3696 lines
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Entry
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- #135150 - BIRT-HOGG-DUBE SYNDROME 1; BHD1
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- OMIM
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<p>
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<span class="h4">#135150</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/135150"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS135150"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#animalModel">Animal Model</a>
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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 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>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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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=BIRT-HOGG-DUBE SYNDROME" 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=8627&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/NBK1522/" 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/8920" 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/birt-hogg-dube-syndrome" 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.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=122" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/cb427101-179d-44ee-ba6a-05fa1b36fd66/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0050676" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/135150" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/OMIA001335/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0050676" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</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> 1263460007<br />
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<strong>ORPHA:</strong> 122<br />
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<strong>DO:</strong> 0050676<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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135150
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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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BIRT-HOGG-DUBE SYNDROME 1; BHD1
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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>
|
|
<span class="mim-font">
|
|
BHD<br />
|
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HORNSTEIN-KNICKENBERG SYNDROME<br />
|
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FIBROFOLLICULOMAS WITH TRICHODISCOMAS AND ACROCHORDONS
|
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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">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/17/264?start=-3&limit=10&highlight=264">
|
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17p11.2
|
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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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Birt-Hogg-Dube syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/135150"> 135150 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
FLCN
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607273"> 607273 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
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|
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<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/135150" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
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|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS135150" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
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|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/135150" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/135150" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- 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 />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Face </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Facial papules <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239514&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239514</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Lung </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Lung cysts (in about 80% of patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/275504005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">275504005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0546483&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0546483</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0032445" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0032445</a>]</span><br /> -
|
|
Bullous disease <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3149269&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3149269</a>]</span><br /> -
|
|
Spontaneous pneumothorax (in about 30% of patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80423007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80423007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J93.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J93.83</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0149781&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0149781</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002108" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002108</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002108" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002108</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Colonic polyps <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/68496003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">68496003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K63.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K63.5</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Z83.71" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Z83.71</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/V18.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">V18.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009376&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009376</a>, <a href="https://bioportal.bioontology.org/search?q=C2911243&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2911243</a>]</span><br /> -
|
|
Colorectal adenomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399432003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399432003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1302401&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1302401</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GENITOURINARY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Kidneys </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Renal tumors (in about 27% of patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/126880001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">126880001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0022665&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022665</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009726</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009726</a>]</span><br /> -
|
|
Renal cysts <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/722223000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">722223000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3887499&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887499</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000107</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000107</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Fibrofolliculomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128683008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128683008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254699007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254699007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0346011&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0346011</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030436" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030436</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030436" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030436</a>]</span><br /> -
|
|
Acrochordons (skin tag) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/31069005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">31069005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/201091002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">201091002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0037293&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037293</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010609" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010609</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Hair </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Trichodiscomas (tumor of the hair disc) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851126&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851126</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEOPLASIA </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
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Parotid oncocytomas <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3149265&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3149265</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031523" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031523</a>]</span><br /> -
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Neural tissue tumors <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3149266&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3149266</a>]</span><br /> -
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Lipomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/134328007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">134328007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/93163002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">93163002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D17.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D17.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/214.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">214.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/214" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">214</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023798</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001012" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001012</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0012032" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012032</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001012" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001012</a>]</span><br /> -
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Angiolipomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/73219006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">73219006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/404057003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">404057003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0206632&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0206632</a>]</span><br />
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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- Features usually appear during adulthood<br /> -
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Intrafamilial variability<br /> -
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Mean age of presentation of renal cancer is 50 years, but earlier onset has been reported<br /> -
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See also isolated pneumothorax (<a href="/entry/173600">173600</a>), an allelic disorder that may represent a mild form of the BHD syndrome<br />
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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<span class="mim-font">
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- Caused by mutation in the folliculin gene (FLCN, <a href="/entry/607273#0001">607273.0001</a>)<br />
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<h5>
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Birt-Hogg-Dube syndrome
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- <a href="/phenotypicSeries/PS135150">PS135150</a>
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- 2 Entries
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</h5>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
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<strong>Location</strong>
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
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<strong>Phenotype</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Inheritance</strong>
