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<title>
Entry
- #193300 - VON HIPPEL-LINDAU SYNDROME; VHLS
- OMIM
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<span class="h4">#193300</span>
<br />
<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/193300"><strong>Clinical Synopsis</strong></a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=VON HIPPEL-LINDAU 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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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:14175" 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>
<div><a href="http://www.informatics.jax.org/disease/193300" 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>
<div><a href="https://wormbase.org/resources/disease/DOID:14175" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:193300" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<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.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 46659004<br />
<strong>ICD10CM:</strong> Q85.83<br />
<strong>ORPHA:</strong> 892<br />
<strong>DO:</strong> 14175<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
193300
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
VON HIPPEL-LINDAU SYNDROME; VHLS
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
VHL
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
VON HIPPEL-LINDAU SYNDROME, MODIFIERS OF, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/52?start=-3&limit=10&highlight=52">
3p25.3
</a>
</span>
</td>
<td>
<span class="mim-font">
von Hippel-Lindau syndrome
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/193300"> 193300 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
VHL
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608537"> 608537 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/697?start=-3&limit=10&highlight=697">
11q13.3
</a>
</span>
</td>
<td>
<span class="mim-font">
{von Hippel-Lindau syndrome, modifier of}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/193300"> 193300 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
CCND1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/168461"> 168461 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/193300" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/193300" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/193300" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Endolymphatic sac tumors (ELSTs) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674005&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674005</a>]</span><br /> -
Hearing loss, sensorineural, associated with ELSTs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674006&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674006</a>]</span><br /> -
Tinnitus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/162352007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">162352007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/162349004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">162349004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/60862001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">60862001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H93.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H93.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H93.19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H93.19</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/388.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">388.3</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/388.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">388.30</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0040264&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040264</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000360" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000360</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000360" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000360</a>]</span><br /> -
Vertigo <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399090003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399090003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399153001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399153001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R42" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R42</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.85" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.85</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1069915&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1069915</a>, <a href="https://bioportal.bioontology.org/search?q=C0042571&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042571</a>, <a href="https://bioportal.bioontology.org/search?q=C1135208&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1135208</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002321" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002321</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002321" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002321</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Retinal angiomata <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/93470007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">93470007</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/228.03" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">228.03</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0154051&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0154051</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Lung </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pulmonary hemangiomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/233949008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">233949008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0340548&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0340548</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005954" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005954</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005954" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005954</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Liver </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Liver hemangiomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/93469006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">93469006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0238246&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0238246</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031207" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031207</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Pancreas </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Multiple pancreatic cysts <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860394&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860394</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001737" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001737</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001737" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001737</a>]</span><br /> -
Pancreatic hemangioblastoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860395&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860395</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Internal Genitalia (Male) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Bilateral papillary cystadenoma of the epididymis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860390&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860390</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009715" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009715</a>]</span><br /> -
