leiomyomata), to a region of approximately 14 cM, flanked by markers D1S517 and D1S2842. Allelic loss studies of tumors indicated that MCUL1 may act as a tumor suppressor. <a href="#1" class="mim-tip-reference" title="Alam, N. A., Bevan, S., Churchman, M., Barclay, E., Barker, K., Jaeger, E. E. M., Nelson, H. M., Healy, E., Pembroke, A. C., Friedmann, P. S., Dalziel, K., Calonje, E., and 12 others. <strong>Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43.</strong> Am. J. Hum. Genet. 68: 1264-1269, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11283798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11283798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11283798[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/10.1086/320124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11283798">Alam et al. (2001)</a> suggested that the MCUL1 gene may harbor low-penetrance variants predisposing to the common form of uterine fibroids and/or may undergo somatic mutation in sporadic leiomyomata. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11283798" 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 genetic marker analysis, <a href="#11" class="mim-tip-reference" title="Launonen, V., Vierimaa, O., Kiuru, M., Isola, J., Roth, S., Pukkala, E., Sistonen, P., Herva, R., Aaltonen, L. A. <strong>Inherited susceptibility to uterine leiomyomas and renal cell cancer.</strong> Proc. Nat. Acad. Sci. 98: 3387-3392, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11248088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11248088</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11248088[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/10.1073/pnas.051633798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11248088">Launonen et al. (2001)</a> mapped the gene for hereditary susceptibility to uterine leiomyomas and renal cell cancer, which they called HLRCC, to 1q42-q44. They suggested that the HLRCC gene is likely to be a tumor suppressor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11248088" 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>Following up on the demonstration that both multiple leiomyoma and the leiomyomatosis/renal cell cancer syndrome maps to chromosome 1q42.3-q43, <a href="#20" class="mim-tip-reference" title="Tomlinson, I. P. M., Alam, N. A., Rowan, A. J., Barclay, E., Jaeger, E. E. M., Kelsell, D., Leigh, I., Gorman, P., Lamlum, H., Rahman, S., Roylance, R. R., Olpin, S., and 19 others. <strong>Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.</strong> Nature Genet. 30: 406-410, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11865300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11865300</a>] [<a href="https://doi.org/10.1038/ng849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11865300">Tomlinson et al. (2002)</a> identified 15 different heterozygous germline mutations in the FH gene (see, e.g., <a href="/entry/136850#0003">136850.0003</a>-<a href="/entry/136850#0006">136850.0006</a>) in 25 families with the disorder. Six families from the U.K. had the same mutation (N64T; <a href="/entry/136850#0004">136850.0004</a>). Activity of this enzyme of the tricarboxylic acid cycle was reduced in lymphoblastoid cells from individuals with leiomyomatosis. The enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity was very low or absent in tumors from individuals with leiomyomatosis, consistent with a Knudson 2-hit hypothesis. The results provided clues to the pathogenesis of fibroids and emphasized the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11865300" 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="#21" class="mim-tip-reference" title="Wei, M.-H., Toure, O., Glenn, G. M., Pithukpakorn, M., Neckers, L., Stolle, C., Choyke, P., Grubb, R., Middelton, L., Turner, M. L., Walther, M. M., Merino, M. J., Zbar, B., Linehan, W. M., Toro, J. R. <strong>Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.</strong> J. Med. Genet. 43: 18-27, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15937070[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/10.1136/jmg.2005.033506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937070">Wei et al. (2006)</a> identified 14 heterozygous mutations in the FH gene, including 9 novel mutations, in affected members of 13 families with HLRCC and 8 families with multiple cutaneous and uterine leiomyomata. Four unrelated families had the R58X mutation (<a href="/entry/136850#0003">136850.0003</a>), and 5 unrelated families had the R190H mutation (<a href="/entry/136850#0007">136850.0007</a>). Cutaneous leiomyomata were present in 16 (76%) of 21 families, ranging from mild to severe. All 22 female mutation carriers from 16 families had uterine fibroids. Renal tumors occurred in 13 (62%) of 21 families. No genotype/phenotype correlations were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15937070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>As part of the French National Cancer Institute study, <a href="#6" class="mim-tip-reference" title="Gardie, B., Remenieras, A., Kattygnarath, D., Bombled, J., Lefevre, S., Perrier-Trudova, V., Rustin, P., Barrois, M., Slama, A., Avril, M.-F., Bessis, D., Caron, O., and 41 others. <strong>Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.</strong> J. Med. Genet. 48: 226-234, 2011. Note: Erratum: J. Med. Genet. 