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<strong>Phenotype<br />mapping key</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />MIM number</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus<br />MIM number</strong>
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<span class="mim-font">
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<a href="/geneMap/11/1091?start=-3&limit=10&highlight=1091"> 11q24.3 </a>
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<span class="mim-font">
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<a href="/entry/620459"> ?Birt-Hogg-Dube syndrome 2 </a>
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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 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 class="mim-font">
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<a href="/entry/620459"> 620459 </a>
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<a href="/entry/618319"> PRDM10 </a>
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<td>
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<span class="mim-font">
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<a href="/entry/618319"> 618319 </a>
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<span class="mim-font">
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<a href="/geneMap/17/264?start=-3&limit=10&highlight=264"> 17p11.2 </a>
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<td>
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<span class="mim-font">
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<a href="/entry/135150"> Birt-Hogg-Dube syndrome </a>
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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 class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<td>
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<span class="mim-font">
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<a href="/entry/135150"> 135150 </a>
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<span class="mim-font">
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<a href="/entry/607273"> FLCN </a>
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<span class="mim-font">
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<a href="/entry/607273"> 607273 </a>
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</h4>
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<p>A number sign (#) is used with this entry because Birt-Hogg-Dube syndrome-1 (BHD1), also known as Hornstein-Knickenberg syndrome, is caused by heterozygous mutation in the FLCN gene (<a href="/entry/607273">607273</a>) on chromosome 17p11.</p><p>Primary spontaneous pneumothorax (<a href="/entry/173600">173600</a>) is an allelic disorder that may represent a milder part of the clinical spectrum of the BHD syndrome.</p>
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<br />
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax (<a href="#16" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12204536" 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>BHD is similar to, but histologically and genetically distinct from, familial multiple discoid fibromas (FMDF; <a href="/entry/190340">190340</a>).</p><p><strong><em>Genetic Heterogeneity of Birt-Hogg-Dube Syndrome</em></strong></p><p>
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See also BHD2 (<a href="/entry/620459">620459</a>), caused by mutation in the PRDM10 gene (<a href="/entry/618319">618319</a>) on chromosome 11q24.</p>
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</span>
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<br />
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</h4>
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<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#5" class="mim-tip-reference" title="Hornstein, O. P., Knickenberg, M. <strong>Perifollicular fibromatosis cutis with polyps of the colon--a cutaneo-intestinal syndrome sui generis.</strong> Arch. Derm. Res. 253: 161-175, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1200700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1200700</a>] [<a href="https://doi.org/10.1007/BF00582068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1200700">Hornstein and Knickenberg (1975)</a> first described this disorder as 'perifollicular fibromatosis cutis with polyps of the colon' in 2 sibs. Their father was reportedly similarly affected, indicating an inherited condition. The proband was a 47-year-old woman who developed multiple perifollicular fibromas and skin tags affecting the neck, face, back, axillae, and groin. The skin lesions were 2 to 4 mm in diameter, flat-topped, solid, and skin-colored. Most had a central pit or plug. Histologic analysis showed whorl-shaped connective tissue fibers surrounding atrophic sebaceous glands. She also was found to have several colonic polyps, one of which showed malignant degeneration. The brother had similar adult onset of the skin lesions, but refused gastrointestinal examination. The patients' father also had renal and lung cysts. The disorder was distinguished from Gardner syndrome (see <a href="/entry/175100">175100</a>). <a href="#5" class="mim-tip-reference" title="Hornstein, O. P., Knickenberg, M. <strong>Perifollicular fibromatosis cutis with polyps of the colon--a cutaneo-intestinal syndrome sui generis.</strong> Arch. Derm. Res. 253: 161-175, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1200700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1200700</a>] [<a href="https://doi.org/10.1007/BF00582068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1200700">Hornstein and Knickenberg (1975)</a> suggested that patients with follicular fibromatosis be examined for intestinal polyps. <a href="#6" class="mim-tip-reference" title="Hornstein, O. P. <strong>Generalized dermal perifollicular fibromas with polyps of the colon.</strong> Hum. Genet. 33: 193-197, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/939573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">939573</a>] [<a href="https://doi.org/10.1007/BF00281897" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="939573">Hornstein (1976)</a> reviewed the condition in this family and considered the disorder a genodermatosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1200700+939573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Birt, A. R., Hogg, G. R., Dube, W. J. <strong>Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.</strong> Arch. Derm. 113: 1674-1677, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/596896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">596896</a>]" pmid="596896">Birt et al. (1977)</a> described fibrofolliculomas with trichodiscomas (see <a href="/entry/190340">190340</a>) and acrochordons in a family. Onset of this dermatologic condition was invariably in adulthood. A central hair was often visible in the lesions. Hereditary medullary carcinoma of the thyroid was also segregating, apparently independently, in the kindred. In a sibship of 9, 6 had medullary carcinoma of the thyroid. Two of those with thyroid cancer and 2 without had numerous small papular skin lesions that <a href="#1" class="mim-tip-reference" title="Birt, A. R., Hogg, G. R., Dube, W. J. <strong>Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.</strong> Arch. Derm. 113: 1674-1677, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/596896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">596896</a>]" pmid="596896">Birt et al. (1977)</a> labeled fibrofolliculoma. The lesion was characterized by abnormal hair follicles with epithelial strands extending from the infundibulum of the hair follicle into a hyperplastic mantle of specialized fibrous tissue. Associated skin lesions were trichodiscomas (tumor of the hair disc) and acrochordons ('wart with a thin neck;' skin tag). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=596896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Fujita, W. H., Barr, R. J., Headley, J. L. <strong>Multiple fibrofolliculomas with trichodiscomas and acrochordons.</strong> Arch. Derm. 117: 32-35, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7458379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7458379</a>]" pmid="7458379">Fujita et al. (1981)</a> reported the cases of 2 brothers and the son of one of them. By history the father of the 2 brothers was considered affected. Clinically the disorder was characterized by asymptomatic dome-shaped papules primarily involving the head, neck, chest, back, and arms. <a href="#27" class="mim-tip-reference" title="Ubogy-Rainey, Z., James, W. D., Lupton, G. P., Rodman, O. G. <strong>Fibrofolliculomas, trichodiscomas, and acrochordons: the Birt-Hogg-Dube syndrome.</strong> J. Am. Acad. Derm. 16: 452-457, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3819093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3819093</a>] [<a href="https://doi.org/10.1016/s0190-9622(87)70060-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3819093">Ubogy-Rainey et al. (1987)</a> likewise reported a family with 3 affected: a mother and her daughter and son. They discussed the clinical differential diagnosis of multiple firm, skin-colored papules. They diagrammed the histogenesis of benign follicular neoplasms, indicating that trichodiscomas are derived from the mesenchymal component of the pilar complex, trichofolliculomas, trichodiscomas, and trichoepitheliomas from epithelial components, and fibrofolliculomas from both epithelial and mesenchymal proliferation. <a href="#23" class="mim-tip-reference" title="Shapiro, P. E., Kopf, A. W. <strong>Familial multiple desmoplastic trichoepitheliomas.</strong> Arch. Derm. 127: 83-87, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1986711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1986711</a>]" pmid="1986711">Shapiro and Kopf (1991)</a> described a family in which a mother and son had multiple desmoplastic trichoepitheliomas. The grandmother had a single cylindroma of the scalp. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3819093+1986711+7458379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Rongioletti, F., Hazini, R., Gianotti, G., Rebora, A. <strong>Fibrofolliculomas, tricodiscomas and acrochordons (Birt-Hogg-Dube) associated with intestinal polyposis.</strong> Clin. Exp. Derm. 14: 72-74, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2805394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2805394</a>] [<a href="https://doi.org/10.1111/j.1365-2230.1989.tb00890.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2805394">Rongioletti et al. (1989)</a> and <a href="#12" class="mim-tip-reference" title="Le Guyadec, T., Dufau, J.-P., Poulain, J.-F., Vaylet, F., Grossin, M., Lanternier, G. <strong>Multiple trichodiscomas associated with intestinal polyposis.</strong> Ann. Derm. Venereol. 125: 717-719, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9835964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9835964</a>]" pmid="9835964">Le Guyadec et al. (1998)</a> described association of Birt-Hogg-Dube syndrome with intestinal polyposis. <a href="#19" class="mim-tip-reference" title="Roth, J. S., Rabinowitz, A. D., Benson, M., Grossman, M. E. <strong>Bilateral renal cell carcinoma in the Birt-Hogg-Dube syndrome.</strong> J. Am. Acad. Derm. 29: 1055-1056, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8245249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8245249</a>] [<a href="https://doi.org/10.1016/s0190-9622(08)82049-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8245249">Roth et al. (1993)</a> observed bilateral renal cell carcinoma in association with BHD. <a href="#2" class="mim-tip-reference" title="Chung, J. Y., Ramos-Caro, F. A., Beers, B., Ford, M. J., Flowers, F. <strong>Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dube syndrome.</strong> Int. J. Derm. 35: 365-367, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8734663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8734663</a>] [<a href="https://doi.org/10.1111/j.1365-4362.1996.tb03642.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8734663">Chung et al. (1996)</a> described multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with BHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8245249+9835964+8734663+2805394" 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="#25" class="mim-tip-reference" title="Toro, J. R., Glenn, G., Duray, P., Darling, T., Weirich, G., Zbar, B., Linehan, M., Turner, M. L. <strong>Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia.</strong> Arch. Derm. 135: 1195-1202, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10522666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10522666</a>] [<a href="https://doi.org/10.1001/archderm.135.10.1195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10522666">Toro et al. (1999)</a> evaluated kindreds with familial renal tumors for cutaneous manifestations of BHD. They performed complete oral and skin examinations of 152 patients from 49 families. In this way, they identified 3 extended kindreds in whom renal neoplasms and BHD appeared to segregate together. Two kindreds had renal oncocytomas and a third had a variant of papillary renal cell carcinoma. Thirteen patients exhibited BHD. Seven individuals, including a set of identical twins, had renal neoplasms and BHD. An additional 4 patients (3 deceased and not examined) in these families had renal neoplasms but not BHD. BHD without renal neoplasms was present in 6 individuals. Thirteen patients with fibrofolliculomas and trichodiscomas presented clinically with multiple smooth skin-colored to grayish-white papules located on the face, auricles, neck, and upper trunk. Oral papules were present in 9 of 28 and acrochordons in 11 of 28 patients. Features of BHD not previously appreciated included deforming lipomas in 5, collagenomas in 4, and pulmonary cysts in 4 of 28 patients. Families with BHD did not display germline mutations in the von Hippel-Lindau gene (<a href="/entry/608537">608537</a>) or in the tyrosine kinase domain of the MET protooncogene (<a href="/entry/164860">164860</a>), which are known to be associated with renal neoplasms. The pedigree pattern was entirely consistent with autosomal dominant inheritance; for example, a father and both of his twin sons had renal tumor and BHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10522666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Weirich, G., Glenn, G., Junker, K., Merino, M., Storkel, S., Lubensky, I., Choyke, P., Pack, S., Amin, M., Walther, M. M., Linehan, W. M., Zbar, B. <strong>Familial renal oncocytoma: clinicopathological study of 5 families.</strong> J. Urol. 160: 335-340, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9679872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9679872</a>] [<a href="https://doi.org/10.1016/s0022-5347(01)62888-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9679872">Weirich et al. (1998)</a> described 5 families in which multiple members had multiple bilateral renal oncocytomas. On dermatologic examination, 13 members of 3 of these families were found to have cutaneous BHD lesions (<a href="#25" class="mim-tip-reference" title="Toro, J. R., Glenn, G., Duray, P., Darling, T., Weirich, G., Zbar, B., Linehan, M., Turner, M. L. <strong>Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia.</strong> Arch. Derm. 135: 1195-1202, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10522666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10522666</a>] [<a href="https://doi.org/10.1001/archderm.135.10.1195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10522666">Toro et al., 1999</a>). Subsequently, through mass mailings to dermatologists, <a href="#21" class="mim-tip-reference" title="Schmidt, L. S., Warren, M. B., Nickerson, M. L., Weirich, G., Matrosova, V., Toro, J. R., Turner, M. L., Duray, P., Merino, M., Hewitt, S., Pavlovich, C. P., Glenn, G., Greenberg, C. R., Linehan, W. M., Zbar, B. <strong>Birt-Hogg-Dube syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2.</strong> Am. J. Hum. Genet. 69: 876-882, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11533913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11533913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11533913[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/10.1086/323744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11533913">Schmidt et al. (2001)</a> identified 33 families with BHD skin lesions and associated renal tumors, lung cysts, or pneumothorax, and/or colonic polyps, including the original Canadian family described by <a href="#1" class="mim-tip-reference" title="Birt, A. R., Hogg, G. R., Dube, W. J. <strong>Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.</strong> Arch. Derm. 113: 1674-1677, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/596896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">596896</a>]" pmid="596896">Birt et al. (1977)</a>. <a href="#29" class="mim-tip-reference" title="Zbar, B., Alvord, W. G., Glenn, G., Turner, M., Pavlovich, C. P., Schmidt, L., Walther, M., Choyke, P., Weirich, G., Hewitt, S. M., Duray, P., Gabril, F., Greenberg, C., Merino, M. J., Toro, J., Linehan, W. M. <strong>Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome.</strong> Cancer Epidemiol. Biomarkers Prev. 11: 393-400, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11927500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11927500</a>]" pmid="11927500">Zbar et al. (2002)</a> showed that BHD confers an increased risk for the development of renal tumors and lung cysts or spontaneous pneumothorax but not for the development of colonic polyps. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9679872+11533913+11927500+596896+10522666" 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>Kidney cancer may be classified into 4 histologic types: clear cell (CCRC, 75%), papillary (PRC, 15%), oncocytoma (5%), and chromophobe (5%) (<a href="#10" class="mim-tip-reference" title="Kovacs, G., Akhtar, M., Beckwith, B. J., Bugert, P., Cooper, C. S., Delahunt, B., Eble, J. N., Fleming, S., Ljungberg, B., Medeiros, L. J., Moch, H., Reuter, V. E., Ritz, E., Roos, G., Schmidt, D., Srigley, J. R., Storkel, S., Van Den Berg, E., Zbar, B. <strong>The Heidelberg classification of renal cell tumors.</strong> J. Path. 183: 131-133, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9390023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9390023</a>] [<a href="https://doi.org/10.1002/(SICI)1096-9896(199710)183:2<131::AID-PATH931>3.0.CO;2-G" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9390023">Kovacs et al., 1997</a>). In a study of 130 renal tumors found in 30 BHD patients, the spectrum of renal histology included 34% chromophobe, 5% oncocytoma, 50% chromophobe/oncocytic hybrid, 9% clear cell, 2% papillary (<a href="#17" class="mim-tip-reference" title="Pavlovich, C. P., Walther, M. W., Eyler, R. A., Hewitt, S. M., Zbar, B., Linehan, W. M., Merino, M. J. <strong>Renal tumors in the Birt-Hogg-Dube syndrome.</strong> Am. J. Surg. Path. 26: 1542-1552, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12459621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12459621</a>] [<a href="https://doi.org/10.1097/00000478-200212000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12459621">Pavlovich et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9390023+12459621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Toro, J. R., Wei, M.-H., Glenn, G. M., Weinreich, M., Toure, O., Vocke, C., Turner, M., Choyke, P., Merino, M. J., Pinto, P. A., Steinberg, S. M., Schmidt, L. S., Linehan, W. M. <strong>BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports.</strong> J. Med. Genet. 45: 321-331, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18234728[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.2007.054304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18234728">Toro et al. (2008)</a> reported the clinical features of 89 individuals from 51 families with BHD syndrome. Forty-six (90%) of 51 families had individuals with multiple fibrofolliculomas, and 26 (57%) of 46 BHD families had individuals with a second histologically confirmed cutaneous lesion, including angiofibroma, trichodiscoma, and perifollicular fibroma. Thirty (34%) of 89 individuals and 25 (49%) of 51 families had kidney tumors. Forty-five (88%) of 51 families and 75 (84%) of 89 individuals had lung cysts on CT imaging. Twenty-seven (53%) of 51 families and 34 (38%) of 89 individuals had a history of spontaneous pneumothorax, most often associated with lung cysts. Eighteen (58%) of 31 individuals with a family history of pneumothorax developed pneumothoraces compared to 16 (28%) of 57 individuals without family history (p = 0.011). <a href="#26" class="mim-tip-reference" title="Toro, J. R., Wei, M.-H., Glenn, G. M., Weinreich, M., Toure, O., Vocke, C., Turner, M., Choyke, P., Merino, M. J., Pinto, P. A., Steinberg, S. M., Schmidt, L. S., Linehan, W. M. <strong>BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports.</strong> J. Med. Genet. 45: 321-331, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18234728[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.2007.054304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18234728">Toro et al. (2008)</a> noted inter- and intrafamilial phenotypic variation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18234728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Kluijt, I., de Jong, D., Teertstra, H. J., Axwijk, P. H., Gille, J. J. P., Bell, K., van Rens, A., van der Velden, A. W. G., Middelton, L., Horenblas, S. <strong>Early onset of renal cancer in a family with Birt-Hogg-Dube syndrome.</strong> Clin. Genet. 75: 537-543, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19320655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19320655</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01159.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19320655">Kluijt et al. (2009)</a> reported a large Dutch family with BHD syndrome confirmed by genetic analysis (<a href="/entry/607273#0015">607273.0015</a>). The proband was a 27-year-old man with metastatic high-grade clear cell carcinoma of the kidney. His 32-year-old brother had high-grade papillary renal cell carcinoma, and a deceased sister of the maternal grandmother had a hybrid chromophobe/oncocytic renal carcinoma at age 71. She also had a history of recurrent pneumothorax. Six of 13 mutation carriers in the family who had a renal MRI scan showed unilateral or bilateral renal cysts; all were 55 years or older. Pneumothorax occurred in 8 mutation carriers at a relatively advanced age (third through sixth decades), and 5 had lung cysts and bullous lung disease. Eleven carriers had facial papules, most with onset after age 40. <a href="#9" class="mim-tip-reference" title="Kluijt, I., de Jong, D., Teertstra, H. J., Axwijk, P. H., Gille, J. J. P., Bell, K., van Rens, A., van der Velden, A. W. G., Middelton, L., Horenblas, S. <strong>Early onset of renal cancer in a family with Birt-Hogg-Dube syndrome.</strong> Clin. Genet. 75: 537-543, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19320655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19320655</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01159.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19320655">Kluijt et al. (2009)</a> suggested that the relatively early age of renal cancer in some family members may be due to a modifier gene. Importantly, the clinical features of the family also illustrated that skin anomalies and/or lung disease are not mandatory for considering BHD in patients with renal cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19320655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Toro, J. R., Wei, M.-H., Glenn, G. M., Weinreich, M., Toure, O., Vocke, C., Turner, M., Choyke, P., Merino, M. J., Pinto, P. A., Steinberg, S. M., Schmidt, L. S., Linehan, W. M. <strong>BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports.</strong> J. Med. Genet. 45: 321-331, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18234728[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.2007.054304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18234728">Toro et al. (2008)</a> reported the clinical features of 89 individuals from 51 families with BHD syndrome and mutation in the FLCN gene. Forty-six (90%) of 51 families had individuals with multiple fibrofolliculomas, and 26 (57%) of 46 BHD families had individuals with a second histologically confirmed cutaneous lesion, including angiofibroma, trichodiscoma, and perifollicular fibroma. Thirty (34%) of 89 individuals and 25 (49%) of 51 families had kidney tumours. Forty-five (88%) of 51 families and 75 (84%) of 89 individuals had lung cysts on CT imaging. Twenty-seven (53%) of 51 families and 34 (38%) of 89 individuals had a history of spontaneous pneumothorax, most often associated with lung cysts. Eighteen (58%) of 31 individuals with a family history of pneumothorax developed pneumothoraces compared to 16 (28%) of 57 individuals without family history (p = 0.011). <a href="#26" class="mim-tip-reference" title="Toro, J. R., Wei, M.-H., Glenn, G. M., Weinreich, M., Toure, O., Vocke, C., Turner, M., Choyke, P., Merino, M. J., Pinto, P. A., Steinberg, S. M., Schmidt, L. S., Linehan, W. M. <strong>BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports.</strong> J. Med. Genet. 45: 321-331, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18234728[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.2007.054304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18234728">Toro et al. (2008)</a> noted inter- and intrafamilial phenotypic variation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18234728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Clinical Variability</em></strong></p><p>
