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Entry
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- #115310 - PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4; PPGL4
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- OMIM
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<p>
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<span class="h4">#115310</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/115310"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS168000"> <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="#diagnosis">Diagnosis</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=PHEOCHROMOCYTOMA/PARAGANGLIOMA 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=8775&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/NBK1548/" 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/5581" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=115310[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=29072" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="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:0050773" 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/115310" 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/OMIA001268/" 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:0050773" 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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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 29072<br />
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<strong>DO:</strong> 0050773<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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115310
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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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PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4; PPGL4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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PARAGANGLIOMAS 4; PGL4<br />
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CAROTID BODY TUMORS AND MULTIPLE EXTRAADRENAL PHEOCHROMOCYTOMAS<br />
|
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PHEOCHROMOCYTOMA, EXTRAADRENAL, AND CERVICAL PARAGANGLIOMA<br />
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PARAGANGLIOMAS, HEREDITARY EXTRAADRENAL<br />
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PHEOCHROMOCYTOMA, FAMILIAL EXTRAADRENAL<br />
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PARAGANGLIOMA, FAMILIAL MALIGNANT
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/209?start=-3&limit=10&highlight=209">
|
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1p36.13
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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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Pheochromocytoma/paraganglioma syndrome 4
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/115310"> 115310 </a>
|
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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SDHB
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/185470"> 185470 </a>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
|
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<a href="/clinicalSynopsis/115310" 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')">
|
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<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
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<div class="btn-group">
|
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|
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<a href="/phenotypicSeries/PS168000" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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<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')">
|
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<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/115310" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/115310" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
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</div>
|
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|
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
|
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
|
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|
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<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 />
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|
|
|
</span>
|
|
</div>
|
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|
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</div>
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</div>
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
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|
|
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Ears </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Pulsatile tinnitus (tympanic paraganglioma) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854340&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854340</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/232322006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">232322006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H93.A" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H93.A</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008629" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008629</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
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|
|
</div>
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|
|
</div>
|
|
|
|
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|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Heart </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Palpitations (with pheochromocytoma) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854346&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854346</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80313002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80313002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R00.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R00.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/785.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">785.1</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001962" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001962</a>]</span><br /> -
|
|
Tachycardia (with pheochromocytoma) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854347&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854347</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86651002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86651002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/3424008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">3424008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R00.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R00.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/785.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">785.0</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001649" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001649</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hypertension (with pheochromocytoma) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1397267&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1397267</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38341003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38341003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/401-405.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">401-405.99</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/997.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">997.91</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
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|
|
|
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|
|
|
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|
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|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Diaphoresis (with pheochromocytoma) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854341&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854341</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/415691001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">415691001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52613005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52613005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R61" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R61</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000975" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000975</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
|
|
|
|
|
|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Headache (with pheochromocytoma) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854337&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854337</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25064002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25064002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R51.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R51.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R51</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/784.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.0</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002315</a>]</span><br /> -
|
|
Cranial nerve palsies can arise with head and neck paragangliomas <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854338&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854338</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Behavioral Psychiatric Manifestations </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Anxiety (with pheochromocytoma) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854339&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854339</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48694002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48694002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197480006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197480006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F41.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F41.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F41.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F41.1</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000739" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000739</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
|
</div>
|
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|
|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEOPLASIA </strong>
|
|
</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Paragangliomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/72787006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">72787006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/127027008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">127027008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253029009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253029009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302833002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302833002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/803009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">803009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0030421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030421</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002668" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002668</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002668" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002668</a>]</span><br /> -
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|
Multiple tumors in 28% of patients <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861849&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861849</a>]</span><br /> -
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Paragangliomas, head and neck (31%) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1333944&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1333944</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002864" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002864</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002864" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002864</a>]</span><br /> -
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Chemodectomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/51747000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">51747000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302834008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302834008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/127028003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">127028003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30699005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30699005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0007279&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007279</a>, <a href="https://bioportal.bioontology.org/search?q=C3494181&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3494181</a>, <a href="https://bioportal.bioontology.org/search?q=C0030422&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030422</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030074" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030074</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002668" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002668</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030074" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030074</a>]</span><br /> -
|