48: 576 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21398687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21398687</a>] [<a href="https://doi.org/10.1136/jmg.2010.085068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21398687">Gardie et al. (2011)</a> identified 32 different heterozygous germline mutations in the FH gene, including 21 novel mutations, in 40 (71.4%) of 56 families with proven HLRCC. In addition, FH mutations were found in 4 (17.4%) of 23 probands with isolated type 2 papillary renal cell carcinoma, including 2 patients with no family history. In vitro functional expression studies showed that all mutations caused about a 50% decrease in FH enzymatic activity. In addition, there were 5 asymptomatic mutation carriers in 3 families, indicating incomplete penetrance. The findings indicated that renal call carcinoma can be the only manifestation of this disorder. No genotype/phenotype correlations were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21398687" 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="#18" class="mim-tip-reference" title="Shuch, B., Li, S., Risch, H., Bindra, R. S., McGillivray, P. D., Gerstein, M. <strong>Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer.</strong> Cancer 126: 3657-3666, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413184</a>] [<a href="https://doi.org/10.1002/cncr.32914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413184">Shuch et al. (2020)</a> analyzed available sequencing datasets to estimate the carrier frequency of FH mutations and to determine a lifetime penetrance of HLRCC kidney cancer risk. By analyzing FH sequencing data in the 1000 Genomes Project (1000GP) and ExAC databases, <a href="#18" class="mim-tip-reference" title="Shuch, B., Li, S., Risch, H., Bindra, R. S., McGillivray, P. D., Gerstein, M. <strong>Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer.</strong> Cancer 126: 3657-3666, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413184</a>] [<a href="https://doi.org/10.1002/cncr.32914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413184">Shuch et al. (2020)</a> generated 3 variant risk tiers based on the likelihood of deleterious consequences: variant tier 1 (VT1), including 'pathogenic' and 'likely pathogenic' mutations reported in ClinVar; variant tier 2 (VT2), including loss of function mutations (premature stop codons and stop loss and start loss variants); and variant tier 3 (VT3), including all missense mutations likely to have functional consequences. ExAC contained 11 FH alterations classified under VT1, with an overall carrier frequency of 0.000744, and none were identified in 1000GP. The frequency of VT1+VT2 FH alterations in ExAC was 0.00111 and in 1000GP was 0.0008. The frequency of VT1+VT2+VT3 FH alterations was 0.00254 in ExAC and 0.00120 in 1000GP. <a href="#18" class="mim-tip-reference" title="Shuch, B., Li, S., Risch, H., Bindra, R. S., McGillivray, P. D., Gerstein, M. <strong>Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer.</strong> Cancer 126: 3657-3666, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413184</a>] [<a href="https://doi.org/10.1002/cncr.32914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32413184">Shuch et al. (2020)</a> next estimated the annual number of renal cell cancer cases that were attributed to HLRCC (HLRCC/RCC) based on 3 distinct cohorts, and the estimates ranged from 0.4% to 1.41% of RCC cases. This provided an annual incidence of HLRCC/RCC ranging from 202 to 703 cases/year in the United States. Based on these estimates of the annual number of HLRCC/RCC cases and the frequency of VT1+VT2 variants, a lifetime penetrance of RCC in FH mutation carriers ranged from 3.9 to 12.8% based on data from ExAC and from 5.3 to 17.3% based on data from 1000GP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32413184" 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="#5" class="mim-tip-reference" title="Fryns, J. P., Haspeslagh, M., de Muelenaere, A., van den Berghe, H. <strong>9p trisomy/18p distal monosomy and multiple cutaneous leiomyomata: another specific chromosomal site (18pter) in dominantly inherited multiple tumors?</strong> Hum. Genet. 70: 284-286, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4018793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4018793</a>] [<a href="https://doi.org/10.1007/BF00273459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4018793">Fryns et al. (1985)</a> described a severely mentally retarded woman with 9p trisomy/18pter monosomy. The patient was judged to have phenotypic features typical of 9p trisomy (<a href="#16" class="mim-tip-reference" title="Rethore, M. O., Larget-Piet, L., Abonyi, D., Boeswillwald, M., Berger, P., Carpentier, S., Cruveiller, J., Dutrillaux, B., Lafourcade, J., Penneau, M., Lejeune, J. <strong>Sur quatre cas de trisomie pour le bras court du chromosome 9: individualisation d'une nouvelle entite morbide.</strong> Ann. Genet. 13: 217-232, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5313386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5313386</a>]" pmid="5313386">Rethore et al., 1970</a>) but she also had multiple cutaneous leiomyomata, of which some were nodular, some linear, and all looked rather like keloids. The authors raised the question of whether this was another example of a specific chromosomal deletion (18pter) in a dominantly inherited multiple tumor, like retinoblastoma and nephroblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5313386+4018793" 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="#Berendes1971" class="mim-tip-reference" title="Berendes, U., Kuhner, A., Schnyder, U. W. <strong>Segmentary and disseminated lesions in multiple hereditary cutaneous leiomyoma.</strong> Humangenetik 13: 81-82, 1971.">Berendes et al. (1971)</a>
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Alam, N. A., Bevan, S., Churchman, M., Barclay, E., Barker, K., Jaeger, E. E. M., Nelson, H. M., Healy, E., Pembroke, A. C., Friedmann, P. S., Dalziel, K., Calonje, E., and 12 others.