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<a href="#14" class="mim-tip-reference" title="Maffe, A., Toschi, B., Circo, G., Giachino, D., Giglio, S., Rizzo, A., Carloni, A., Poletti, V., Tomassetti, S., Ginardi, C., Ungari, S., Genuardi, M. <strong>Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dube syndrome ascertained for non-cutaneous manifestations.</strong> Clin. Genet. 79: 345-354, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20618353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20618353</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01480.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20618353">Maffe et al. (2011)</a> found FLCN mutations in 9 (47%) of 19 probands who presented initially with extracutaneous manifestations suggestive of BHD syndrome, either a renal tumor or pneumothorax/lung cysts. Five (56%) of the 9 probands were found to have cutaneous hamartomas. Family history showed that 8 of the patients had affected relatives; however, 7 (44%) of 16 heterozygous relatives over the age of 20 years were asymptomatic. One patient had bilateral parotid oncocytomas, and tumor tissue showed loss of heterozygosity (LOH) for the wildtype FLCN allele. <a href="#14" class="mim-tip-reference" title="Maffe, A., Toschi, B., Circo, G., Giachino, D., Giglio, S., Rizzo, A., Carloni, A., Poletti, V., Tomassetti, S., Ginardi, C., Ungari, S., Genuardi, M. <strong>Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dube syndrome ascertained for non-cutaneous manifestations.</strong> Clin. Genet. 79: 345-354, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20618353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20618353</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2010.01480.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20618353">Maffe et al. (2011)</a> noted that although most patients with BHD are ascertained on the basis of skin lesions, the diagnosis should be suspected in those who present with extracutaneous manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20618353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pathologic Findings</em></strong></p><p>
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The Hornstein-Knickenberg syndrome had been thought to be characterized by perifollicular fibromas, whereas BHD was characterized by fibrofolliculomas and trichodiscomas. <a href="#22" class="mim-tip-reference" title="Schulz, T., Hartschuh, W. <strong>Birt-Hogg-Dube-syndrome and Hornstein-Knickenberg syndrome are the same: different sectioning technique as the cause of different histology.</strong> J. Cutan. Path. 26: 55-61, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10189247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10189247</a>] [<a href="https://doi.org/10.1111/j.1600-0560.1999.tb01792.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10189247">Schulz and Hartschuh (1999)</a> reported a father and daughter with a diagnosis of BHD. Extensive histologic examination of papular skin lesions indicated that histologic differences between the skin lesions are artificial and caused by interpretation of different sectioning planes; thus, fibrofolliculoma, perifollicular fibroma, and so-called trichodiscoma are in fact the same lesion. Similarly, some think that acrochordons are in fact fibrofolliculomas (<a href="#4" class="mim-tip-reference" title="Happle, R. <strong>Hornstein-Birt-Hogg-Dube syndrome: a renaming and reconsideration.</strong> Am. J. Med. Genet. 158A: 1247-1251, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22581760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22581760</a>] [<a href="https://doi.org/10.1002/ajmg.a.35330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22581760">Happle, 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22581760+10189247" 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="#24" class="mim-tip-reference" title="Starink, T. M., Houweling, A. C., van Doorn, M. B. A., Leter, E. M., Jaspars, E. H., van Moorselaar, R. J. A., Postmus, P. E., Johannesma, P. C., van Waesberghe, J. H., Ploeger, M. H., Kramer, M. T., Gille, J. J. P., Waisfisz, Q., Menko, F. H. <strong>Familial multiple discoid fibromas: a look-alike of Birt-Hogg-Dube syndrome not linked to the FLCN locus.</strong> J. Am. Acad. Derm. 66: 259.e1-e9, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21794948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21794948</a>] [<a href="https://doi.org/10.1016/j.jaad.2010.11.039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21794948">Starink et al. (2012)</a> favored use of the term 'discoid fibroma' rather than 'trichodiscoma,' and suggested that most lesions described as 'trichodiscoma' in BHD were in fact 'fibrofolliculomas.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21794948" 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="Birt, A. R., Hogg, G. R., Dube, W. J. <strong>Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.</strong> Arch. Derm. 113: 1674-1677, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/596896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">596896</a>]" pmid="596896">Birt et al. (1977)</a> observed this disorder in 15 persons in 3 generations, with male-to-male transmission, consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=596896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Khoo, S. K., Bradley, M., Wong, F. K., Hedblad, M.-A., Nordenskjold, M., Teh, B. T. <strong>Birt-Hogg-Dube syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2.</strong> Oncogene 20: 5239-5242, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11526515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11526515</a>] [<a href="https://doi.org/10.1038/sj.onc.1204703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11526515">Khoo et al. (2001)</a> mapped the BHD locus by a genomewide linkage analysis using polymorphic microsatellite markers in a large Swedish family. They found evidence of linkage to chromosome 17p12-q11.2, with a maximum lod score of 3.58 for marker D17S1852. Further haplotype analysis defined a candidate interval of approximately 35 cM between the 2 flanking markers, D17S1791 and D17S798. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11526515" 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="Schmidt, L. S., Warren, M. B., Nickerson, M. L., Weirich, G., Matrosova, V., Toro, J. R., Turner, M. L., Duray, P., Merino, M., Hewitt, S., Pavlovich, C. P., Glenn, G., Greenberg, C. R., Linehan, W. M., Zbar, B. <strong>Birt-Hogg-Dube syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2.</strong> Am. J. Hum. Genet. 69: 876-882, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11533913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11533913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11533913[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/10.1086/323744" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11533913">Schmidt et al. (2001)</a> performed a genomewide scan in a large kindred with BHD and, by linkage analysis, localized the BHD locus to the pericentromeric region of 17p, with a lod score of 4.98 at D17S740 (recombination fraction = 0.0). Two-point linkage analysis of 8 additional families with BHD produced a maximum lod score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within an interval of less than 4-cM between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to 17p, suggesting genetic heterogeneity. The BHD locus lies within the chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy number repeat elements, is unstable and is associated with a number of diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11533913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> narrowed the critical region for the BHD locus to a 700-kb segment on chromosome 17p11.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12204536" 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="#15" class="mim-tip-reference" title="Napolitano, G., Di Malta, C., Esposito, A., de Araujo, M. E. G., Pece, S., Bertalot, G., Matarese, M., Benedetti, V., Zampelli, A., Stasyk, T., Siciliano, D., Venuta, A., Cesana, M., Vilardo, C., Nusco, E., Monfregola, J., Calcagni, A., Di Fiore, P. P., Huber, L. A., Ballabio, A. <strong>A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dube syndrome.</strong> Nature 585: 597-602, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32612235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32612235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32612235[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2444-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32612235">Napolitano et al. (2020)</a> showed that TFEB (<a href="/entry/600744">600744</a>), a master regulator of lysosomal biogenesis and autophagy, is phosphorylated by mTORC1 (see <a href="/entry/601231">601231</a>) via a substrate-specific mechanism that is mediated by Rag GTPases. Owing to this mechanism, the phosphorylation of TFEB is strictly dependent on the amino-acid-mediated activation of RagC (<a href="/entry/608267">608267</a>) and RagD (<a href="/entry/608268">608268</a>) GTPases, but is insensitive to RHEB activity induced by growth factors. This mechanism has a crucial role in Birt-Hogg-Dube syndrome, a disorder that is caused by mutations in the RagC and RagD activator folliculin (FLCN). <a href="#15" class="mim-tip-reference" title="Napolitano, G., Di Malta, C., Esposito, A., de Araujo, M. E. G., Pece, S., Bertalot, G., Matarese, M., Benedetti, V., Zampelli, A., Stasyk, T., Siciliano, D., Venuta, A., Cesana, M., Vilardo, C., Nusco, E., Monfregola, J., Calcagni, A., Di Fiore, P. P., Huber, L. A., Ballabio, A. <strong>A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dube syndrome.</strong> Nature 585: 597-602, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32612235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32612235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32612235[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2444-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32612235">Napolitano et al. (2020)</a> found that constitutive activation of TFEB is the main driver of the kidney abnormalities and mTORC1 hyperactivity in a mouse model of Birt-Hogg-Dube syndrome. Accordingly, depletion of TFEB in kidneys of these mice fully rescued the disease phenotype and associated lethality, and normalized mTORC1 activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32612235" 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>By positional cloning, <a href="#16" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> identified a novel gene, first designated BHD and later FLCN, in the BHD critical region on 17p11.2. In several BHD families, they identified protein-truncating mutations in the FLCN gene (<a href="/entry/607273#0001">607273.0001</a>-<a href="/entry/607273#0005">607273.0005</a>). <a href="#16" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> stated that their identification of this novel kidney cancer gene associated with renal oncocytoma or chromophobe renal cancer could contribute to understanding the role of folliculin in pathways common to skin, lung, and kidney development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12204536" 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="#8" class="mim-tip-reference" title="Khoo, S. K., Giraud, S., Kahnoski, K., Chen, J., Motorna, O., Nickolov, R., Binet, O., Lambert, D., Friedel, J., Levy, R., Ferlicot, S., Wolkenstein, P., Hammel, P., Bergerheim, U., Hedblad, M.-A., Bradley, M., Teh, B. T., Nordenskjold, M., Richard, S. <strong>Clinical and genetic studies of Birt-Hogg-Dube syndrome.</strong> J. Med. Genet. 39: 906-912, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471204</a>] [<a href="https://doi.org/10.1136/jmg.39.12.906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471204">Khoo et al. (2002)</a> studied 4 sporadic BHD cases and 4 families with a total of 23 affected subjects. Haplotype analysis of these families using BHD-linked markers showed that they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified 2 germline mutations on exon 11 in 3 of 4 families as well as 2 of 4 sporadic cases. A novel somatic mutation was detected in a BHD-related chromophobe renal carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Schmidt, L. S., Nickerson, M. L., Warren, M. B., Glenn, G. M., Toro, J. R., Merino, M. J., Turner, M. L., Choyke, P. L., Sharma, N., Peterson, J., Morrison, P., Maher, E. R., Walther, M. M., Zbar, B., Linehan, W. M. <strong>Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome.</strong> Am. J. Hum. Genet. 76: 1023-1033, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15852235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15852235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15852235[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/10.1086/430842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15852235">Schmidt et al. (2005)</a> performed direct sequencing of the BHD gene in 30 families with BHD and reported that combined with their previous data (<a href="#16" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al., 2002</a>), they had identified germline BHD mutations in 51 (84%) of 61 families with BHD. Each family's mutation cosegregated with disease and was not found in at least 160 unaffected individuals. Of the 51 families with a germline BHD mutation, 27 (53%) had a cytosine insertion or deletion in the mononucleotide tract of 8 cytosines in exon 11 (1285insC, <a href="/entry/607273#0001">607273.0001</a>; 1285delC, <a href="/entry/607273#0002">607273.0002</a>, respectively), which appears to represent a mutation hotspot. Two large families with BHD, one of them the original family reported by <a href="#1" class="mim-tip-reference" title="Birt, A. R., Hogg, G. R., Dube, W. J. <strong>Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.</strong> Arch. Derm. 113: 1674-1677, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/596896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">596896</a>]" pmid="596896">Birt et al. (1977)</a>, showed linkage to 17p11.2 but had no mutation in the BHD gene by direct sequencing. <a href="#20" class="mim-tip-reference" title="Schmidt, L. S., Nickerson, M. L., Warren, M. B., Glenn, G. M., Toro, J. R., Merino, M. J., Turner, M. L., Choyke, P. L., Sharma, N., Peterson, J., Morrison, P., Maher, E. R., Walther, M. M., Zbar, B., Linehan, W. M. <strong>Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome.</strong> Am. J. Hum. Genet. 76: 1023-1033, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15852235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15852235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15852235[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/10.1086/430842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15852235">Schmidt et al. (2005)</a> noted that most reported mutations were predicted to terminate folliculin prematurely and to result in loss of function and suggested that BHD may act as a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12204536+596896+15852235" 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 affected individuals from 51 (88%) of 58 families with BHD, <a href="#26" class="mim-tip-reference" title="Toro, J. R., Wei, M.-H., Glenn, G. M., Weinreich, M., Toure, O., Vocke, C., Turner, M., Choyke, P., Merino, M. J., Pinto, P. A., Steinberg, S. M., Schmidt, L. S., Linehan, W. M. <strong>BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports.</strong> J. Med. Genet. 45: 321-331, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18234728[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.2007.054304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18234728">Toro et al. (2008)</a> identified 23 different mutations in the FLCN gene, including 13 novel mutations (see, e.g., <a href="/entry/607273#0014">607273.0014</a>). The 1285insC or 1285delC mutations were most common, occurring in 14 and 5 families, respectively. All mutations except one were predicted to result in a truncated protein. There were no apparent genotype/phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18234728" 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="Kunogi, M., Kurihara, M., Ikegami, T. S., Kobayashi, T., Shindo, N., Kumasaka, T., Gunji, Y., Kikkawa, M., Iwakami, S., Hino, O., Takahashi, K., Seyama, K. <strong>Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature.</strong> J. Med. Genet. 47: 281-287, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20413710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20413710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20413710[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.2009.070565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20413710">Kunogi et al. (2010)</a> screened the FLCN gene by DHPLC in 36 Japanese patients with multiple lung cysts of undetermined causes, all but 1 of whom had suffered at least 1 pneumothorax, and identified 13 different germline mutations in 23 of the patients, respectively. The remaining 13 patients were further analyzed by quantitative PCR, and large genomic deletions (see, e.g., <a href="/entry/607273#0017">607273.0017</a>) were found in 2; thus 25 (69.4%) of the 36 patients had germline FLCN mutations. Only 6 of the mutation-positive patients had skin lesions, and 2 others had renal tumors, 1 of which was an angiomyolipoma and the other a renal cancer (histopathologic information unavailable). <a href="#11" class="mim-tip-reference" title="Kunogi, M., Kurihara, M., Ikegami, T. S., Kobayashi, T., Shindo, N., Kumasaka, T., Gunji, Y., Kikkawa, M., Iwakami, S., Hino, O., Takahashi, K., Seyama, K. <strong>Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature.</strong> J. Med. Genet. 47: 281-287, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20413710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20413710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20413710[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.2009.070565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20413710">Kunogi et al. (2010)</a> noted that 13 (52%) of the 25 mutations were located in the 3-prime end of the FLCN gene, and that these Japanese patients with FLCN mutations had a very low incidence of skin and renal involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20413710" 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="#4" class="mim-tip-reference" title="Happle, R. <strong>Hornstein-Birt-Hogg-Dube syndrome: a renaming and reconsideration.</strong> Am. J. Med. Genet. 158A: 1247-1251, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22581760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22581760</a>] [<a href="https://doi.org/10.1002/ajmg.a.35330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22581760">Happle (2012)</a> noted that <a href="#5" class="mim-tip-reference" title="Hornstein, O. P., Knickenberg, M. <strong>Perifollicular fibromatosis cutis with polyps of the colon--a cutaneo-intestinal syndrome sui generis.</strong> Arch. Derm. Res. 253: 161-175, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1200700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1200700</a>] [<a href="https://doi.org/10.1007/BF00582068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1200700">Hornstein and Knickenberg (1975)</a> first described this disorder as 'perifollicular fibromatosis with polyps of the colon--a cutaneo-intestinal syndrome.' Since the designation 'Birt-Hogg-Dube syndrome' is entrenched in the medical literature, it is retained here as the preferred title; 'Hornstein-Knickenberg syndrome' is used here as an alternative title to give credit to the original authors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22581760+1200700" 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>Hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a naturally occurring canine kidney cancer syndrome that was originally described in German shepherd dogs. <a href="#13" class="mim-tip-reference" title="Lingaas, F., Comstock, K. E., Kirkness, E. F., Sorensen, A., Aarskaug, T., Hitte, C., Nickerson, M. L., Moe, L., Schmidt, L. S., Thomas, R., Breen, M., Galibert, F., Zbar, B., Ostrander, E. A. <strong>A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog.</strong> Hum. Molec. Genet. 12: 3043-3053, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14532326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14532326</a>] [<a href="https://doi.org/10.1093/hmg/ddg336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14532326">Lingaas et al. (2003)</a> narrowed the RCND interval to a small region on canine chromosome 5 that overlapped the human BHD gene. The authors described a his255-to-arg mutation in exon 7 of the canine Bhd gene that segregated with the disease phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14532326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.</strong>
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Arch. Derm. 113: 1674-1677, 1977.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/596896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">596896</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=596896" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Chung, J. Y., Ramos-Caro, F. A., Beers, B., Ford, M. J., Flowers, F.
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<strong>Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dube syndrome.</strong>
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Int. J. Derm. 35: 365-367, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8734663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8734663</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8734663" 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.1365-4362.1996.tb03642.x" target="_blank">Full Text</a>]
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Fujita, W. H., Barr, R. J., Headley, J. L.
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<strong>Multiple fibrofolliculomas with trichodiscomas and acrochordons.</strong>
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Arch. Derm. 117: 32-35, 1981.
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[<a href="https://doi.org/10.1007/BF00582068" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00281897" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.39.12.906" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8245249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8245249</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8245249" 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/s0190-9622(08)82049-x" target="_blank">Full Text</a>]
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<a id="Schmidt2005" class="mim-anchor"></a>
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Schmidt, L. S., Nickerson, M. L., Warren, M. B., Glenn, G. M., Toro, J. R., Merino, M. J., Turner, M. L., Choyke, P. L., Sharma, N., Peterson, J., Morrison, P., Maher, E. R., Walther, M. M., Zbar, B., Linehan, W. M.
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<strong>Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome.</strong>
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Am. J. Hum. Genet. 76: 1023-1033, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15852235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15852235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15852235[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=15852235" 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/10.1086/430842" target="_blank">Full Text</a>]
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Schmidt, L. S., Warren, M. B., Nickerson, M. L., Weirich, G., Matrosova, V., Toro, J. R., Turner, M. L., Duray, P., Merino, M., Hewitt, S., Pavlovich, C. P., Glenn, G., Greenberg, C. R., Linehan, W. M., Zbar, B.
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<strong>Birt-Hogg-Dube syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2.</strong>
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Am. J. Hum. Genet. 69: 876-882, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11533913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11533913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11533913[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=11533913" 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/10.1086/323744" target="_blank">Full Text</a>]
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Schulz, T., Hartschuh, W.
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<strong>Birt-Hogg-Dube-syndrome and Hornstein-Knickenberg syndrome are the same: different sectioning technique as the cause of different histology.</strong>
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J. Cutan. Path. 26: 55-61, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10189247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10189247</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10189247" 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.1600-0560.1999.tb01792.x" target="_blank">Full Text</a>]
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Shapiro, P. E., Kopf, A. W.