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Carotid body tumors <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/127028003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">127028003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30699005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30699005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0007279&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007279</a>, <a href="https://bioportal.bioontology.org/search?q=C3494181&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3494181</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030074" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030074</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002668" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002668</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002668" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002668</a>]</span><br /> -
|
|
Glomus jugular tumors <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/127030001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">127030001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0017671&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017671</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003001</a>]</span><br /> -
|
|
Pheochromocytomas, adrenal (28%) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85583005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85583005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302835009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302835009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551683&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551683</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006748" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006748</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006748" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006748</a>]</span><br /> -
|
|
Pheochromocytomas, extraadrenal (48%) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1257877&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1257877</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006737" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006737</a>]</span><br /> -
|
|
Malignancy (34%) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1240414004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1240414004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/372087000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">372087000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/363346000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">363346000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C80" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C80</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/C80.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C80.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/199" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">199</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0006826&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0006826</a>, <a href="https://bioportal.bioontology.org/search?q=C1306459&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1306459</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002664" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002664</a>]</span><br /> -
|
|
Gastrointestinal stromal tumors (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128755003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128755003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/420120006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">420120006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1187383001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1187383001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C49.A" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C49.A</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0238198&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0238198</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100723" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100723</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100723" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100723</a>]</span><br /> -
|
|
Renal cell carcinoma (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/702391001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">702391001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/41607009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">41607009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1187306007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1187306007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254915003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254915003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0007134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007134</a>, <a href="https://bioportal.bioontology.org/search?q=C0279702&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0279702</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005584" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005584</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0006770" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006770</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005584" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005584</a>]</span><br /> -
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Neuroblastoma (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/87364003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">87364003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432328008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432328008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700095&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700095</a>, <a href="https://bioportal.bioontology.org/search?q=C0027819&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027819</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003006</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> LABORATORY ABNORMALITIES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Increased urinary catecholamines (with pheochromocytoma) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861855&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861855</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Adult onset (mean 30 years, range 10-65 years) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853562&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853562</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span><br /> -
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Incomplete penetrance (range 13% to 77% by 50 years of age) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836598&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836598</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span><br /> -
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Signs and symptoms depend on tumor location and activity<br /> -
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Patients may have head and neck paragangliomas only, adrenal or extraadrenal pheochromocytomas only, or both<br /> -
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See also PGL1 (<a href="/entry/168000">168000</a>)<br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the succinate dehydrogenase complex subunit B gene (SDHB, <a href="/entry/185470#0001">185470.0001</a>)<br />
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</span>
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</div>
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<h5>
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Pheochromocytoma/paraganglioma syndrome
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- <a href="/phenotypicSeries/PS168000">PS168000</a>
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- 7 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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<table class="table table-bordered table-condensed table-hover mim-table-padding">
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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>
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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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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />mapping key</strong>
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</th>
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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>
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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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<strong>Gene/Locus<br />MIM number</strong>
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<tbody>
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<span class="mim-font">
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<a href="/geneMap/1/209?start=-3&limit=10&highlight=209"> 1p36.13 </a>
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</span>
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</td>
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<span class="mim-font">
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<a href="/entry/115310"> Pheochromocytoma/paraganglioma syndrome 4 </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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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<span class="mim-font">
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<a href="/entry/115310"> 115310 </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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<a href="/entry/185470"> SDHB </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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<a href="/entry/185470"> 185470 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/1349?start=-3&limit=10&highlight=1349"> 1q23.3 </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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<a href="/entry/605373"> Pheochromocytoma/paraganglioma syndrome 3 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/605373"> 605373 </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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<a href="/entry/602413"> SDHC </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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<a href="/entry/602413"> 602413 </a>
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</span>
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</td>
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</tr>
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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/5/9?start=-3&limit=10&highlight=9"> 5p15.33 </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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<a href="/entry/614165"> Pheochromocytoma/paraganglioma syndrome 5 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614165"> 614165 </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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<a href="/entry/600857"> SDHA </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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<a href="/entry/600857"> 600857 </a>
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</span>
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</td>
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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/11/456?start=-3&limit=10&highlight=456"> 11q12.2 </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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<a href="/entry/601650"> Pheochromocytoma/paraganglioma syndrome 2 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/601650"> 601650 </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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<a href="/entry/613019"> SDHAF2 </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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<a href="/entry/613019"> 613019 </a>
|
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</span>
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</td>
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</tr>
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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/11/930?start=-3&limit=10&highlight=930"> 11q23.1 </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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<a href="/entry/168000"> Pheochromocytoma/paraganglioma syndrome 1 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/168000"> 168000 </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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<a href="/entry/602690"> SDHD </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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<a href="/entry/602690"> 602690 </a>
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</span>
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</td>
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</tr>
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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/14/392?start=-3&limit=10&highlight=392"> 14q24.3 </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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<a href="/entry/618475"> Pheochromocytoma/paraganglioma syndrome 7 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/618475"> 618475 </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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<a href="/entry/126063"> DLST </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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<a href="/entry/126063"> 126063 </a>
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</span>
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</td>
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</tr>