Bilateral papillary cystadenomas of the broad ligament <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860391&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860391</a>]</span><br /> -
Epididymal cyst <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43077002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43077002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N50.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N50.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5442141&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5442141</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030424" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030424</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030424" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030424</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Renal hemangioblastoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860392&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860392</a>]</span><br /> -
Renal cell carcinoma (e.g., <a href="/entry/193300#0002">193300.0002</a>) <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 /> -
Multiple renal cysts <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253883006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253883006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0431718&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0431718</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005562" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005562</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005562" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005562</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<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">
- Cerebellar hemangioblastoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1332900&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1332900</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006880</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006880</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Peripheral Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Spinal cord hemangioblastoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860389&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860389</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ENDOCRINE FEATURES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Hypertension <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">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020538&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020538</a> 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> <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 /> -
Adrenal hemangiomas <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860388&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860388</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Polycythemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/127062003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">127062003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/109992005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">109992005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D75.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D75.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0032461&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0032461</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001901" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001901</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001901" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001901</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEOPLASIA </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Pheochromocytoma <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=C0031511&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0031511</a>, <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:0002666" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002666</a>, <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:0002666" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002666</a>]</span><br /> -
Hemangioblastoma, sporadic cerebellar (e.g., <a href="/entry/193300#0007">193300.0007</a>) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1332900&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1332900</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006880</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006880</a>]</span><br /> -
Hypernephroma <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 /> -
Pancreatic cancer <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/372142002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">372142002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/363418001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">363418001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C25" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C25</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/C25.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C25.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/157.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">157.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/157" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">157</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235974&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235974</a>, <a href="https://bioportal.bioontology.org/search?q=C0346647&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0346647</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002894" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002894</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002894" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002894</a>]</span><br /> -
Paraganglioma <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 /> -
Adenocarcinoma of ampulla of Vater <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1332243&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1332243</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Incidence of 1 in 39,000<br /> -
Highly variable phenotype, even within families <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866210&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866210</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span><br /> -
VHL type 1 - renal carcinoma and hemangioblastoma<br /> -
VHL type 2A - hemangioblastoma and pheochromocytoma<br /> -
VHL type 2B - renal carcinoma and pheochromocytoma<br /> -
VHL type 2C - pheochromocytoma only<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the von Hippel-Lindau gene (VHL, <a href="/entry/608537#0001">608537.0001</a>)<br />
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because von Hippel-Lindau syndrome (VHLS) is caused by heterozygous mutation in the VHL gene (<a href="/entry/608537">608537</a>) on chromosome 3p25.</p><p>Evidence suggests that variation in the cyclin D1 gene (CCND1; <a href="/entry/168461">168461</a>) on chromosome 11q13 may modify the phenotype.</p><p>Homozygous or compound heterozygous mutations in the VHL gene cause familial erythrocytosis-2 (ECYT2; <a href="/entry/263400">263400</a>).</p>
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<strong>Description</strong>