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<strong>Familial multiple desmoplastic trichoepitheliomas.</strong>
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Arch. Derm. 127: 83-87, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1986711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1986711</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1986711" 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="Starink2012" class="mim-anchor"></a>
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Starink, T. M., Houweling, A. C., van Doorn, M. B. A., Leter, E. M., Jaspars, E. H., van Moorselaar, R. J. A., Postmus, P. E., Johannesma, P. C., van Waesberghe, J. H., Ploeger, M. H., Kramer, M. T., Gille, J. J. P., Waisfisz, Q., Menko, F. H.
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<strong>Familial multiple discoid fibromas: a look-alike of Birt-Hogg-Dube syndrome not linked to the FLCN locus.</strong>
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J. Am. Acad. Derm. 66: 259.e1-e9, 2012. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21794948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21794948</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21794948" 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/j.jaad.2010.11.039" target="_blank">Full Text</a>]
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Toro, J. R., Glenn, G., Duray, P., Darling, T., Weirich, G., Zbar, B., Linehan, M., Turner, M. L.
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<strong>Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia.</strong>
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Arch. Derm. 135: 1195-1202, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10522666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10522666</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10522666" 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.135.10.1195" target="_blank">Full Text</a>]
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Toro, J. R., Wei, M.-H., Glenn, G. M., Weinreich, M., Toure, O., Vocke, C., Turner, M., Choyke, P., Merino, M. J., Pinto, P. A., Steinberg, S. M., Schmidt, L. S., Linehan, W. M.
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<strong>BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports.</strong>
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J. Med. Genet. 45: 321-331, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18234728[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=18234728" 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.2007.054304" target="_blank">Full Text</a>]
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Ubogy-Rainey, Z., James, W. D., Lupton, G. P., Rodman, O. G.
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<strong>Fibrofolliculomas, trichodiscomas, and acrochordons: the Birt-Hogg-Dube syndrome.</strong>
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J. Am. Acad. Derm. 16: 452-457, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3819093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3819093</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3819093" 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/s0190-9622(87)70060-7" target="_blank">Full Text</a>]
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Weirich, G., Glenn, G., Junker, K., Merino, M., Storkel, S., Lubensky, I., Choyke, P., Pack, S., Amin, M., Walther, M. M., Linehan, W. M., Zbar, B.
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<strong>Familial renal oncocytoma: clinicopathological study of 5 families.</strong>
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J. Urol. 160: 335-340, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9679872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9679872</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9679872" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0022-5347(01)62888-x" target="_blank">Full Text</a>]
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Zbar, B., Alvord, W. G., Glenn, G., Turner, M., Pavlovich, C. P., Schmidt, L., Walther, M., Choyke, P., Weirich, G., Hewitt, S. M., Duray, P., Gabril, F., Greenberg, C., Merino, M. J., Toro, J., Linehan, W. M.
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<strong>Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome.</strong>
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Cancer Epidemiol. Biomarkers Prev. 11: 393-400, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11927500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11927500</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11927500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Marla J. F. O'Neill - updated : 07/28/2023
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Ada Hamosh - updated : 01/29/2021<br>Cassandra L. Kniffin - updated : 8/22/2012<br>Cassandra L. Kniffin - updated : 5/18/2011<br>Marla J. F. O'Neill - updated : 9/24/2010<br>Cassandra L. Kniffin - updated : 6/1/2010<br>Cassandra L. Kniffin - updated : 10/2/2008<br>George E. Tiller - updated : 1/11/2006<br>Marla J. F. O'Neill - updated : 5/26/2005<br>Victor A. McKusick - updated : 6/30/2003<br>Victor A. McKusick - updated : 11/20/2002<br>Victor A. McKusick - updated : 10/2/2002<br>Victor A. McKusick - updated : 1/10/2002<br>Victor A. McKusick - updated : 10/17/2001<br>Victor A. McKusick - updated : 2/4/2000<br>Victor A. McKusick - updated : 1/19/2000
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Victor A. McKusick : 6/4/1986
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carol : 07/31/2023<br>carol : 07/28/2023<br>carol : 02/01/2021<br>alopez : 01/29/2021<br>carol : 08/29/2016<br>carol : 08/11/2016<br>carol : 12/16/2013<br>carol : 3/21/2013<br>terry : 9/7/2012<br>carol : 9/5/2012<br>ckniffin : 8/22/2012<br>wwang : 5/31/2011<br>ckniffin : 5/18/2011<br>wwang : 9/27/2010<br>terry : 9/24/2010<br>wwang : 7/8/2010<br>wwang : 6/2/2010<br>ckniffin : 6/1/2010<br>wwang : 7/21/2009<br>wwang : 10/7/2008<br>ckniffin : 10/2/2008<br>wwang : 11/13/2007<br>ckniffin : 10/31/2007<br>wwang : 11/27/2006<br>wwang : 1/23/2006<br>terry : 1/11/2006<br>alopez : 7/14/2005<br>tkritzer : 6/1/2005<br>terry : 5/26/2005<br>ckniffin : 3/23/2004<br>tkritzer : 7/8/2003<br>terry : 6/30/2003<br>tkritzer : 5/7/2003<br>cwells : 11/21/2002<br>terry : 11/20/2002<br>carol : 10/8/2002<br>tkritzer : 10/3/2002<br>tkritzer : 10/2/2002<br>alopez : 9/11/2002<br>terry : 3/5/2002<br>carol : 1/14/2002<br>terry : 1/10/2002<br>carol : 10/19/2001<br>terry : 10/17/2001<br>cwells : 2/22/2001<br>terry : 11/6/2000<br>mcapotos : 2/14/2000<br>terry : 2/4/2000<br>mcapotos : 1/28/2000<br>mcapotos : 1/27/2000<br>mcapotos : 1/19/2000<br>terry : 1/19/2000<br>mimadm : 9/24/1994<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>supermim : 2/18/1990<br>supermim : 2/16/1990<br>ddp : 10/26/1989
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<strong>#</strong> 135150
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BIRT-HOGG-DUBE SYNDROME 1; BHD1
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<h4>
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<span class="mim-font">
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BHD<br />
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HORNSTEIN-KNICKENBERG SYNDROME<br />
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FIBROFOLLICULOMAS WITH TRICHODISCOMAS AND ACROCHORDONS
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</h4>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1263460007;
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<strong>ORPHA:</strong> 122;
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<strong>DO:</strong> 0050676;
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</p>
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<h4>
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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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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Phenotype <br /> mapping key
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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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</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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17p11.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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Birt-Hogg-Dube syndrome
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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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135150
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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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FLCN
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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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607273
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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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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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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 Birt-Hogg-Dube syndrome-1 (BHD1), also known as Hornstein-Knickenberg syndrome, is caused by heterozygous mutation in the FLCN gene (607273) on chromosome 17p11.</p><p>Primary spontaneous pneumothorax (173600) is an allelic disorder that may represent a milder part of the clinical spectrum of the BHD syndrome.</p>
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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>Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax (Nickerson et al., 2002). </p><p>BHD is similar to, but histologically and genetically distinct from, familial multiple discoid fibromas (FMDF; 190340).</p><p><strong><em>Genetic Heterogeneity of Birt-Hogg-Dube Syndrome</em></strong></p><p>
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See also BHD2 (620459), caused by mutation in the PRDM10 gene (618319) on chromosome 11q24.</p>