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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/17/93?start=-3&limit=10&highlight=93"> 17p13.2 </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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<a href="/entry/618464"> Pheochromocytoma/paraganglioma syndrome 6 </a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/618464"> 618464 </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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<a href="/entry/604165"> SLC25A11 </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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<a href="/entry/604165"> 604165 </a>
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</span>
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</td>
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</tbody>
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</table>
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<div class="text-right small">
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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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</span>
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</h4>
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<p>A number sign (#) is used with this entry because of evidence that pheochromocytoma/paraganglioma syndrome-4 (PPGL4) is caused by heterozygous mutation in the SDHB gene (<a href="/entry/185470">185470</a>), which encodes the iron sulfur subunit of succinate dehydrogenase, on chromosome 1p36.</p>
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<br />
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<div>
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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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<p>Pheochromocytoma/paraganglioma syndrome-4 (PPGL4) is an autosomal dominant disorder characterized by the development of neuroendocrine tumors, usually in adulthood. Paragangliomas are tumors derived from paraganglia located throughout the body. Nonchromaffin types primarily serve as chemoreceptors and are located in the head and neck region (i.e., carotid body, jugular, vagal, and tympanic regions), whereas chromaffin types have endocrine activity, conventionally referred to as 'pheochromocytomas,' and are usually located below the head and neck (i.e., adrenal medulla and pre- and paravertebral thoracoabdominal regions). PPGL can manifest as nonchromaffin head and neck tumors only, adrenal and/or extraadrenal pheochromocytomas only, or a combination of the 2 types of tumors (<a href="#5" class="mim-tip-reference" title="Baysal, B. E. <strong>Hereditary paraganglioma targets diverse paraganglia.</strong> J. Med. Genet. 39: 617-622, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12205103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12205103</a>] [<a href="https://doi.org/10.1136/jmg.39.9.617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12205103">Baysal, 2002</a>; <a href="#18" class="mim-tip-reference" title="Neumann, H. P. H., Pawlu, C., Peczkowska, M., Bausch, B., McWhinney, S. R., Muresan, M., Buchta, M., Franke, G., Klisch, J., Bley, T. A., Hoegerle, S., Boedeker, C. C., Opocher, G., Schipper, J., Januszewicz, A., Eng. C. <strong>Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations.</strong> JAMA 292: 943-951, 2004. Note: Erratum: JAMA 292: 1686 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15328326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15328326</a>] [<a href="https://doi.org/10.1001/jama.292.8.943" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15328326">Neumann et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15328326+12205103" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of pheochromocytoma/paraganglioma syndrome, see PPGL1 (<a href="/entry/168000">168000</a>).</p>
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<br />
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<div>
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<strong>Clinical Features</strong>
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<p><a href="#7" class="mim-tip-reference" title="Bogdasarian, R. S., Lotz, P. R. <strong>Multiple simultaneous paragangliomas of the head and neck in association with multiple retroperitoneal pheochromocytomas.</strong> Otolaryng. Head Neck Surg. 87: 648-652, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/503530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">503530</a>] [<a href="https://doi.org/10.1177/019459987908700520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="503530">Bogdasarian and Lotz (1979)</a> reported a family in which affected individuals had multiple catecholamine-secreting head and neck paragangliomas and retroperitoneal pheochromocytomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=503530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Glowniak, J. V., Shapiro, B., Sisson, J. C., Thompson, N. W., Coran, A. G., Lloyd, R., Kelsch, R. C., Beierwaltes, W. H. <strong>Familial extra-adrenal pheochromocytoma: a new syndrome.</strong> Arch. Intern. Med. 145: 257-261, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3977485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3977485</a>]" pmid="3977485">Glowniak et al. (1985)</a> reported a family in which 3 individuals spanning 3 generations had pheochromocytoma of the right renal hilum; 1 of these patients had metastatic disease. In the 2 previous generations, pheochromocytoma was suspected in 3 persons, including a hypertensive girl who died suddenly at age 16 years. The pedigree had an obligatory carrier, according to the hypothesis of autosomal dominant inheritance, who at age 52 years showed no signs of pheochromocytoma by any test including CT scans and scintigraphy with radioiodine-tagged metaiodobenzylguanidine. <a href="#13" class="mim-tip-reference" title="Glowniak, J. V., Shapiro, B., Sisson, J. C., Thompson, N. W., Coran, A. G., Lloyd, R., Kelsch, R. C., Beierwaltes, W. H. <strong>Familial extra-adrenal pheochromocytoma: a new syndrome.</strong> Arch. Intern. Med. 145: 257-261, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3977485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3977485</a>]" pmid="3977485">Glowniak et al. (1985)</a> referred to reports by <a href="#9" class="mim-tip-reference" title="Cook, J. E., Urich, R. W., Sample, H. G., Jr., Fawcett, N. W. <strong>Peculiar familial and malignant pheochromocytomas of the organs of Zuckerkandl.</strong> Ann. Intern. Med. 52: 126-133, 1960.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13811705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13811705</a>] [<a href="https://doi.org/10.7326/0003-4819-52-1-126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13811705">Cook et al. (1960)</a>, who described a brother and sister with pheochromocytoma of the organs of Zuckerkandl, which are masses of chromaffin tissue found at the aortic bifurcation, and <a href="#24" class="mim-tip-reference" title="Spring, D. B., Palubinskas, A. J. <strong>Familial pheochromocytoma: a rare case of hydronephrosis and hydroureter in two generations.</strong> Brit. J. Radiol. 50: 596-599, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/890238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">890238</a>] [<a href="https://doi.org/10.1259/0007-1285-50-596-596" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="890238">Spring and Palubinskas (1977)</a>, who described a mother and son with pheochromocytoma involving the lower urinary tract. <a href="#13" class="mim-tip-reference" title="Glowniak, J. V., Shapiro, B., Sisson, J. C., Thompson, N. W., Coran, A. G., Lloyd, R., Kelsch, R. C., Beierwaltes, W. H. <strong>Familial extra-adrenal pheochromocytoma: a new syndrome.</strong> Arch. Intern. Med. 145: 257-261, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3977485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3977485</a>]" pmid="3977485">Glowniak et al. (1985)</a> suggested that primary extraadrenal pheochromocytoma was a distinct genetic entity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3977485+13811705+890238" 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="#19" class="mim-tip-reference" title="Pritchett, J. W. <strong>Familial concurrence of carotid body tumor and pheochromocytoma.</strong> Cancer 49: 2578-2579, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7074575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7074575</a>] [<a href="https://doi.org/10.1002/1097-0142(19820615)49:12<2578::aid-cncr2820491227>3.0.co;2-m" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7074575">Pritchett (1982)</a> and <a href="#16" class="mim-tip-reference" title="Jensen, J. C., Choyke, P. L., Rosenfeld, M., Pass, H. I., Keiser, H., White, B., Travis, W., Linehan, W. M. <strong>A report of familial carotid body tumors and multiple extra-adrenal pheochromocytomas.</strong> J. Urol. 145: 1040-1042, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2016787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2016787</a>] [<a href="https://doi.org/10.1016/s0022-5347(17)38524-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2016787">Jensen et al. (1991)</a> reported familial concurrence of carotid body tumors and adrenal and extraadrenal pheochromocytomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2016787+7074575" 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="#23" class="mim-tip-reference" title="Skoldberg, F., Grimelius, L., Woodward, E. R., Rorsman, F., Van Schothorst, E. W., Winqvist, O., Karlsson, F. A., Akerstrom, G., Kampe, O., Husebye, E. S. <strong>A family with hereditary extra-adrenal paragangliomas without evidence for mutations in the von Hippel-Lindau disease or ret genes.</strong> Clin. Endocr. 48: 11-16, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9509062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9509062</a>] [<a href="https://doi.org/10.1046/j.1365-2265.1998.00320.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9509062">Skoldberg et al. (1998)</a> reported a Swedish family in which members of 3 successive generations had extramedullary pheochromocytomas (familial chromaffin paragangliomas). An affected woman in the first generation had paragangliomas in the thyroid gland and bladder. Thyrotoxicosis was diagnosed at the age of 59; she died at the age of 69 of acute heart failure associated with thyrotoxicosis. This woman's daughter had paragangliomas retroperitoneally and in the neck, and her grandson had 2 retroperitoneal paragangliomas. The transmission from 2 females differentiated the condition from PLG1, which shows imprinting with inheritance only from the father. No mutations were found in the VHL gene (<a href="/entry/608537">608537</a>) or the RET gene (<a href="/entry/164761">164761</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9509062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Young, A. L., Baysal, B. E., Deb, A., Young, W. F., Jr. <strong>Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene.</strong> J. Clin. Endocr. Metab. 87: 4101-4105, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12213855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12213855</a>] [<a href="https://doi.org/10.1210/jc.2002-020312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12213855">Young et al. (2002)</a> reported a man diagnosed with metastatic catecholamine-secreting paragangliomas in 1972. He presented with signs of catecholamine excess, including recurrent throbbing headache, palpitations, diaphoresis, and anxiety. He had hypertension and increased excretion of urinary catecholamines and total metanephrines. Laparotomy identified 3 paragangliomas: 2 periaortic and 1 adjacent to the adrenal gland. He was later found to have paragangliomas behind the head of the pancreas, beneath the diaphragm, within the liver, in the femur, and in the thorax. He was well in 2002. His 27-year-old son also developed extraadrenal catecholamine-secreting paragangliomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12213855" 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="Vanharanta, S., Buchta, M., McWhinney, S. R., Virta, S. K., Peczkowska, M., Morrison, C. D., Lehtonen, R., Januszewicz, A., Jarvinen, H., Juhola, M., Mecklin, J.-P., Pukkala, E., Herva, R., Kiuru, M., Nupponen, N. N., Aaltonen, L. A., Neumann, H. P. H., Eng, C. <strong>Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.</strong> Am. J. Hum. Genet. 74: 153-159, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14685938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14685938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14685938[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/10.1086/381054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14685938">Vanharanta et al. (2004)</a> reported a family in which the proband was diagnosed with metastatic renal clear cell carcinoma (RCC; <a href="/entry/144700">144700</a>) at age 28 years. The patient's mother had a malignant PGL within the heart. The patient and his mother both had a heterozygous germline mutation in the SDHB gene (<a href="/entry/185470#0006">185470.0006</a>); tumor tissue from both patients showed loss of heterozygosity (LOH) of the wildtype SDHB allele. In an unrelated family, 2 sibs had PGL and developed RCC in their twenties. Both sibs had a heterozygous germline mutation in the SDHB gene (<a href="/entry/185470#0005">185470.0005</a>); PGL tissue from 1 patient and both RCC tumor tissue showed somatic LOH of the wildtype allele. No SDHB mutations were identified in 35 renal cell carcinomas diagnosed before age 50 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14685938" 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="Timmers, H. J. L. M., Kozupa, A., Eisenhofer, G., Raygada, M., Adams, K. T., Solis, D., Lenders, J. W. M., Pacak, K. <strong>Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas.</strong> J. Clin. Endocr. Metab. 