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<strong>Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43.</strong>
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Am. J. Hum. Genet. 68: 1264-1269, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11283798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11283798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11283798[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=11283798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/320124" target="_blank">Full Text</a>]
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Berendes, U., Kuhner, A., Schnyder, U. W.
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<strong>Segmentary and disseminated lesions in multiple hereditary cutaneous leiomyoma.</strong>
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Humangenetik 13: 81-82, 1971.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5115893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5115893</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5115893" 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/BF00446422" target="_blank">Full Text</a>]
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Carvajal-Carmona, L. G., Alam, N. A., Pollard, P. J., Jones, A. M., Barclay, E., Wortham, N., Pignatelli, M., Freeman, A., Pomplun, S., Ellis, I., Poulsom, R., El-Bahrawy, M. A., Berney, D. M., Tomlinson, I. P. M.
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<strong>Adult Leydig cell tumors of the testis caused by germline fumarate hydratase mutations.</strong>
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J. Clin. Endocr. Metab. 91: 3071-3075, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16757530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16757530</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16757530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2006-0183" target="_blank">Full Text</a>]
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Engelke, H., Christophers, E.
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<strong>Leiomyomatosis cutis et uteri.</strong>
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Acta Derm. Venerol. 59 (suppl. 85): 51-54, 1979.
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Fryns, J. P., Haspeslagh, M., de Muelenaere, A., van den Berghe, H.
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<strong>9p trisomy/18p distal monosomy and multiple cutaneous leiomyomata: another specific chromosomal site (18pter) in dominantly inherited multiple tumors?</strong>
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Hum. Genet. 70: 284-286, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4018793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4018793</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4018793" 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/BF00273459" target="_blank">Full Text</a>]
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Gardie, B., Remenieras, A., Kattygnarath, D., Bombled, J., Lefevre, S., Perrier-Trudova, V., Rustin, P., Barrois, M., Slama, A., Avril, M.-F., Bessis, D., Caron, O., and 41 others.
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<strong>Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.</strong>
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J. Med. Genet. 48: 226-234, 2011. Note: Erratum: J. Med. Genet. 48: 576 only, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21398687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21398687</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21398687" 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.2010.085068" target="_blank">Full Text</a>]
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Guillet, G., Grau, P., Sassolas, B., Zagnoli, A., Leroy, J. P., Labouche, F.
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<strong>Leiomyomes cutanes multiples et fibromes uterins: a propos d'une observation d'un cas non familial.</strong>
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Happle, R.
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<strong>A rule concerning the segmental manifestation of autosomal dominant skin disorders: review of clinical examples providing evidence for dichotomous types of severity.</strong>
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Arch. Derm. 133: 1505-1509, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9420534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9420534</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9420534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Kiuru, M., Launonen, V., Hietala, M., Aittomaki, K., Vierimaa, O., Salovaara, R., Arola, J., Pukkala, E., Sistonen, P., Herva, R., Aaltonen, L. A.
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<strong>Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11549574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11549574</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11549574[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=11549574" 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/S0002-9440(10)61757-9" target="_blank">Full Text</a>]
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Kloepfer, H. W., Krafchuk, J., Derbes, V., Burks, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13520698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13520698</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13520698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Launonen, V., Vierimaa, O., Kiuru, M., Isola, J., Roth, S., Pukkala, E., Sistonen, P., Herva, R., Aaltonen, L. A.
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<strong>Inherited susceptibility to uterine leiomyomas and renal cell cancer.</strong>
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Proc. Nat. Acad. Sci. 98: 3387-3392, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11248088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11248088</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11248088[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=11248088" 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/10.1073/pnas.051633798" target="_blank">Full Text</a>]
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<a id="Lehtonen2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lehtonen, H. J.
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<strong>Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics.</strong>
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Familial Cancer 10: 397-411, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21404119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21404119</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21404119" 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/s10689-011-9428-z" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Mezzadra1965" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mezzadra, G.