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</span>
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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>Hornstein and Knickenberg (1975) first described this disorder as 'perifollicular fibromatosis cutis with polyps of the colon' in 2 sibs. Their father was reportedly similarly affected, indicating an inherited condition. The proband was a 47-year-old woman who developed multiple perifollicular fibromas and skin tags affecting the neck, face, back, axillae, and groin. The skin lesions were 2 to 4 mm in diameter, flat-topped, solid, and skin-colored. Most had a central pit or plug. Histologic analysis showed whorl-shaped connective tissue fibers surrounding atrophic sebaceous glands. She also was found to have several colonic polyps, one of which showed malignant degeneration. The brother had similar adult onset of the skin lesions, but refused gastrointestinal examination. The patients' father also had renal and lung cysts. The disorder was distinguished from Gardner syndrome (see 175100). Hornstein and Knickenberg (1975) suggested that patients with follicular fibromatosis be examined for intestinal polyps. Hornstein (1976) reviewed the condition in this family and considered the disorder a genodermatosis. </p><p>Birt et al. (1977) described fibrofolliculomas with trichodiscomas (see 190340) and acrochordons in a family. Onset of this dermatologic condition was invariably in adulthood. A central hair was often visible in the lesions. Hereditary medullary carcinoma of the thyroid was also segregating, apparently independently, in the kindred. In a sibship of 9, 6 had medullary carcinoma of the thyroid. Two of those with thyroid cancer and 2 without had numerous small papular skin lesions that Birt et al. (1977) labeled fibrofolliculoma. The lesion was characterized by abnormal hair follicles with epithelial strands extending from the infundibulum of the hair follicle into a hyperplastic mantle of specialized fibrous tissue. Associated skin lesions were trichodiscomas (tumor of the hair disc) and acrochordons ('wart with a thin neck;' skin tag). </p><p>Fujita et al. (1981) reported the cases of 2 brothers and the son of one of them. By history the father of the 2 brothers was considered affected. Clinically the disorder was characterized by asymptomatic dome-shaped papules primarily involving the head, neck, chest, back, and arms. Ubogy-Rainey et al. (1987) likewise reported a family with 3 affected: a mother and her daughter and son. They discussed the clinical differential diagnosis of multiple firm, skin-colored papules. They diagrammed the histogenesis of benign follicular neoplasms, indicating that trichodiscomas are derived from the mesenchymal component of the pilar complex, trichofolliculomas, trichodiscomas, and trichoepitheliomas from epithelial components, and fibrofolliculomas from both epithelial and mesenchymal proliferation. Shapiro and Kopf (1991) described a family in which a mother and son had multiple desmoplastic trichoepitheliomas. The grandmother had a single cylindroma of the scalp. </p><p>Rongioletti et al. (1989) and Le Guyadec et al. (1998) described association of Birt-Hogg-Dube syndrome with intestinal polyposis. Roth et al. (1993) observed bilateral renal cell carcinoma in association with BHD. Chung et al. (1996) described multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with BHD. </p><p>Toro et al. (1999) evaluated kindreds with familial renal tumors for cutaneous manifestations of BHD. They performed complete oral and skin examinations of 152 patients from 49 families. In this way, they identified 3 extended kindreds in whom renal neoplasms and BHD appeared to segregate together. Two kindreds had renal oncocytomas and a third had a variant of papillary renal cell carcinoma. Thirteen patients exhibited BHD. Seven individuals, including a set of identical twins, had renal neoplasms and BHD. An additional 4 patients (3 deceased and not examined) in these families had renal neoplasms but not BHD. BHD without renal neoplasms was present in 6 individuals. Thirteen patients with fibrofolliculomas and trichodiscomas presented clinically with multiple smooth skin-colored to grayish-white papules located on the face, auricles, neck, and upper trunk. Oral papules were present in 9 of 28 and acrochordons in 11 of 28 patients. Features of BHD not previously appreciated included deforming lipomas in 5, collagenomas in 4, and pulmonary cysts in 4 of 28 patients. Families with BHD did not display germline mutations in the von Hippel-Lindau gene (608537) or in the tyrosine kinase domain of the MET protooncogene (164860), which are known to be associated with renal neoplasms. The pedigree pattern was entirely consistent with autosomal dominant inheritance; for example, a father and both of his twin sons had renal tumor and BHD. </p><p>Weirich et al. (1998) described 5 families in which multiple members had multiple bilateral renal oncocytomas. On dermatologic examination, 13 members of 3 of these families were found to have cutaneous BHD lesions (Toro et al., 1999). Subsequently, through mass mailings to dermatologists, Schmidt et al. (2001) identified 33 families with BHD skin lesions and associated renal tumors, lung cysts, or pneumothorax, and/or colonic polyps, including the original Canadian family described by Birt et al. (1977). Zbar et al. (2002) showed that BHD confers an increased risk for the development of renal tumors and lung cysts or spontaneous pneumothorax but not for the development of colonic polyps. </p><p>Kidney cancer may be classified into 4 histologic types: clear cell (CCRC, 75%), papillary (PRC, 15%), oncocytoma (5%), and chromophobe (5%) (Kovacs et al., 1997). In a study of 130 renal tumors found in 30 BHD patients, the spectrum of renal histology included 34% chromophobe, 5% oncocytoma, 50% chromophobe/oncocytic hybrid, 9% clear cell, 2% papillary (Pavlovich et al., 2002). </p><p>Toro et al. (2008) reported the clinical features of 89 individuals from 51 families with BHD syndrome. Forty-six (90%) of 51 families had individuals with multiple fibrofolliculomas, and 26 (57%) of 46 BHD families had individuals with a second histologically confirmed cutaneous lesion, including angiofibroma, trichodiscoma, and perifollicular fibroma. Thirty (34%) of 89 individuals and 25 (49%) of 51 families had kidney tumors. Forty-five (88%) of 51 families and 75 (84%) of 89 individuals had lung cysts on CT imaging. Twenty-seven (53%) of 51 families and 34 (38%) of 89 individuals had a history of spontaneous pneumothorax, most often associated with lung cysts. Eighteen (58%) of 31 individuals with a family history of pneumothorax developed pneumothoraces compared to 16 (28%) of 57 individuals without family history (p = 0.011). Toro et al. (2008) noted inter- and intrafamilial phenotypic variation. </p><p>Kluijt et al. (2009) reported a large Dutch family with BHD syndrome confirmed by genetic analysis (607273.0015). The proband was a 27-year-old man with metastatic high-grade clear cell carcinoma of the kidney. His 32-year-old brother had high-grade papillary renal cell carcinoma, and a deceased sister of the maternal grandmother had a hybrid chromophobe/oncocytic renal carcinoma at age 71. She also had a history of recurrent pneumothorax. Six of 13 mutation carriers in the family who had a renal MRI scan showed unilateral or bilateral renal cysts; all were 55 years or older. Pneumothorax occurred in 8 mutation carriers at a relatively advanced age (third through sixth decades), and 5 had lung cysts and bullous lung disease. Eleven carriers had facial papules, most with onset after age 40. Kluijt et al. (2009) suggested that the relatively early age of renal cancer in some family members may be due to a modifier gene. Importantly, the clinical features of the family also illustrated that skin anomalies and/or lung disease are not mandatory for considering BHD in patients with renal cancer. </p><p>Toro et al. (2008) reported the clinical features of 89 individuals from 51 families with BHD syndrome and mutation in the FLCN gene. Forty-six (90%) of 51 families had individuals with multiple fibrofolliculomas, and 26 (57%) of 46 BHD families had individuals with a second histologically confirmed cutaneous lesion, including angiofibroma, trichodiscoma, and perifollicular fibroma. Thirty (34%) of 89 individuals and 25 (49%) of 51 families had kidney tumours. Forty-five (88%) of 51 families and 75 (84%) of 89 individuals had lung cysts on CT imaging. Twenty-seven (53%) of 51 families and 34 (38%) of 89 individuals had a history of spontaneous pneumothorax, most often associated with lung cysts. Eighteen (58%) of 31 individuals with a family history of pneumothorax developed pneumothoraces compared to 16 (28%) of 57 individuals without family history (p = 0.011). Toro et al. (2008) noted inter- and intrafamilial phenotypic variation. </p><p><strong><em>Clinical Variability</em></strong></p><p>
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Maffe et al. (2011) found FLCN mutations in 9 (47%) of 19 probands who presented initially with extracutaneous manifestations suggestive of BHD syndrome, either a renal tumor or pneumothorax/lung cysts. Five (56%) of the 9 probands were found to have cutaneous hamartomas. Family history showed that 8 of the patients had affected relatives; however, 7 (44%) of 16 heterozygous relatives over the age of 20 years were asymptomatic. One patient had bilateral parotid oncocytomas, and tumor tissue showed loss of heterozygosity (LOH) for the wildtype FLCN allele. Maffe et al. (2011) noted that although most patients with BHD are ascertained on the basis of skin lesions, the diagnosis should be suspected in those who present with extracutaneous manifestations. </p><p><strong><em>Pathologic Findings</em></strong></p><p>