92: 779-786, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200167</a>] [<a href="https://doi.org/10.1210/jc.2006-2315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200167">Timmers et al. (2007)</a> reviewed the findings in 29 patients (16 males) with SDHB-related abdominal or thoracic PGL. PGL often presented as apparently sporadic PGL with symptoms related to tumor mass effect rather than to catecholamine excess. The predominant biochemical phenotype consisted of hypersecretion of norepinephrine and/or dopamine, but 10% of tumors were biochemically silent. The clinical expression of the tumors could not be predicted by the genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200167" 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="Timmers, H. J. L. M., Kozupa, A., Eisenhofer, G., Raygada, M., Adams, K. T., Solis, D., Lenders, J. W. M., Pacak, K. <strong>Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas.</strong> J. Clin. Endocr. Metab. 92: 779-786, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200167</a>] [<a href="https://doi.org/10.1210/jc.2006-2315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200167">Timmers et al. (2007)</a> studied 29 patients (16 males) with SDHB-related abdominal or thoracic PGL. Mean +/- SD age at diagnosis was 33.7 +/- 15.7 years. Tumor-related pain was among the presenting symptoms in 54% of patients and was the sole symptom in 14%. Seventy-six percent had hypertension, and 90% lacked a family history of PGL. All primary tumors but one originated from extraadrenal locations. Mean +/- SD tumor size was 7.8 +/- 3.7 cm. In this referral-based study, 28% presented with metastatic disease and all but one eventually developed metastases after 2.7 +/- 4.1 years. Ten percent had additional head and neck PGLs. The biochemical phenotype was consistent with hypersecretion of both norepinephrine and dopamine in 46%, norepinephrine only in 41%, and dopamine only in 3%. SDHB-related PGL often presents as apparently sporadic PGL with symptoms related to tumor mass effect rather than to catecholamine excess. The predominant biochemical phenotype consists of hypersecretion of norepinephrine and/or dopamine, whereas 10% of tumors are biochemically silent. <a href="#25" class="mim-tip-reference" title="Timmers, H. J. L. M., Kozupa, A., Eisenhofer, G., Raygada, M., Adams, K. T., Solis, D., Lenders, J. W. M., Pacak, K. <strong>Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas.</strong> J. Clin. Endocr. Metab. 92: 779-786, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200167</a>] [<a href="https://doi.org/10.1210/jc.2006-2315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200167">Timmers et al. (2007)</a> concluded that the clinical expression of these tumors cannot be predicted by the genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200167" 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="#2" class="mim-tip-reference" title="Armstrong, R., Greenhalgh, K. L., Rattenberry, E., Judd, B., Shukla, R., Losty, P. D., Maher, E. R. <strong>Succinate dehydrogenase subunit B (SDHB) gene deletion associated with a composite paraganglioma/neuroblastoma. (Letter)</strong> J. Med. Genet. 46: 215-216, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251979</a>] [<a href="https://doi.org/10.1136/jmg.2008.060749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251979">Armstrong et al. (2009)</a> reported a 13-year-old girl with a composite paraganglioma/neuroblastoma (<a href="/entry/256700">256700</a>) who had a heterozygous germline deletion of the SDHB gene. She was initially found to have a paravertebral extraadrenal pheochromocytoma with features of a paraganglioma on histologic examination of the resected tumor, but further analysis showed an area with morphology of a differentiating neuroblastoma. The authors referred to a patient reported by <a href="#8" class="mim-tip-reference" title="Cascon, A., Landa, I., Lopez-Jimenez, E., Diez-Hernandez, A., Buchta, M., Montero-Conde, C., Leskela, S., Leandro-Garcia, L. J., Leton, R., Rodriguez-Antona, C., Eng, C., Neumann, H. P. H., Robledo, M. <strong>Molecular characterisation of a common SDHB deletion in paraganglioma patients. (Letter)</strong> J. Med. Genet. 45: 233-238, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18057081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18057081</a>] [<a href="https://doi.org/10.1136/jmg.2007.054965" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18057081">Cascon et al. (2008)</a> who had an adrenal neuroblastoma and partial deletion of the SDHB gene (<a href="/entry/185470#0017">185470.0017</a>). <a href="#2" class="mim-tip-reference" title="Armstrong, R., Greenhalgh, K. L., Rattenberry, E., Judd, B., Shukla, R., Losty, P. D., Maher, E. R. <strong>Succinate dehydrogenase subunit B (SDHB) gene deletion associated with a composite paraganglioma/neuroblastoma. (Letter)</strong> J. Med. Genet. 46: 215-216, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251979</a>] [<a href="https://doi.org/10.1136/jmg.2008.060749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19251979">Armstrong et al. (2009)</a> noted that both paragangliomas and neuroblastomas show common embryogenesis from the neural crest, which may explain the composite histologic tumor identified in their patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19251979+18057081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Schimke, R. N., Collins, D. L., Stolle, C. A. <strong>Paraganglioma, neuroblastoma, and a SDHB mutation: resolution of a 30-year-old mystery.</strong> Am. J. Med. Genet. 152A: 1531-1535, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503330</a>] [<a href="https://doi.org/10.1002/ajmg.a.33384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503330">Schimke et al. (2010)</a> reported 2 adult sibs with paraspinal paragangliomas. The family was of note because a deceased sib, previously reported by <a href="#11" class="mim-tip-reference" title="Fairchild, R. S., Kyner, J. L., Hermreck, A., Schimke, R. N. <strong>Neuroblastoma, pheochromocytoma, and renal cell carcinoma: occurrence in a single patient.</strong> JAMA 242: 2210-2211, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/490809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">490809</a>]" pmid="490809">Fairchild et al. (1979)</a>, had neuroblastoma as an infant, metastatic extraadrenal sympathetic paragangliomas consistent with pheochromocytoma as a young adult, and renal cell carcinoma as an adult. <a href="#11" class="mim-tip-reference" title="Fairchild, R. S., Kyner, J. L., Hermreck, A., Schimke, R. N. <strong>Neuroblastoma, pheochromocytoma, and renal cell carcinoma: occurrence in a single patient.</strong> JAMA 242: 2210-2211, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/490809/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">490809</a>]" pmid="490809">Fairchild et al. (1979)</a> noted that occurrence of these cancers in the same patient was unique. In addition, a first cousin of these sibs had died from metastatic renal cell carcinoma and had a history of a benign paraaortic PGL. Genetic analysis identified a heterozygous mutation in the SDHB gene (V140F; <a href="/entry/185470#0016">185470.0016</a>). There were 2 unaffected family members, suggesting decreased penetrance or a 'leaky' mutation. <a href="#22" class="mim-tip-reference" title="Schimke, R. N., Collins, D. L., Stolle, C. A. <strong>Paraganglioma, neuroblastoma, and a SDHB mutation: resolution of a 30-year-old mystery.</strong> Am. J. Med. Genet. 152A: 1531-1535, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20503330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20503330</a>] [<a href="https://doi.org/10.1002/ajmg.a.33384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20503330">Schimke et al. (2010)</a> noted the importance of family history in elucidating the etiology of this inherited disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20503330+490809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Heesterman, B. L., Bayley, J. P., Tops, C. M., Hes, F. J., van Brussel, B. T. J., Corssmit, E. P. M., Hamming, J. F., van der Mey, A. G. L., Jansen, J. C. <strong>High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations.</strong> Europ. J. Hum. Genet. 21: 469-470, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22948026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22948026</a>] [<a href="https://doi.org/10.1038/ejhg.2012.203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22948026">Heesterman et al. (2013)</a> found that 2 (11.8%) of 17 asymptomatic SDHB mutation carriers screened with MRI had an occult paraganglioma, both of which were vagal body tumors. One SDHB mutation carrier had a sympathetic paraganglioma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22948026" 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="Rijken, J. A., Niemeijer, N. D., Corssmit, E. P. M., Jonker, M. A., Leemans, C. R., Menko, F. H., Hensen, E. F. <strong>Low penetrance of paraganglioma and pheochromocytoma in an extended kindred with a germline SDHB exon 3 deletion.</strong> Clin. Genet. 89: 128-132, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25827221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25827221</a>] [<a href="https://doi.org/10.1111/cge.12591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25827221">Rijken et al. (2016)</a> reported a large multigenerational Dutch family in which 6 individuals had PGL4. Three patients had a pheochromocytoma, 2 of which were malignant; 1 patient had a carotid body PGL, 1 had a jugulotympanic PGL, and another had an extraadrenal PGL. There was evidence of incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25827221" 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>PGL4 is transmitted in an autosomal dominant pattern with incomplete penetrance. Reports of penetrance have varied, but have been generally high: e.g., 77% by age 50 years, 100% by 80 years (<a href="#18" class="mim-tip-reference" title="Neumann, H. P. H., Pawlu, C., Peczkowska, M., Bausch, B., McWhinney, S. R., Muresan, M., Buchta, M., Franke, G., Klisch, J., Bley, T. A., Hoegerle, S., Boedeker, C. C., Opocher, G., Schipper, J., Januszewicz, A., Eng. C. <strong>Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations.</strong> JAMA 292: 943-951, 2004. Note: Erratum: JAMA 292: 1686 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15328326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15328326</a>] [<a href="https://doi.org/10.1001/jama.292.8.943" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15328326">Neumann et al., 2004</a>). <a href="#21" class="mim-tip-reference" title="Schiavi, F., Milne, R. L., Anda, E., Blay, P., Castellano, M., Opocher, G., Robledo, M., Cascon, A. <strong>Are we overestimating the penetrance of mutations in SDHB? (Letter)</strong> Hum. Mutat. 31: 761-762, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513144</a>] [<a href="https://doi.org/10.1002/humu.21269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513144">Schiavi et al. (2010)</a> studied 437 individuals from 24 families with PGL4, including 135 SDHB mutation carriers. Individuals were followed from birth to the last follow-up or to age 80 years. Penetrance was estimated to be 13% at age 50, and 30% for lifetime. These figures were substantially lower than previous reports, which <a href="#21" class="mim-tip-reference" title="Schiavi, F., Milne, R. L., Anda, E., Blay, P., Castellano, M., Opocher, G., Robledo, M., Cascon, A. <strong>Are we overestimating the penetrance of mutations in SDHB? (Letter)</strong> Hum. Mutat. 31: 761-762, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513144</a>] [<a href="https://doi.org/10.1002/humu.21269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513144">Schiavi et al. (2010)</a> attributed to ascertainment bias. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20513144+15328326" 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="#12" class="mim-tip-reference" title="Gill, A. J., Pachter, N. S., Clarkson, A., Tucker, K. M., Winship, I. M., Benn, D. E., Robinson, B. G., Clifton-Bligh, R. J. <strong>Renal tumors and hereditary pheochromocytoma-paraganglioma syndrome type 4. (Letter)</strong> New Eng. J. Med. 364: 885-886, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21366490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21366490</a>] [<a href="https://doi.org/10.1056/NEJMc1012357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21366490">Gill et al. (2011)</a> found that SDHB immunostaining was completely negative in renal cell carcinoma specimens from 3 kindreds with germline SDHB mutations. In contrast, SDHB immunostaining was positive in 70 unselected renal tumor specimens, including clear cell carcinomas, papillary renal carcinomas, and other forms of renal cancer. <a href="#12" class="mim-tip-reference" title="Gill, A. J., Pachter, N. S., Clarkson, A., Tucker, K. M., Winship, I. M., Benn, D. E., Robinson, B. G., Clifton-Bligh, R. J. <strong>Renal tumors and hereditary pheochromocytoma-paraganglioma syndrome type 4. (Letter)</strong> New Eng. J. Med. 364: 885-886, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21366490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21366490</a>] [<a href="https://doi.org/10.1056/NEJMc1012357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21366490">Gill et al. (2011)</a> concluded that immunostaining for SDHB in renal cell carcinomas can direct genetic testing for paraganglioma-related disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21366490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of 3 families with pheochromocytoma and paragangliomas, <a href="#3" class="mim-tip-reference" title="Astuti, D., Latif, F., Dallol, A., Dahia, P. L. M., Douglas, F., George, E., Skoldberg, F., Husebye, E. S., Eng, C., Maher, E. R. <strong>Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.</strong> Am. J. Hum. Genet. 69: 49-54, 2001. Note: Erratum: Am. J. Hum. Genet. 70: 565 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11404820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11404820</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11404820[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/10.1086/321282" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11404820">Astuti et al. (2001)</a> identified a mutation in the SDHB gene (<a href="/entry/185470#0001">185470.0001</a>). One of the families had been reported by <a href="#23" class="mim-tip-reference" title="Skoldberg, F., Grimelius, L., Woodward, E. R., Rorsman, F., Van Schothorst, E. W., Winqvist, O., Karlsson, F. A., Akerstrom, G., Kampe, O., Husebye, E. S. <strong>A family with hereditary extra-adrenal paragangliomas without evidence for mutations in the von Hippel-Lindau disease or ret genes.