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<strong>Leiomioma cutaneo multiplo ereditario. Studio di un caso sistematizzato in soggetto maschile appartenente a famiglia portatrice di leiomiomatosi cutanea e fibromiomatosi uterina.</strong>
|
|
Minerva Derm. 40: 388-393, 1965.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5855898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5855898</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5855898" 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="14" class="mim-anchor"></a>
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<a id="Pithukpakorn2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pithukpakorn, M., Wei, M.-H., Toure, O., Steinbach, P. J., Glenn, G. M., Zbar, B., Linehan, W. M., Toro, J. R.
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|
<strong>Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer. (Letter)</strong>
|
|
J. Med. Genet. 43: 755-762, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16597677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16597677</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16597677[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=16597677" 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.2006.041087" target="_blank">Full Text</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="15" class="mim-anchor"></a>
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<a id="Reed1973" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Reed, W. B., Walker, R., Horowitz, R.
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|
<strong>Cutaneous leiomyomata with uterine leiomyomata.</strong>
|
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Acta Derm. Venerol. 53: 409-416, 1973.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4127477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4127477</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4127477" 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="16" class="mim-anchor"></a>
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<a id="Rethore1970" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rethore, M. O., Larget-Piet, L., Abonyi, D., Boeswillwald, M., Berger, P., Carpentier, S., Cruveiller, J., Dutrillaux, B., Lafourcade, J., Penneau, M., Lejeune, J.
|
|
<strong>Sur quatre cas de trisomie pour le bras court du chromosome 9: individualisation d'une nouvelle entite morbide.</strong>
|
|
Ann. Genet. 13: 217-232, 1970.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5313386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5313386</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5313386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="17" class="mim-anchor"></a>
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<a id="Rudner1964" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rudner, E. J., Schwartz, O. D., Grekin, J. N.
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<strong>Multiple cutaneous leiomyoma in identical twins.</strong>
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Arch. Derm. 90: 81-82, 1964.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14149729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14149729</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14149729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archderm.1964.01600010087018" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Shuch2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shuch, B., Li, S., Risch, H., Bindra, R. S., McGillivray, P. D., Gerstein, M.
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<strong>Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer.</strong>
|
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Cancer 126: 3657-3666, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32413184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32413184</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32413184" 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/cncr.32914" target="_blank">Full Text</a>]
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Smit2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Smit, D. L., Mensenkamp, A. R., Badeloe, S., Breuning, M. H., Simon, M. E. H., van Spaendonck, K. Y., Aalfs, C. M., Post, J. G., Shanley, S., Krapels, I. P. C., Hoefsloot, L. H., van Moorselaar, R. J. A., Starink, T. M., Bayley, J.-P., Frank, J., van Steensel, M. A. M., Menko, F. H.
|
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<strong>Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis.</strong>
|
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Clin. Genet. 79: 49-59, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20618355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20618355</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20618355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2010.01486.x" target="_blank">Full Text</a>]
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</p>
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<a id="20" class="mim-anchor"></a>
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<a id="Tomlinson2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tomlinson, I. P. M., Alam, N. A., Rowan, A. J., Barclay, E., Jaeger, E. E. M., Kelsell, D., Leigh, I., Gorman, P., Lamlum, H., Rahman, S., Roylance, R. R., Olpin, S., and 19 others.
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<strong>Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.</strong>
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Nature Genet. 30: 406-410, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11865300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11865300</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11865300" 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/10.1038/ng849" target="_blank">Full Text</a>]
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<a id="21" class="mim-anchor"></a>
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<a id="Wei2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wei, M.-H., Toure, O., Glenn, G. M., Pithukpakorn, M., Neckers, L., Stolle, C., Choyke, P., Grubb, R., Middelton, L., Turner, M. L., Walther, M. M., Merino, M. J., Zbar, B., Linehan, W. M., Toro, J. R.
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<strong>Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.</strong>
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J. Med. Genet. 43: 18-27, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15937070[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=15937070" 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.2005.033506" target="_blank">Full Text</a>]
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<a id="22" class="mim-anchor"></a>
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<a id="Weilbaecher1967" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weilbaecher, R. G.
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<strong>Personal Communication.</strong>
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New Orleans, La. 1967.