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The Hornstein-Knickenberg syndrome had been thought to be characterized by perifollicular fibromas, whereas BHD was characterized by fibrofolliculomas and trichodiscomas. Schulz and Hartschuh (1999) reported a father and daughter with a diagnosis of BHD. Extensive histologic examination of papular skin lesions indicated that histologic differences between the skin lesions are artificial and caused by interpretation of different sectioning planes; thus, fibrofolliculoma, perifollicular fibroma, and so-called trichodiscoma are in fact the same lesion. Similarly, some think that acrochordons are in fact fibrofolliculomas (Happle, 2012). </p><p>Starink et al. (2012) favored use of the term 'discoid fibroma' rather than 'trichodiscoma,' and suggested that most lesions described as 'trichodiscoma' in BHD were in fact 'fibrofolliculomas.' </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>Birt et al. (1977) observed this disorder in 15 persons in 3 generations, with male-to-male transmission, 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>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>Khoo et al. (2001) mapped the BHD locus by a genomewide linkage analysis using polymorphic microsatellite markers in a large Swedish family. They found evidence of linkage to chromosome 17p12-q11.2, with a maximum lod score of 3.58 for marker D17S1852. Further haplotype analysis defined a candidate interval of approximately 35 cM between the 2 flanking markers, D17S1791 and D17S798. </p><p>Schmidt et al. (2001) performed a genomewide scan in a large kindred with BHD and, by linkage analysis, localized the BHD locus to the pericentromeric region of 17p, with a lod score of 4.98 at D17S740 (recombination fraction = 0.0). Two-point linkage analysis of 8 additional families with BHD produced a maximum lod score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within an interval of less than 4-cM between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to 17p, suggesting genetic heterogeneity. The BHD locus lies within the chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy number repeat elements, is unstable and is associated with a number of diseases. </p><p>Nickerson et al. (2002) narrowed the critical region for the BHD locus to a 700-kb segment on chromosome 17p11.2. </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>Napolitano et al. (2020) showed that TFEB (600744), a master regulator of lysosomal biogenesis and autophagy, is phosphorylated by mTORC1 (see 601231) via a substrate-specific mechanism that is mediated by Rag GTPases. Owing to this mechanism, the phosphorylation of TFEB is strictly dependent on the amino-acid-mediated activation of RagC (608267) and RagD (608268) GTPases, but is insensitive to RHEB activity induced by growth factors. This mechanism has a crucial role in Birt-Hogg-Dube syndrome, a disorder that is caused by mutations in the RagC and RagD activator folliculin (FLCN). Napolitano et al. (2020) found that constitutive activation of TFEB is the main driver of the kidney abnormalities and mTORC1 hyperactivity in a mouse model of Birt-Hogg-Dube syndrome. Accordingly, depletion of TFEB in kidneys of these mice fully rescued the disease phenotype and associated lethality, and normalized mTORC1 activity. </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>By positional cloning, Nickerson et al. (2002) identified a novel gene, first designated BHD and later FLCN, in the BHD critical region on 17p11.2. In several BHD families, they identified protein-truncating mutations in the FLCN gene (607273.0001-607273.0005). Nickerson et al. (2002) stated that their identification of this novel kidney cancer gene associated with renal oncocytoma or chromophobe renal cancer could contribute to understanding the role of folliculin in pathways common to skin, lung, and kidney development. </p><p>Khoo et al. (2002) studied 4 sporadic BHD cases and 4 families with a total of 23 affected subjects. Haplotype analysis of these families using BHD-linked markers showed that they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified 2 germline mutations on exon 11 in 3 of 4 families as well as 2 of 4 sporadic cases. A novel somatic mutation was detected in a BHD-related chromophobe renal carcinoma. </p><p>Schmidt et al. (2005) performed direct sequencing of the BHD gene in 30 families with BHD and reported that combined with their previous data (Nickerson et al., 2002), they had identified germline BHD mutations in 51 (84%) of 61 families with BHD. Each family's mutation cosegregated with disease and was not found in at least 160 unaffected individuals. Of the 51 families with a germline BHD mutation, 27 (53%) had a cytosine insertion or deletion in the mononucleotide tract of 8 cytosines in exon 11 (1285insC, 607273.0001; 1285delC, 607273.0002, respectively), which appears to represent a mutation hotspot. Two large families with BHD, one of them the original family reported by Birt et al. (1977), showed linkage to 17p11.2 but had no mutation in the BHD gene by direct sequencing. Schmidt et al. (2005) noted that most reported mutations were predicted to terminate folliculin prematurely and to result in loss of function and suggested that BHD may act as a tumor suppressor gene. </p><p>In affected individuals from 51 (88%) of 58 families with BHD, Toro et al. (2008) identified 23 different mutations in the FLCN gene, including 13 novel mutations (see, e.g., 607273.0014). The 1285insC or 1285delC mutations were most common, occurring in 14 and 5 families, respectively. All mutations except one were predicted to result in a truncated protein. There were no apparent genotype/phenotype correlations. </p><p>Kunogi et al. (2010) screened the FLCN gene by DHPLC in 36 Japanese patients with multiple lung cysts of undetermined causes, all but 1 of whom had suffered at least 1 pneumothorax, and identified 13 different germline mutations in 23 of the patients, respectively. The remaining 13 patients were further analyzed by quantitative PCR, and large genomic deletions (see, e.g., 607273.0017) were found in 2; thus 25 (69.4%) of the 36 patients had germline FLCN mutations. Only 6 of the mutation-positive patients had skin lesions, and 2 others had renal tumors, 1 of which was an angiomyolipoma and the other a renal cancer (histopathologic information unavailable). Kunogi et al. (2010) noted that 13 (52%) of the 25 mutations were located in the 3-prime end of the FLCN gene, and that these Japanese patients with FLCN mutations had a very low incidence of skin and renal involvement. </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>Nomenclature</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>Happle (2012) noted that Hornstein and Knickenberg (1975) first described this disorder as 'perifollicular fibromatosis with polyps of the colon--a cutaneo-intestinal syndrome.' Since the designation 'Birt-Hogg-Dube syndrome' is entrenched in the medical literature, it is retained here as the preferred title; 'Hornstein-Knickenberg syndrome' is used here as an alternative title to give credit to the original authors. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a naturally occurring canine kidney cancer syndrome that was originally described in German shepherd dogs. Lingaas et al. (2003) narrowed the RCND interval to a small region on canine chromosome 5 that overlapped the human BHD gene. The authors described a his255-to-arg mutation in exon 7 of the canine Bhd gene that segregated with the disease phenotype. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Birt, A. R., Hogg, G. R., Dube, W. J.
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<strong>Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.</strong>
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Arch. Derm. 113: 1674-1677, 1977.
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[PubMed: 596896]
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 07/28/2023<br>Ada Hamosh - updated : 01/29/2021<br>Cassandra L. Kniffin - updated : 8/22/2012<br>Cassandra L. Kniffin - updated : 5/18/2011<br>Marla J. F. O'Neill - updated : 9/24/2010<br>Cassandra L. Kniffin - updated : 6/1/2010<br>Cassandra L. Kniffin - updated : 10/2/2008<br>George E. Tiller - updated : 1/11/2006<br>Marla J. F. O'Neill - updated : 5/26/2005<br>Victor A. McKusick - updated : 6/30/2003<br>Victor A. McKusick - updated : 11/20/2002<br>Victor A. McKusick - updated : 10/2/2002<br>Victor A. McKusick - updated : 1/10/2002<br>Victor A. McKusick - updated : 10/17/2001<br>Victor A. McKusick - updated : 2/4/2000<br>Victor A. McKusick - updated : 1/19/2000
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</span>
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Victor A. McKusick : 6/4/1986
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carol : 02/29/2024<br>carol : 07/31/2023<br>carol : 07/28/2023<br>carol : 02/01/2021<br>alopez : 01/29/2021<br>carol : 08/29/2016<br>carol : 08/11/2016<br>carol : 12/16/2013<br>carol : 3/21/2013<br>terry : 9/7/2012<br>carol : 9/5/2012<br>ckniffin : 8/22/2012<br>wwang : 5/31/2011<br>ckniffin : 5/18/2011<br>wwang : 9/27/2010<br>terry : 9/24/2010<br>wwang : 7/8/2010<br>wwang : 6/2/2010<br>ckniffin : 6/1/2010<br>wwang : 7/21/2009<br>wwang : 10/7/2008<br>ckniffin : 10/2/2008<br>wwang : 11/13/2007<br>ckniffin : 10/31/2007<br>wwang : 11/27/2006<br>wwang : 1/23/2006<br>terry : 1/11/2006<br>alopez : 7/14/2005<br>tkritzer : 6/1/2005<br>terry : 5/26/2005<br>ckniffin : 3/23/2004<br>tkritzer : 7/8/2003<br>terry : 6/30/2003<br>tkritzer : 5/7/2003<br>cwells : 11/21/2002<br>terry : 11/20/2002<br>carol : 10/8/2002<br>tkritzer : 10/3/2002<br>tkritzer : 10/2/2002<br>alopez : 9/11/2002<br>terry : 3/5/2002<br>carol : 1/14/2002<br>terry : 1/10/2002<br>carol : 10/19/2001<br>terry : 10/17/2001<br>cwells : 2/22/2001<br>terry : 11/6/2000<br>mcapotos : 2/14/2000<br>terry : 2/4/2000<br>mcapotos : 1/28/2000<br>mcapotos : 1/27/2000<br>mcapotos : 1/19/2000<br>terry : 1/19/2000<br>mimadm : 9/24/1994<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>supermim : 2/18/1990<br>supermim : 2/16/1990<br>ddp : 10/26/1989
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