</strong> Clin. Endocr. 48: 11-16, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9509062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9509062</a>] [<a href="https://doi.org/10.1046/j.1365-2265.1998.00320.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9509062">Skoldberg et al. (1998)</a>. In the second family, the proband presented with extraadrenal pheochromocytoma at age 10 years and her mother had a cervical paraganglioma (glomus jugulare tumor) removed at age 45 years; in the third family, 2 sibs developed early-onset pheochromocytoma before age 30 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11404820+9509062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a population-based genetic study of 334 unrelated patients with adrenal or extraadrenal pheochromocytomas and 83 patients with head and neck paragangliomas, <a href="#18" class="mim-tip-reference" title="Neumann, H. P. H., Pawlu, C., Peczkowska, M., Bausch, B., McWhinney, S. R., Muresan, M., Buchta, M., Franke, G., Klisch, J., Bley, T. A., Hoegerle, S., Boedeker, C. C., Opocher, G., Schipper, J., Januszewicz, A., Eng. C. <strong>Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations.</strong> JAMA 292: 943-951, 2004. Note: Erratum: JAMA 292: 1686 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15328326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15328326</a>] [<a href="https://doi.org/10.1001/jama.292.8.943" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15328326">Neumann et al. (2004)</a> found that 12% of patients had a mutation in either the SDHB or SDHD (<a href="/entry/602690">602690</a>) gene, with equal distribution between the 2 genes (25 and 24 patients with mutations in the SDHB and SDHD genes, respectively). Mean age at diagnosis was similar between the 2 groups (approximately 30 years). Inheritance of SDHD mutations was consistent with maternal imprinting. Examination of relatives yielded a total of 32 and 34 manifesting carriers of SDHB and SDHD mutations, respectively. Multiple tumors occurred in 28% of SDHB carriers and 74% of SDHD carriers; adrenal pheochromocytomas occurred in 28% of SDHB carriers and 53% of SDHD carriers, whereas extraadrenal pheochromocytomas were identified in 48% of SDHB carriers and 21% of SDHD carriers; head and neck paragangliomas occurred in 31% of SDHB carriers and 79% of SDHD carriers; and malignancy occurred in 34% of SDHB carriers but no SDHD carriers. Two related SDHB carriers had renal cell carcinoma, and 1 SDHB and 1 SDHD carrier each had papillary thyroid carcinoma. Age-related penetrance for carriers of the 2 mutations were similar: SDHB and SDHD carriers showed 77% and 86% penetrance by age 50 years, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15328326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Benn, D. E., Gimenez-Roqueplo, A.-P., Reilly, J. R., Bertherat, J., Burgess, J., Byth, K., Croxson, M., Dahia, P. L. M., Elston, M., Gimm, O., Henley, D., Herman, P., and 9 others. <strong>Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.</strong> J. Clin. Endocr. Metab. 91: 827-836, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16317055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16317055</a>] [<a href="https://doi.org/10.1210/jc.2005-1862" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16317055">Benn et al. (2006)</a> determined genotype/phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs 28 years, respectively; p = 0.3). However, when all 112 mutation carriers were included, the estimated age-related penetrance was different for SDHB versus SDHD mutation carriers (p = 0.008). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16317055" 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="Amar, L., Baudin, E., Burnichon, N., Peyrard, S., Silvera, S., Bertherat, J., Bertagna, X., Schlumberger, M., Jeunemaitre, X., Gimenez-Roqueplo, A.-P., Plouin, P.-F. <strong>Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas.</strong> J. Clin. Endocr. Metab. 92: 3822-3828, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17652212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17652212</a>] [<a href="https://doi.org/10.1210/jc.2007-0709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17652212">Amar et al. (2007)</a> studied a total of 54 patients with malignant pheochromocytomas and paragangliomas, of whom 23 were found to have a germline mutation in the SDHB gene. The presence of SDHB mutations was significantly and independently associated with mortality (relative risk, 2.7; 95% CI, 1.2, 6.4; p = 0.021). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17652212" 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 northern Spain, where cervical paraganglioma is particularly frequent, <a href="#17" class="mim-tip-reference" title="Lima, J., Feijao, T., Ferreira da Silva, A., Pereira-Castro, I., Fernandez-Ballester, G., Maximo, V., Herrero, A., Serrano, L., Sobrinho-Simoes, M., Garcia-Rostan, G. <strong>High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain: mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathologic al correlations.</strong> J. Clin. Endocr. Metab. 92: 4853-4864, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17848412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17848412</a>] [<a href="https://doi.org/10.1210/jc.2007-0640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17848412">Lima et al. (2007)</a> screened 48 patients for mutations in the SDHB, SDHC (<a href="/entry/602413">602413</a>), and SDHD genes. Eight sporadic cases (22.2%) carried pathogenic germline mutations, 6 of which were in SDHB and 2 in SDHD. Three families had mutations in SDHD and 1 in SDHB; 7 of 11 different pathogenic mutations (64%) affected SDHB. Ten mutations were novel. Missense mutations were primarily found in SDHB and frameshift mutations in SDHD. The authors concluded that a significant proportion of sporadic cervical PGLs arise as a consequence of intrinsic genetic factors. In patients with germline SDHB mutations, they found no evidence for distant metastases or extraparaganglial malignancies after 7 years' follow-up. <a href="#17" class="mim-tip-reference" title="Lima, J., Feijao, T., Ferreira da Silva, A., Pereira-Castro, I., Fernandez-Ballester, G., Maximo, V., Herrero, A., Serrano, L., Sobrinho-Simoes, M., Garcia-Rostan, G. <strong>High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain: mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathologic al correlations.</strong> J. Clin. Endocr. Metab. 92: 4853-4864, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17848412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17848412</a>] [<a href="https://doi.org/10.1210/jc.2007-0640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17848412">Lima et al. (2007)</a> concluded that occult familial cases and familial cases with a proven disease history have a common clinicopathologic signature that distinguishes them from truly sporadic cervical paraganglioma patients without germline mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17848412" 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="Hensen, E. F., van Duinen, N., Jansen, J. C., Corssmit, E. P. M., Tops, C. M. J., Romijn, J. A., Vriends, A. H. J. T., van der Mey, A. G. L., Cornelisse, C. J., Devilee, P., Bayley, J. P. <strong>High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands.</strong> Clin. Genet. 81: 284-288, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21348866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21348866</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2011.01653.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21348866">Hensen et al. (2012)</a> determined the mutation frequency of 4 succinate dehydrogenase genes in a total of 1,045 patients from 340 Dutch families with paraganglioma and pheochromocytoma. Mutations were identified in 690 cases from 239 families. The most commonly affected gene in mutation carriers was SDHD (<a href="/entry/602690">602690</a>) (87.1%), followed by SDHAF2 (<a href="/entry/613019">613019</a>) (6.7%), SDHB (5.9%), and SDHC (<a href="/entry/602413">602413</a>) (0.3%). Almost 70% of all carriers had the founder mutation D92Y (<a href="/entry/602690#0004">602690.0004</a>) in SDHD; approximately 89% of all SDH mutation carriers had 1 of 6 Dutch founder mutations. The most common mutation in SDHB was a splice site mutation (<a href="/entry/185470#0019">185470.0019</a>), which was found in 22 patients from 9 families. The dominance of SDHD mutations was unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21348866" 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 9 apparently unrelated Dutch patients with PGL4, <a href="#4" class="mim-tip-reference" title="Bayley, J.-P., Grimbergen, A. E. M., van Bunderen, P. A., van der Wielen, M., Kunst, H. P., Lenders, J. W., Jansen, J. C., Dullaart, R. P. F., Devilee, P., Corssmit, E. P., Vriends, A. H., Losekoot, M., Weiss, M. M. <strong>The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients.</strong> BMC Med. Genet. 10: 34, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19368708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19368708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19368708[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/10.1186/1471-2350-10-34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19368708">Bayley et al. (2009)</a> identified a heterozygous 7.9-kb deletion (c.201-4429_287-933del) in the SDHB gene (<a href="/entry/185470#0021">185470.0021</a>), predicted to result in a frameshift and premature termination (Cys68HisfsTer21). The deletion was found by multiplex ligation-dependent probe amplification (MLPA) analysis of 126 patients who did not carry point mutations in SDH genes, and all patients had the same breakpoints. Haplotype analysis indicated a founder effect. Only 1 patient had a family history of PGL, 5 patients had no family history, and family information from 3 patients was not available. The patients presented with head and neck PGL, extraadrenal PGL, and pheochromocytoma. <a href="#4" class="mim-tip-reference" title="Bayley, J.-P., Grimbergen, A. E. M., van Bunderen, P. A., van der Wielen, M., Kunst, H. P., Lenders, J. W., Jansen, J. C., Dullaart, R. P. F., Devilee, P., Corssmit, E. P., Vriends, A. H., Losekoot, M., Weiss, M. M. <strong>The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients.</strong> BMC Med. Genet. 10: 34, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19368708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19368708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19368708[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/10.1186/1471-2350-10-34" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19368708">Bayley et al. (2009)</a> suggested incomplete penetrance associated with this mutation. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19368708" 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="Rijken, J. A., Niemeijer, N. D., Corssmit, E. P. M., Jonker, M. A., Leemans, C. R., Menko, F. H., Hensen, E. F. <strong>Low penetrance of paraganglioma and pheochromocytoma in an extended kindred with a germline SDHB exon 3 deletion.</strong> Clin. Genet. 89: 128-132, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25827221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25827221</a>] [<a href="https://doi.org/10.1111/cge.12591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25827221">Rijken et al. (2016)</a> reported a large multigenerational Dutch family with PGL4 due to the Dutch founder 7.9-kb deletion in the SDGB gene. There were 17 family members who carried the mutation, but only 6 had clinical manifestations; 11 patients were disease-free, indicating incomplete penetrance. The age-dependent penetrance of this mutation in this family was estimated to be 9% at age 50 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25827221" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#DeAngelis1987" class="mim-tip-reference" title="DeAngelis, L. M., Kelleher, M. B., Post, K. D., Fetell, M. R. <strong>Multiple paragangliomas in neurofibromatosis: a new neuroendocrine neoplasia.</strong> Neurology 37: 129-133, 1987.">DeAngelis et al. (1987)</a>
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Amar, L., Baudin, E., Burnichon, N., Peyrard, S., Silvera, S., Bertherat, J., Bertagna, X., Schlumberger, M., Jeunemaitre, X., Gimenez-Roqueplo, A.-P., Plouin, P.-F.
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<strong>Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas.</strong>
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J. Clin. Endocr. Metab. 92: 3822-3828, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17652212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17652212</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17652212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2007-0709" target="_blank">Full Text</a>]
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Armstrong, R., Greenhalgh, K. L., Rattenberry, E., Judd, B., Shukla, R., Losty, P. D., Maher, E. R.
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<strong>Succinate dehydrogenase subunit B (SDHB) gene deletion associated with a composite paraganglioma/neuroblastoma. (Letter)</strong>
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J. Med. Genet. 46: 215-216, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19251979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19251979</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19251979" 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.2008.060749" target="_blank">Full Text</a>]
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Astuti, D., Latif, F., Dallol, A., Dahia, P. L. M., Douglas, F., George, E., Skoldberg, F., Husebye, E. S., Eng, C., Maher, E. R.