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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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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Hilary J. Vernon - updated : 11/16/2020
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 8/11/2011<br>Cassandra L. Kniffin - updated : 2/13/2006<br>Victor A. McKusick - updated : 2/28/2002<br>Victor A. McKusick - updated : 6/5/2001<br>Victor A. McKusick - updated : 8/5/1999
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<a id="creationDate" class="mim-anchor"></a>
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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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<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 : 6/2/1986
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</span>
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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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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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carol : 11/16/2020
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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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carol : 11/16/2017<br>carol : 12/23/2015<br>carol : 3/12/2015<br>carol : 9/15/2011<br>ckniffin : 9/13/2011<br>wwang : 8/16/2011<br>ckniffin : 8/11/2011<br>wwang : 3/1/2006<br>ckniffin : 2/13/2006<br>alopez : 6/7/2002<br>carol : 4/4/2002<br>ckniffin : 4/4/2002<br>alopez : 3/18/2002<br>alopez : 3/1/2002<br>terry : 2/28/2002<br>cwells : 6/13/2001<br>carol : 6/13/2001<br>cwells : 6/8/2001<br>terry : 6/5/2001<br>jlewis : 8/25/1999<br>terry : 8/5/1999<br>carol : 5/18/1999<br>terry : 5/3/1999<br>mimadm : 11/5/1994<br>supermim : 3/16/1992<br>supermim : 3/24/1990<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>root : 12/15/1988
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</span>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 150800
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER; HLRCC
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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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<span class="mim-font">
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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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MULTIPLE CUTANEOUS AND UTERINE LEIOMYOMATA 1, WITH OR WITHOUT RENAL CELL CARCINOMA; MCUL1<br />
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LEIOMYOMATOSIS AND RENAL CELL CANCER, HEREDITARY; LRCC<br />
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LEIOMYOMA, MULTIPLE CUTANEOUS; MCL
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</span>
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</h4>
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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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1162799008;
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<strong>ORPHA:</strong> 523;
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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>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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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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1q43
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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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Leiomyomatosis and renal cell cancer
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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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150800
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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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FH
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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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136850
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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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<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>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 multiple cutaneous and uterine leiomyomatosis with or without renal cell carcinoma, also referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC), is caused by heterozygous mutation in the gene encoding fumarate hydratase (FH; 136850) on chromosome 1q43.</p><p>Homozygous mutation in the FH gene causes fumarase deficiency (FMRD; 606812).</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>Description</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>Hereditary leiomyomatosis and renal cell cancer is an autosomal dominant tumor predisposition syndrome characterized by the variable development of 3 tumors: cutaneous piloleiomyomata that develop in essentially all patients by age 40 years; leiomyomata (fibroids) of the uterus, and rarely leiomyosarcomas, at a mean age of 30 years (range, 18 to 52 years); and type 2 papillary renal cell carcinoma at a mean age of 46 years (range, 17 to 75 years), which occurs in about 20% of patients. Type 2 papillary renal cell carcinoma is a pathologic subtype characterized by large tumor cells with eosinophilic cytoplasm and pseudostratified nuclei; it shows an aggressive clinical course. Some patients with FH mutations may develop collecting duct renal cell carcinoma. The main focus of management in HLRCC is prevention of disease and death due to renal cancer (summary by Gardie et al., 2011; Smit et al., 2011; and Lehtonen, 2011). </p><p>For a general discussion of papillary renal cell carcinoma, see RCCP1 (605074).