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<strong>Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.</strong>
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Am. J. Hum. Genet. 69: 49-54, 2001. Note: Erratum: Am. J. Hum. Genet. 70: 565 only, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11404820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11404820</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11404820[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=11404820" 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/10.1086/321282" target="_blank">Full Text</a>]
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Bayley, J.-P., Grimbergen, A. E. M., van Bunderen, P. A., van der Wielen, M., Kunst, H. P., Lenders, J. W., Jansen, J. C., Dullaart, R. P. F., Devilee, P., Corssmit, E. P., Vriends, A. H., Losekoot, M., Weiss, M. M.
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<strong>The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients.</strong>
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BMC Med. Genet. 10: 34, 2009. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19368708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19368708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19368708[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=19368708" 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/10.1186/1471-2350-10-34" target="_blank">Full Text</a>]
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Baysal, B. E.
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<strong>Hereditary paraganglioma targets diverse paraganglia.</strong>
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J. Med. Genet. 39: 617-622, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12205103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12205103</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12205103" 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.39.9.617" target="_blank">Full Text</a>]
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Benn, D. E., Gimenez-Roqueplo, A.-P., Reilly, J. R., Bertherat, J., Burgess, J., Byth, K., Croxson, M., Dahia, P. L. M., Elston, M., Gimm, O., Henley, D., Herman, P., and 9 others.
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<strong>Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.</strong>
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J. Clin. Endocr. Metab. 91: 827-836, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16317055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16317055</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16317055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2005-1862" target="_blank">Full Text</a>]
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<a id="Bogdasarian1979" class="mim-anchor"></a>
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Bogdasarian, R. S., Lotz, P. R.
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<strong>Multiple simultaneous paragangliomas of the head and neck in association with multiple retroperitoneal pheochromocytomas.</strong>
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Otolaryng. Head Neck Surg. 87: 648-652, 1979.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/503530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">503530</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=503530" 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/10.1177/019459987908700520" target="_blank">Full Text</a>]
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Cascon, A., Landa, I., Lopez-Jimenez, E., Diez-Hernandez, A., Buchta, M., Montero-Conde, C., Leskela, S., Leandro-Garcia, L. J., Leton, R., Rodriguez-Antona, C., Eng, C., Neumann, H. P. H., Robledo, M.
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<strong>Molecular characterisation of a common SDHB deletion in paraganglioma patients. (Letter)</strong>
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J. Med. Genet. 45: 233-238, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18057081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18057081</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18057081" 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.2007.054965" target="_blank">Full Text</a>]
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Cook, J. E., Urich, R. W., Sample, H. G., Jr., Fawcett, N. W.
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<strong>Peculiar familial and malignant pheochromocytomas of the organs of Zuckerkandl.</strong>
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Ann. Intern. Med. 52: 126-133, 1960.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13811705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13811705</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13811705" 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/10.7326/0003-4819-52-1-126" target="_blank">Full Text</a>]
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DeAngelis, L. M., Kelleher, M. B., Post, K. D., Fetell, M. R.
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<strong>Multiple paragangliomas in neurofibromatosis: a new neuroendocrine neoplasia.</strong>
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Neurology 37: 129-133, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14685938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14685938</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14685938[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=14685938" 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/10.1086/381054" target="_blank">Full Text</a>]
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<a id="Young2002" class="mim-anchor"></a>
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Young, A. L., Baysal, B. E., Deb, A., Young, W. F., Jr.
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<strong>Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene.</strong>
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J. Clin. Endocr. Metab. 87: 4101-4105, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12213855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12213855</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12213855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2002-020312" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 04/25/2018
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Cassandra L. Kniffin - updated : 5/8/2013<br>Cassandra L. Kniffin - updated : 3/5/2013<br>Cassandra L. Kniffin - updated : 4/11/2012<br>Cassandra L. Kniffin - updated : 3/21/2011<br>Cassandra L. Kniffin - updated : 11/30/2010<br>Cassandra L. Kniffin - updated : 5/29/2009<br>John A. Phillips, III - updated : 7/25/2008<br>John A. Phillips, III - updated : 5/21/2008<br>John A. Phillips, III - updated : 2/13/2008<br>John A. Phillips, III - updated : 1/23/2008<br>John A. Phillips, III - updated : 4/9/2007<br>Cassandra L. Kniffin - reorganized : 1/31/2005<br>Cassandra L. Kniffin - updated : 1/19/2005<br>Victor A. McKusick - updated : 2/10/1999
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Creation Date:
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Victor A. McKusick : 6/25/1991
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carol : 10/18/2023
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carol : 10/17/2023<br>ckniffin : 10/11/2023<br>carol : 05/01/2018<br>alopez : 04/30/2018<br>ckniffin : 04/25/2018<br>alopez : 10/06/2016<br>alopez : 01/28/2015<br>carol : 5/20/2013<br>ckniffin : 5/8/2013<br>carol : 3/8/2013<br>ckniffin : 3/5/2013<br>alopez : 4/13/2012<br>alopez : 4/13/2012<br>terry : 4/11/2012<br>ckniffin : 4/11/2012<br>terry : 3/20/2012<br>wwang : 3/22/2011<br>ckniffin : 3/21/2011<br>wwang : 12/29/2010<br>wwang : 12/1/2010<br>ckniffin : 11/30/2010<br>ckniffin : 9/16/2009<br>wwang : 6/10/2009<br>ckniffin : 5/29/2009<br>alopez : 7/25/2008<br>carol : 5/21/2008<br>carol : 2/13/2008<br>carol : 1/23/2008<br>carol : 4/9/2007<br>wwang : 1/17/2006<br>ckniffin : 1/13/2006<br>carol : 1/31/2005<br>ckniffin : 1/19/2005<br>ckniffin : 3/23/2004<br>alopez : 9/7/2001<br>mgross : 2/16/1999<br>mgross : 2/15/1999<br>terry : 2/10/1999<br>terry : 2/10/1999<br>mimadm : 6/25/1994<br>supermim : 3/16/1992<br>carol : 6/26/1991<br>carol : 6/25/1991
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<strong>#</strong> 115310
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PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 4; PPGL4
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PARAGANGLIOMAS 4; PGL4<br />
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CAROTID BODY TUMORS AND MULTIPLE EXTRAADRENAL PHEOCHROMOCYTOMAS<br />
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PHEOCHROMOCYTOMA, EXTRAADRENAL, AND CERVICAL PARAGANGLIOMA<br />
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PARAGANGLIOMAS, HEREDITARY EXTRAADRENAL<br />
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PHEOCHROMOCYTOMA, FAMILIAL EXTRAADRENAL<br />
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PARAGANGLIOMA, FAMILIAL MALIGNANT
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<strong>ORPHA:</strong> 29072;
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<strong>DO:</strong> 0050773;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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1p36.13
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Pheochromocytoma/paraganglioma syndrome 4
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115310
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Autosomal dominant
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3
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SDHB
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185470
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that pheochromocytoma/paraganglioma syndrome-4 (PPGL4) is caused by heterozygous mutation in the SDHB gene (185470), which encodes the iron sulfur subunit of succinate dehydrogenase, on chromosome 1p36.</p>
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<strong>Description</strong>
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<p>Pheochromocytoma/paraganglioma syndrome-4 (PPGL4) is an autosomal dominant disorder characterized by the development of neuroendocrine tumors, usually in adulthood. Paragangliomas are tumors derived from paraganglia located throughout the body. Nonchromaffin types primarily serve as chemoreceptors and are located in the head and neck region (i.e., carotid body, jugular, vagal, and tympanic regions), whereas chromaffin types have endocrine activity, conventionally referred to as 'pheochromocytomas,' and are usually located below the head and neck (i.e., adrenal medulla and pre- and paravertebral thoracoabdominal regions). PPGL can manifest as nonchromaffin head and neck tumors only, adrenal and/or extraadrenal pheochromocytomas only, or a combination of the 2 types of tumors (Baysal, 2002; Neumann et al., 2004). </p><p>For a discussion of genetic heterogeneity of pheochromocytoma/paraganglioma syndrome, see PPGL1 (168000).</p>
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<strong>Clinical Features</strong>
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<p>Bogdasarian and Lotz (1979) reported a family in which affected individuals had multiple catecholamine-secreting head and neck paragangliomas and retroperitoneal pheochromocytomas. </p><p>Glowniak et al. (1985) reported a family in which 3 individuals spanning 3 generations had pheochromocytoma of the right renal hilum; 1 of these patients had metastatic disease. In the 2 previous generations, pheochromocytoma was suspected in 3 persons, including a hypertensive girl who died suddenly at age 16 years. The pedigree had an obligatory carrier, according to the hypothesis of autosomal dominant inheritance, who at age 52 years showed no signs of pheochromocytoma by any test including CT scans and scintigraphy with radioiodine-tagged metaiodobenzylguanidine. Glowniak et al. (1985) referred to reports by Cook et al. (1960), who described a brother and sister with pheochromocytoma of the organs of Zuckerkandl, which are masses of chromaffin tissue found at the aortic bifurcation, and Spring and Palubinskas (1977), who described a mother and son with pheochromocytoma involving the lower urinary tract. Glowniak et al. (1985) suggested that primary extraadrenal pheochromocytoma was a distinct genetic entity. </p><p>Pritchett (1982) and Jensen et al. (1991) reported familial concurrence of carotid body tumors and adrenal and extraadrenal pheochromocytomas. </p><p>Skoldberg et al. (1998) reported a Swedish family in which members of 3 successive generations had extramedullary pheochromocytomas (familial chromaffin paragangliomas). An affected woman in the first generation had paragangliomas in the thyroid gland and bladder. Thyrotoxicosis was diagnosed at the age of 59; she died at the age of 69 of acute heart failure associated with thyrotoxicosis. This woman's daughter had paragangliomas retroperitoneally and in the neck, and her grandson had 2 retroperitoneal paragangliomas. The transmission from 2 females differentiated the condition from PLG1, which shows imprinting with inheritance only from the father. No mutations were found in the VHL gene (608537) or the RET gene (164761). </p><p>Young et al. (2002) reported a man diagnosed with metastatic catecholamine-secreting paragangliomas in 1972. He presented with signs of catecholamine excess, including recurrent throbbing headache, palpitations, diaphoresis, and anxiety. He had hypertension and increased excretion of urinary catecholamines and total metanephrines. Laparotomy identified 3 paragangliomas: 2 periaortic and 1 adjacent to the adrenal gland. He was later found to have paragangliomas behind the head of the pancreas, beneath the diaphragm, within the liver, in the femur, and in the thorax. He was well in 2002. His 27-year-old son also developed extraadrenal catecholamine-secreting paragangliomas. </p><p>Vanharanta et al. (2004) reported a family in which the proband was diagnosed with metastatic renal clear cell carcinoma (RCC; 144700) at age 28 years. The patient's mother had a malignant PGL within the heart. The patient and his mother both had a heterozygous germline mutation in the SDHB gene (185470.0006); tumor tissue from both patients showed loss of heterozygosity (LOH) of the wildtype SDHB allele. In an unrelated family, 2 sibs had PGL and developed RCC in their twenties. Both sibs had a heterozygous germline mutation in the SDHB gene (185470.0005); PGL tissue from 1 patient and both RCC tumor tissue showed somatic LOH of the wildtype allele. No SDHB mutations were identified in 35 renal cell carcinomas diagnosed before age 50 years. </p><p>Timmers et al. (2007) reviewed the findings in 29 patients (16 males) with SDHB-related abdominal or thoracic PGL. PGL often presented as apparently sporadic PGL with symptoms related to tumor mass effect rather than to catecholamine excess. The predominant biochemical phenotype consisted of hypersecretion of norepinephrine and/or dopamine, but 10% of tumors were biochemically silent. The clinical expression of the tumors could not be predicted by the genotype. </p><p>Timmers et al. (2007) studied 29 patients (16 males) with SDHB-related abdominal or thoracic PGL. Mean +/- SD age at diagnosis was 33.7 +/- 15.7 years. Tumor-related pain was among the presenting symptoms in 54% of patients and was the sole symptom in 14%. Seventy-six percent had hypertension, and 90% lacked a family history of PGL. All primary tumors but one originated from extraadrenal locations. Mean +/- SD tumor size was 7.8 +/- 3.7 cm. In this referral-based study, 28% presented with metastatic disease and all but one eventually developed metastases after 2.7 +/- 4.1 years. Ten percent had additional head and neck PGLs. The biochemical phenotype was consistent with hypersecretion of both norepinephrine and dopamine in 46%, norepinephrine only in 41%, and dopamine only in 3%. SDHB-related PGL often presents as apparently sporadic PGL with symptoms related to tumor mass effect rather than to catecholamine excess. The predominant biochemical phenotype consists of hypersecretion of norepinephrine and/or dopamine, whereas 10% of tumors are biochemically silent. Timmers et al. (2007) concluded that the clinical expression of these tumors cannot be predicted by the genotype. </p><p>Armstrong et al. (2009) reported a 13-year-old girl with a composite paraganglioma/neuroblastoma (256700) who had a heterozygous germline deletion of the SDHB gene. She was initially found to have a paravertebral extraadrenal pheochromocytoma with features of a paraganglioma on histologic examination of the resected tumor, but further analysis showed an area with morphology of a differentiating neuroblastoma. The authors referred to a patient reported by Cascon et al. (2008) who had an adrenal neuroblastoma and partial deletion of the SDHB gene (185470.0017). Armstrong et al. (2009) noted that both paragangliomas and neuroblastomas show common embryogenesis from the neural crest, which may explain the composite histologic tumor identified in their patient. </p><p>Schimke et al. (2010) reported 2 adult sibs with paraspinal paragangliomas. The family was of note because a deceased sib, previously reported by Fairchild et al. (1979), had neuroblastoma as an infant, metastatic extraadrenal sympathetic paragangliomas consistent with pheochromocytoma as a young adult, and renal cell carcinoma as an adult. Fairchild et al. (1979) noted that occurrence of these cancers in the same patient was unique. In addition, a first cousin of these sibs had died from metastatic renal cell carcinoma and had a history of a benign paraaortic PGL. Genetic analysis identified a heterozygous mutation in the SDHB gene (V140F; 185470.0016). There were 2 unaffected family members, suggesting decreased penetrance or a 'leaky' mutation. Schimke et al. (2010) noted the importance of family history in elucidating the etiology of this inherited disorder. </p><p>Heesterman et al. (2013) found that 2 (11.8%) of 17 asymptomatic SDHB mutation carriers screened with MRI had an occult paraganglioma, both of which were vagal body tumors. One SDHB mutation carrier had a sympathetic paraganglioma. </p><p>Rijken et al. (2016) reported a large multigenerational Dutch family in which 6 individuals had PGL4. Three patients had a pheochromocytoma, 2 of which were malignant; 1 patient had a carotid body PGL, 1 had a jugulotympanic PGL, and another had an extraadrenal PGL. There was evidence of incomplete penetrance. </p>
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<span class="mim-font">
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<strong>Inheritance</strong>
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<span class="mim-text-font">
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<p>PGL4 is transmitted in an autosomal dominant pattern with incomplete penetrance. Reports of penetrance have varied, but have been generally high: e.g., 77% by age 50 years, 100% by 80 years (Neumann et al., 2004). Schiavi et al. (2010) studied 437 individuals from 24 families with PGL4, including 135 SDHB mutation carriers. Individuals were followed from birth to the last follow-up or to age 80 years. Penetrance was estimated to be 13% at age 50, and 30% for lifetime. These figures were substantially lower than previous reports, which Schiavi et al. (2010) attributed to ascertainment bias. </p>
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<strong>Diagnosis</strong>
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<p>Gill et al. (2011) found that SDHB immunostaining was completely negative in renal cell carcinoma specimens from 3 kindreds with germline SDHB mutations. In contrast, SDHB immunostaining was positive in 70 unselected renal tumor specimens, including clear cell carcinomas, papillary renal carcinomas, and other forms of renal cancer. Gill et al. (2011) concluded that immunostaining for SDHB in renal cell carcinomas can direct genetic testing for paraganglioma-related disorders. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</h4>
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<p>In affected members of 3 families with pheochromocytoma and paragangliomas, Astuti et al. (2001) identified a mutation in the SDHB gene (185470.0001). One of the families had been reported by Skoldberg et al. (1998). In the second family, the proband presented with extraadrenal pheochromocytoma at age 10 years and her mother had a cervical paraganglioma (glomus jugulare tumor) removed at age 45 years; in the third family, 2 sibs developed early-onset pheochromocytoma before age 30 years. </p>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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<p>In a population-based genetic study of 334 unrelated patients with adrenal or extraadrenal pheochromocytomas and 83 patients with head and neck paragangliomas, Neumann et al. (2004) found that 12% of patients had a mutation in either the SDHB or SDHD (602690) gene, with equal distribution between the 2 genes (25 and 24 patients with mutations in the SDHB and SDHD genes, respectively). Mean age at diagnosis was similar between the 2 groups (approximately 30 years). Inheritance of SDHD mutations was consistent with maternal imprinting. Examination of relatives yielded a total of 32 and 34 manifesting carriers of SDHB and SDHD mutations, respectively. Multiple tumors occurred in 28% of SDHB carriers and 74% of SDHD carriers; adrenal pheochromocytomas occurred in 28% of SDHB carriers and 53% of SDHD carriers, whereas extraadrenal pheochromocytomas were identified in 48% of SDHB carriers and 21% of SDHD carriers; head and neck paragangliomas occurred in 31% of SDHB carriers and 79% of SDHD carriers; and malignancy occurred in 34% of SDHB carriers but no SDHD carriers. Two related SDHB carriers had renal cell carcinoma, and 1 SDHB and 1 SDHD carrier each had papillary thyroid carcinoma. Age-related penetrance for carriers of the 2 mutations were similar: SDHB and SDHD carriers showed 77% and 86% penetrance by age 50 years, respectively. </p><p>Benn et al. (2006) determined genotype/phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs 28 years, respectively; p = 0.3). However, when all 112 mutation carriers were included, the estimated age-related penetrance was different for SDHB versus SDHD mutation carriers (p = 0.008). </p><p>Amar et al. (2007) studied a total of 54 patients with malignant pheochromocytomas and paragangliomas, of whom 23 were found to have a germline mutation in the SDHB gene. The presence of SDHB mutations was significantly and independently associated with mortality (relative risk, 2.7; 95% CI, 1.2, 6.4; p = 0.021). </p><p>In northern Spain, where cervical paraganglioma is particularly frequent, Lima et al. (2007) screened 48 patients for mutations in the SDHB, SDHC (602413), and SDHD genes. Eight sporadic cases (22.2%) carried pathogenic germline mutations, 6 of which were in SDHB and 2 in SDHD. Three families had mutations in SDHD and 1 in SDHB; 7 of 11 different pathogenic mutations (64%) affected SDHB. Ten mutations were novel. Missense mutations were primarily found in SDHB and frameshift mutations in SDHD. The authors concluded that a significant proportion of sporadic cervical PGLs arise as a consequence of intrinsic genetic factors. In patients with germline SDHB mutations, they found no evidence for distant metastases or extraparaganglial malignancies after 7 years' follow-up. Lima et al. (2007) concluded that occult familial cases and familial cases with a proven disease history have a common clinicopathologic signature that distinguishes them from truly sporadic cervical paraganglioma patients without germline mutations. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</span>