</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>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>Kloepfer et al. (1958) described 3 Italian half first cousins with multiple leiomyomata of the skin. The parents and common grandparent were not known to be affected, but all critical individuals were not examined. The skin tumors were composed of smooth muscle fibers and were thought to arise from the erector pilorum muscles. </p><p>Rudner et al. (1964) described identical twins with multiple cutaneous leiomyomata and a history of hysterectomy for uterine leiomyomata. Mezzadra (1965) described 3 generations of an Italian family with cutaneous leiomyomata associated with uterine myomata. Reed et al. (1973) also emphasized the association of uterine myomata. Engelke and Christophers (1979) commented on the unusually early age of onset of uterine myofibromas. Guillet et al. (1987) described a nonfamilial case of associated multiple cutaneous leiomyomas and uterine fibromas. </p><p>Launonen et al. (2001) reported the clinical, histopathologic, and molecular features of a cancer syndrome with predisposition to uterine leiomyomas and papillary renal cell carcinoma. In the Finnish family they studied, 11 members had uterine leiomyomas and 2 had uterine leiomyosarcoma. Seven individuals had a history of cutaneous nodules, 2 of which were confirmed to be cutaneous leiomyomatosis. The 4 kidney cancer cases occurred in young (33- to 48-year-old) females and displayed a unique natural history. All these kidney cancers displayed a distinct papillary histology and presented as unilateral solitary lesions that had metastasized at the time of diagnosis. A second, smaller family was also studied. </p><p>In a 55-year-old man with HLRCC and an N64T mutation in the FH gene (136850.0004), Carvajal-Carmona et al. (2006) identified a Leydig cell tumor of the testis. They suggested that this was part of the phenotypic spectrum of HLRCC. </p><p>As part of the French National Cancer Institute study, Gardie et al. (2011) identified 44 families with genetically-confirmed HLRCC. Cutaneous leiomyomas occurred in 37 (84.1%) of 44 families and in 102 (67.5%) of 151 affected members. Uterine leiomyomas occurred in 32 families and in 76 (81.7%) of 93 female affected members; renal tumors occurred in 15 (34%) families and in 27 (17.9%) of 151 affected members. The average age at diagnosis of renal cell carcinoma was 43 years (range, 28 to 70 years). Twenty (74.1%) of 27 patient died of metastatic renal cell carcinoma. Four patients had isolated type 2 papillary renal cell carcinoma, indicating that this can be a sole manifestation of the disorder. There was significant intrafamilial variability. </p><p>In a retrospective study, Smit et al. (2011) analyzed 14 families from the Netherlands with genetically-confirmed HLRCC. There was intrafamilial variability, but all families had at least 1 member with multiple cutaneous piloleiomyomas, which manifested between the second and fourth decade of life. These skin lesions tended to grow in size and number over time, and about 75% of patients reported pain or itching. Uterine leiomyomas occurred in 17 of 21 mutation carriers, with most (86%) occurring before 40 years of age. Renal cell cancer occurred in 1 member of 2 unrelated families: 1 patient had type 2 papillary renal cell carcinoma at age 30 years, and the other had a Wilms tumor at age 2, although it was unclear if this was related. A patient in a third family had reportedly died of metastatic renal cancer at age 21. Three mutation carriers had other malignancies: 2 with basal cell carcinoma and 1 with leukemia. One patient had an incidental adrenal adenoma. </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>Based on an Italian family with multiple leiomyomata of the skin, Kloepfer et al. (1958) suggested autosomal dominant inheritance with reduced penetrance. Dominant inheritance with incomplete penetrance was supported by the pedigree of Mezzadra (1965), who described cutaneous leiomyomata associated with uterine myomata in 3 generations of an Italian family. </p><p>Weilbaecher (1967) observed a Swedish family with 5 affected members in 3 generations and male-to-male transmission.</p><p>Autosomal dominant skin disorders sometimes become manifest in a mosaic form, involving the body in a linear, patchy, or otherwise circumscribed arrangement. Such cases can be explained by an early postzygotic mutation. The segmental lesions usually show the same degree of severity as that found in the corresponding nonmosaic trait, which Happle (1997) referred to as type 1 segmental involvement. Occasionally, however, the intensity of involvement observed in the circumscribed area is far more pronounced. Happle (1997) suggested that this phenomenon can be explained by the loss of heterozygosity (LOH) at the same locus that caused the less severe, diffuse involvement. Happle (1997) pointed to cutaneous leiomyomatosis as an autosomal dominant disorder in which sporadic cases of segmental leiomyomatosis had been reported by many authors. He referred to this involvement as type 1. He pointed to several families affected with cutaneous leiomyomatosis in which there was superimposed severe segmental leiomyomatosis, providing evidence of type 2 involvement. Sporadic cases showing both severe segmental and ordinary disseminated lesions can be best explained as examples of type 2 involvement. </p><p>The transmission pattern of uterine leiomyomas and renal cell cancer in the families studied by Launonen et al. (2001) was consistent with autosomal dominant inheritance. </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>Diagnosis</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>Smit et al. (2011) proposed criteria for the clinical diagnosis of HLRCC. The major criterion is multiple cutaneous piloleiomyomas; minor criteria include severely symptomatic early-onset uterine leiomyomas, type 2 papillary renal carcinoma before age 40, and a first-degree relative who meets 1 of the these criteria. </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>Pathogenesis</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>Kiuru et al. (2001) concluded that familial cutaneous leiomyomatosis is a 2-hit condition associated with renal cell carcinoma with characteristic histopathology. </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>Biochemical 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">
|
|