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</h4>
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<p>Hensen et al. (2012) determined the mutation frequency of 4 succinate dehydrogenase genes in a total of 1,045 patients from 340 Dutch families with paraganglioma and pheochromocytoma. Mutations were identified in 690 cases from 239 families. The most commonly affected gene in mutation carriers was SDHD (602690) (87.1%), followed by SDHAF2 (613019) (6.7%), SDHB (5.9%), and SDHC (602413) (0.3%). Almost 70% of all carriers had the founder mutation D92Y (602690.0004) in SDHD; approximately 89% of all SDH mutation carriers had 1 of 6 Dutch founder mutations. The most common mutation in SDHB was a splice site mutation (185470.0019), which was found in 22 patients from 9 families. The dominance of SDHD mutations was unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere. </p><p>In 9 apparently unrelated Dutch patients with PGL4, Bayley et al. (2009) identified a heterozygous 7.9-kb deletion (c.201-4429_287-933del) in the SDHB gene (185470.0021), predicted to result in a frameshift and premature termination (Cys68HisfsTer21). The deletion was found by multiplex ligation-dependent probe amplification (MLPA) analysis of 126 patients who did not carry point mutations in SDH genes, and all patients had the same breakpoints. Haplotype analysis indicated a founder effect. Only 1 patient had a family history of PGL, 5 patients had no family history, and family information from 3 patients was not available. The patients presented with head and neck PGL, extraadrenal PGL, and pheochromocytoma. Bayley et al. (2009) suggested incomplete penetrance associated with this mutation. Functional studies of the variant and studies of patient cells were not performed. </p><p>Rijken et al. (2016) reported a large multigenerational Dutch family with PGL4 due to the Dutch founder 7.9-kb deletion in the SDGB gene. There were 17 family members who carried the mutation, but only 6 had clinical manifestations; 11 patients were disease-free, indicating incomplete penetrance. The age-dependent penetrance of this mutation in this family was estimated to be 9% at age 50 years. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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DeAngelis et al. (1987)
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</span>
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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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<strong>Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas.</strong>
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<strong>Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.</strong>
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JAMA 242: 2210-2211, 1979.
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Heesterman, B. L., Bayley, J. P., Tops, C. M., Hes, F. J., van Brussel, B. T. J., Corssmit, E. P. M., Hamming, J. F., van der Mey, A. G. L., Jansen, J. C.
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<strong>High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations.</strong>
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Hensen, E. F., van Duinen, N., Jansen, J. C., Corssmit, E. P. M., Tops, C. M. J., Romijn, J. A., Vriends, A. H. J. T., van der Mey, A. G. L., Cornelisse, C. J., Devilee, P., Bayley, J. P.
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<strong>High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands.</strong>
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Jensen, J. C., Choyke, P. L., Rosenfeld, M., Pass, H. I., Keiser, H., White, B., Travis, W., Linehan, W. M.
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<strong>A report of familial carotid body tumors and multiple extra-adrenal pheochromocytomas.</strong>
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<p class="mim-text-font">
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Lima, J., Feijao, T., Ferreira da Silva, A., Pereira-Castro, I., Fernandez-Ballester, G., Maximo, V., Herrero, A., Serrano, L., Sobrinho-Simoes, M., Garcia-Rostan, G.
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<strong>High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain: mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathologic al correlations.</strong>
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[PubMed: 17848412]
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<p class="mim-text-font">
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Neumann, H. P. H., Pawlu, C., Peczkowska, M., Bausch, B., McWhinney, S. R., Muresan, M., Buchta, M., Franke, G., Klisch, J., Bley, T. A., Hoegerle, S., Boedeker, C. C., Opocher, G., Schipper, J., Januszewicz, A., Eng. C.
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<strong>Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations.</strong>
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JAMA 292: 943-951, 2004. Note: Erratum: JAMA 292: 1686 only, 2004.
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[PubMed: 15328326]
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Pritchett, J. W.
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<strong>Familial concurrence of carotid body tumor and pheochromocytoma.</strong>
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Cancer 49: 2578-2579, 1982.
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[PubMed: 7074575]
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[Full Text: https://doi.org/10.1002/1097-0142(19820615)49:12<2578::aid-cncr2820491227>3.0.co;2-m]
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</p>
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<p class="mim-text-font">
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Rijken, J. A., Niemeijer, N. D., Corssmit, E. P. M., Jonker, M. A., Leemans, C. R., Menko, F. H., Hensen, E. F.
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<strong>Low penetrance of paraganglioma and pheochromocytoma in an extended kindred with a germline SDHB exon 3 deletion.</strong>
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Clin. Genet. 89: 128-132, 2016.
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[PubMed: 25827221]
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[Full Text: https://doi.org/10.1111/cge.12591]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Schiavi, F., Milne, R. L., Anda, E., Blay, P., Castellano, M., Opocher, G., Robledo, M., Cascon, A.
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<strong>Are we overestimating the penetrance of mutations in SDHB? (Letter)</strong>
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Hum. Mutat. 31: 761-762, 2010.
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[PubMed: 20513144]
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[Full Text: https://doi.org/10.1002/humu.21269]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Schimke, R. N., Collins, D. L., Stolle, C. A.
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Skoldberg, F., Grimelius, L., Woodward, E. R., Rorsman, F., Van Schothorst, E. W., Winqvist, O., Karlsson, F. A., Akerstrom, G., Kampe, O., Husebye, E. S.
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<strong>A family with hereditary extra-adrenal paragangliomas without evidence for mutations in the von Hippel-Lindau disease or ret genes.</strong>
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Spring, D. B., Palubinskas, A. J.
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<strong>Familial pheochromocytoma: a rare case of hydronephrosis and hydroureter in two generations.</strong>
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Brit. J. Radiol. 50: 596-599, 1977.
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Timmers, H. J. L. M., Kozupa, A., Eisenhofer, G., Raygada, M., Adams, K. T., Solis, D., Lenders, J. W. M., Pacak, K.
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<strong>Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas.</strong>
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Vanharanta, S., Buchta, M., McWhinney, S. R., Virta, S. K., Peczkowska, M., Morrison, C. D., Lehtonen, R., Januszewicz, A., Jarvinen, H., Juhola, M., Mecklin, J.-P., Pukkala, E., Herva, R., Kiuru, M., Nupponen, N. N., Aaltonen, L. A., Neumann, H. P. H., Eng, C.
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<strong>Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.</strong>
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Young, A. L., Baysal, B. E., Deb, A., Young, W. F., Jr.
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<strong>Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene.</strong>
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Cassandra L. Kniffin - updated : 04/25/2018<br>Cassandra L. Kniffin - updated : 5/8/2013<br>Cassandra L. Kniffin - updated : 3/5/2013<br>Cassandra L. Kniffin - updated : 4/11/2012<br>Cassandra L. Kniffin - updated : 3/21/2011<br>Cassandra L. Kniffin - updated : 11/30/2010<br>Cassandra L. Kniffin - updated : 5/29/2009<br>John A. Phillips, III - updated : 7/25/2008<br>John A. Phillips, III - updated : 5/21/2008<br>John A. Phillips, III - updated : 2/13/2008<br>John A. Phillips, III - updated : 1/23/2008<br>John A. Phillips, III - updated : 4/9/2007<br>Cassandra L. Kniffin - reorganized : 1/31/2005<br>Cassandra L. Kniffin - updated : 1/19/2005<br>Victor A. McKusick - updated : 2/10/1999
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Victor A. McKusick : 6/25/1991
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