<p>Pithukpakorn et al. (2006) studied FH enzyme activity in the whole cell and in cytosolic, and mitochondrial fractions in 50 lymphoblastoid and 16 fibroblast cell lines including cell lines from individuals with HLRCC with 16 different mutations. Lower FH enzyme activity was observed in cells from individuals with HLRCC than in cells from normal controls. The enzyme activity in lymphoblastoid cell lines from 3 individuals with mutations in R190 was not significantly different from individuals with other missense mutations. Cell lines from other hereditary renal cancer syndromes showed FH enzyme levels not significantly different from those of control cell lines. </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>Mapping</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>Alam et al. (2001) performed a genomewide screen of 11 families with this disorder and found linkage to 1q42.3-q43 (maximum multipoint lod score of 5.40). By haplotype construction and analysis of recombinations, they refined the minimal interval containing the locus, which they designated MCUL1 (multiple cutaneous and uterine leiomyomata), to a region of approximately 14 cM, flanked by markers D1S517 and D1S2842. Allelic loss studies of tumors indicated that MCUL1 may act as a tumor suppressor. Alam et al. (2001) suggested that the MCUL1 gene may harbor low-penetrance variants predisposing to the common form of uterine fibroids and/or may undergo somatic mutation in sporadic leiomyomata. </p><p>By genetic marker analysis, Launonen et al. (2001) mapped the gene for hereditary susceptibility to uterine leiomyomas and renal cell cancer, which they called HLRCC, to 1q42-q44. They suggested that the HLRCC gene is likely to be a tumor suppressor. </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>Following up on the demonstration that both multiple leiomyoma and the leiomyomatosis/renal cell cancer syndrome maps to chromosome 1q42.3-q43, Tomlinson et al. (2002) identified 15 different heterozygous germline mutations in the FH gene (see, e.g., 136850.0003-136850.0006) in 25 families with the disorder. Six families from the U.K. had the same mutation (N64T; 136850.0004). Activity of this enzyme of the tricarboxylic acid cycle was reduced in lymphoblastoid cells from individuals with leiomyomatosis. The enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity was very low or absent in tumors from individuals with leiomyomatosis, consistent with a Knudson 2-hit hypothesis. The results provided clues to the pathogenesis of fibroids and emphasized the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumors. </p><p>Wei et al. (2006) identified 14 heterozygous mutations in the FH gene, including 9 novel mutations, in affected members of 13 families with HLRCC and 8 families with multiple cutaneous and uterine leiomyomata. Four unrelated families had the R58X mutation (136850.0003), and 5 unrelated families had the R190H mutation (136850.0007). Cutaneous leiomyomata were present in 16 (76%) of 21 families, ranging from mild to severe. All 22 female mutation carriers from 16 families had uterine fibroids. Renal tumors occurred in 13 (62%) of 21 families. No genotype/phenotype correlations were identified. </p><p>As part of the French National Cancer Institute study, Gardie et al. (2011) identified 32 different heterozygous germline mutations in the FH gene, including 21 novel mutations, in 40 (71.4%) of 56 families with proven HLRCC. In addition, FH mutations were found in 4 (17.4%) of 23 probands with isolated type 2 papillary renal cell carcinoma, including 2 patients with no family history. In vitro functional expression studies showed that all mutations caused about a 50% decrease in FH enzymatic activity. In addition, there were 5 asymptomatic mutation carriers in 3 families, indicating incomplete penetrance. The findings indicated that renal call carcinoma can be the only manifestation of this disorder. No genotype/phenotype correlations were identified. </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>Population 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>Shuch et al. (2020) analyzed available sequencing datasets to estimate the carrier frequency of FH mutations and to determine a lifetime penetrance of HLRCC kidney cancer risk. By analyzing FH sequencing data in the 1000 Genomes Project (1000GP) and ExAC databases, Shuch et al. (2020) generated 3 variant risk tiers based on the likelihood of deleterious consequences: variant tier 1 (VT1), including 'pathogenic' and 'likely pathogenic' mutations reported in ClinVar; variant tier 2 (VT2), including loss of function mutations (premature stop codons and stop loss and start loss variants); and variant tier 3 (VT3), including all missense mutations likely to have functional consequences. ExAC contained 11 FH alterations classified under VT1, with an overall carrier frequency of 0.000744, and none were identified in 1000GP. The frequency of VT1+VT2 FH alterations in ExAC was 0.00111 and in 1000GP was 0.0008. The frequency of VT1+VT2+VT3 FH alterations was 0.00254 in ExAC and 0.00120 in 1000GP. Shuch et al. (2020) next estimated the annual number of renal cell cancer cases that were attributed to HLRCC (HLRCC/RCC) based on 3 distinct cohorts, and the estimates ranged from 0.4% to 1.41% of RCC cases. This provided an annual incidence of HLRCC/RCC ranging from 202 to 703 cases/year in the United States. Based on these estimates of the annual number of HLRCC/RCC cases and the frequency of VT1+VT2 variants, a lifetime penetrance of RCC in FH mutation carriers ranged from 3.9 to 12.8% based on data from ExAC and from 5.3 to 17.3% based on data from 1000GP. </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>Fryns et al. (1985) described a severely mentally retarded woman with 9p trisomy/18pter monosomy. The patient was judged to have phenotypic features typical of 9p trisomy (Rethore et al., 1970) but she also had multiple cutaneous leiomyomata, of which some were nodular, some linear, and all looked rather like keloids. The authors raised the question of whether this was another example of a specific chromosomal deletion (18pter) in a dominantly inherited multiple tumor, like retinoblastoma and nephroblastoma. </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>
|
|
<span class="mim-text-font">
|
|
Berendes et al. (1971)
|
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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">
|
|
<strong>REFERENCES</strong>
|
|
</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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Alam, N. A., Bevan, S., Churchman, M., Barclay, E., Barker, K., Jaeger, E. E. M., Nelson, H. M., Healy, E., Pembroke, A. C., Friedmann, P. S., Dalziel, K., Calonje, E., and 12 others.
|
|
<strong>Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43.</strong>
|
|
Am. J. Hum. Genet. 68: 1264-1269, 2001.
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[PubMed: 11283798]
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[Full Text: https://doi.org/10.1086/320124]
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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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Berendes, U., Kuhner, A., Schnyder, U. W.
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<strong>Segmentary and disseminated lesions in multiple hereditary cutaneous leiomyoma.</strong>
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Humangenetik 13: 81-82, 1971.
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[PubMed: 5115893]
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[Full Text: https://doi.org/10.1007/BF00446422]
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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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Carvajal-Carmona, L. G., Alam, N. A., Pollard, P. J., Jones, A. M., Barclay, E., Wortham, N., Pignatelli, M., Freeman, A., Pomplun, S., Ellis, I., Poulsom, R., El-Bahrawy, M. A., Berney, D. M., Tomlinson, I. P. M.
|
|
<strong>Adult Leydig cell tumors of the testis caused by germline fumarate hydratase mutations.</strong>
|
|
J. Clin. Endocr. Metab. 91: 3071-3075, 2006.
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[PubMed: 16757530]
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[Full Text: https://doi.org/10.1210/jc.2006-0183]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Engelke, H., Christophers, E.
|
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<strong>Leiomyomatosis cutis et uteri.</strong>
|
|
Acta Derm. Venerol. 59 (suppl. 85): 51-54, 1979.
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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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Fryns, J. P., Haspeslagh, M., de Muelenaere, A., van den Berghe, H.
|
|
<strong>9p trisomy/18p distal monosomy and multiple cutaneous leiomyomata: another specific chromosomal site (18pter) in dominantly inherited multiple tumors?</strong>
|
|
Hum. Genet. 70: 284-286, 1985.
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[PubMed: 4018793]
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[Full Text: https://doi.org/10.1007/BF00273459]
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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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Gardie, B., Remenieras, A., Kattygnarath, D., Bombled, J., Lefevre, S., Perrier-Trudova, V., Rustin, P., Barrois, M., Slama, A., Avril, M.-F., Bessis, D., Caron, O., and 41 others.
|
|
<strong>Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.</strong>
|
|
J. Med. Genet. 48: 226-234, 2011. Note: Erratum: J. Med. Genet. 48: 576 only, 2011.
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[PubMed: 21398687]
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[Full Text: https://doi.org/10.1136/jmg.2010.085068]
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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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Guillet, G., Grau, P., Sassolas, B., Zagnoli, A., Leroy, J. P., Labouche, F.
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<strong>Leiomyomes cutanes multiples et fibromes uterins: a propos d'une observation d'un cas non familial.</strong>
|
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Semin. Hop. Paris 63: 65-67, 1987.
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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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Happle, R.
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<strong>A rule concerning the segmental manifestation of autosomal dominant skin disorders: review of clinical examples providing evidence for dichotomous types of severity.</strong>
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Arch. Derm. 133: 1505-1509, 1997.
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Wei, M.-H., Toure, O., Glenn, G. M., Pithukpakorn, M., Neckers, L., Stolle, C., Choyke, P., Grubb, R., Middelton, L., Turner, M. L., Walther, M. M., Merino, M. J., Zbar, B., Linehan, W. M., Toro, J. R.
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Hilary J. Vernon - updated : 11/16/2020<br>Cassandra L. Kniffin - updated : 8/11/2011<br>Cassandra L. Kniffin - updated : 2/13/2006<br>Victor A. McKusick - updated : 2/28/2002<br>Victor A. McKusick - updated : 6/5/2001<br>Victor A. McKusick - updated : 8/5/1999
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