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<p>Von Hippel-Lindau syndrome (VHLS) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors.</p><p><a href="#90" class="mim-tip-reference" title="Neumann, H. P. H., Wiestler, O. D. &lt;strong&gt;Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus.&lt;/strong&gt; Lancet 337: 1052-1054, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1673491/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1673491&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(91)91705-y&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1673491">Neumann and Wiestler (1991)</a> classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma). <a href="#6" class="mim-tip-reference" title="Brauch, H., Kishida, T., Glavac, D., Chen, F., Pausch, F., Hofler, H., Latif, F., Lerman, M. I., Zbar, B., Neumann, H. P. H. &lt;strong&gt;Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect.&lt;/strong&gt; Hum. Genet. 95: 551-556, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7759077/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7759077&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00223868&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7759077">Brauch et al. (1995)</a> further subdivided VHL type 2 into type 2A (with pheochromocytoma) and type 2B (with pheochromocytoma and renal cell carcinoma). <a href="#51" class="mim-tip-reference" title="Hoffman, M. A., Ohh, M., Yang, H., Kico, J. M., Ivan, M., Kaelin, W. G., Jr. &lt;strong&gt;von Hippel-Lindau, protein mutants linked to type 2C VHL disease preserve the ability to downregulated HIF.&lt;/strong&gt; Hum. Molec. Genet. 10: 1019-1027, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11331612/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11331612&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.10.1019&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11331612">Hoffman et al. (2001)</a> noted that VHL type 2C refers to patients with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma. <a href="#88" class="mim-tip-reference" title="McNeill, A., Rattenberry, E., Barber, R., Killick, P., MacDonald, F., Maher, E. R. &lt;strong&gt;Genotype-phenotype correlations in VHL exon deletions.&lt;/strong&gt; Am. J. Med. Genet. 149A: 2147-2151, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19764026/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19764026&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33023&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19764026">McNeill et al. (2009)</a> proposed that patients with VHL syndrome caused by large VHL deletions that include the HSPC300 gene (C3ORF10; <a href="/entry/611183">611183</a>) have a specific subtype of VHL syndrome characterized by protection from renal cell carcinoma, which the authors proposed be named VHL type 1B. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7759077+1673491+19764026+11331612" 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="#92" class="mim-tip-reference" title="Nordstrom-O&#x27;Brien, M., van der Luijt, R. B., van Rooijen, E., van den Ouweland, A. M., Majoor-Krakauer, D. F., Lolkema, M. P., van Brussel, A., Voest, E. E., Giles, R. H. &lt;strong&gt;Genetic analysis of von Hippel-Lindau disease.&lt;/strong&gt; Hum. Mutat. 31: 521-537, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20151405/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20151405&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.21219&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20151405">Nordstrom-O'Brien et al. (2010)</a> provided a review of the genetics of von Hippel-Lindau disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20151405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Clinical Features</strong>
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<p>The cardinal features of von Hippel-Lindau syndrome are angiomata of the retina and hemangioblastoma of the cerebellum. Hemangioma of the spinal cord has also been observed. Pheochromocytoma occurs in some patients. The combination of hypertension with angioma may lead to subarachnoid hemorrhage. Hypernephroma-like renal tumors occur in some patients. Polycythemia may be due to either the hemangioblastoma of the cerebellum or the hypernephroma. Hemangiomas of the adrenals, lungs, and liver, and multiple cysts of the pancreas and kidneys, have been observed in some instances.</p><p>Although there were many earlier reports of this syndrome (see HISTORY), <a href="#89" class="mim-tip-reference" title="Melmon, K. L., Rosen, S. W. &lt;strong&gt;Lindau&#x27;s disease: review of the literature and study of a large kindred.&lt;/strong&gt; Am. J. Med. 36: 595-617, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14142412/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14142412&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(64)90107-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14142412">Melmon and Rosen (1964)</a> introduced the term 'von Hippel-Landau' syndrome and described a large kindred with multiple features of the disorder. The condition of arteriovenous aneurysm of retina and midbrain with facial nevus, described by <a href="#4" class="mim-tip-reference" title="Bonnet, P., Dechaume, J., Blanc, E. &lt;strong&gt;L&#x27;anevrisme cirsoide de la retine l&#x27;anevrisme racemeux, ses relations avec l&#x27;anevrisme cirsoide de la face et l&#x27;anevrisme cirsoid du cerveau.&lt;/strong&gt; Bull. Soc. Ophtal. Franc. 51: 521-524, 1938."None>Bonnet et al. (1938)</a> and by <a href="#131" class="mim-tip-reference" title="Wyburn-Mason, R. &lt;strong&gt;Arteriovenous aneurysm of mid-brain and retina, facial naevi and mental changes.&lt;/strong&gt; Brain 66: 163-203, 1943."None>Wyburn-Mason (1943)</a>, is of uncertain relationship to this condition. Metastatic renal cancer occurs in some instances (<a href="#67" class="mim-tip-reference" title="Kranes, A., Balogh, K., Jr. &lt;strong&gt;Liver disease in a patient with von Hippel-Lindau disease.&lt;/strong&gt; New Eng. J. Med. 275: 950-959, 1966."None>Kranes and Balogh, 1966</a>). <a href="#40" class="mim-tip-reference" title="Goldberg, M. F., Duke, J. R. &lt;strong&gt;Von Hippel-Lindau disease: histopathologic findings in a treated and untreated eye.&lt;/strong&gt; Am. J. Ophthal. 66: 693-705, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4891878/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4891878&lt;/a&gt;]" pmid="4891878">Goldberg and Duke (1968)</a> examined the eyes of an affected 51-year-old black male whose mother died of cerebellar tumor at age 26 years. The same case was described by <a href="#87" class="mim-tip-reference" title="McKusick, V. A. &lt;strong&gt;Medical genetics 1960.&lt;/strong&gt; J. Chronic Dis. 14: 1-198, 1961. Note: Fig. 71."None>McKusick (1961)</a>. In addition to the association of tumors of the brain and adrenal medulla that occurs in neurofibromatosis and in von Hippel-Lindau disease, cerebellar tumors sometimes produce paroxysmal hypertension similar to that of pheochromocytoma. Urinary catecholamines are normal in such cases (<a href="#10" class="mim-tip-reference" title="Cameron, S. J., Doig, A. &lt;strong&gt;Cerebellar tumors presented with clinical features of phaeochromocytoma.&lt;/strong&gt; Lancet 295: 492-494, 1970. Note: Originally Volume I.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4190179/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4190179&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(70)91579-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4190179">Cameron and Doig, 1970</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14142412+4190179+4891878" 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>Cysts and 'hypernephroid' tumors of the epididymis have been described in VHL patients (<a href="#44" class="mim-tip-reference" title="Grossman, M., Melmon, K. L. &lt;strong&gt;Von Hippel-Lindau disease. In: Vinken, P. J.; Bruyn, G. W.: Handbook of Clinical Neurology. Vol. 14. The Phakomatoses.&lt;/strong&gt; Amsterdam: North Holland (pub.) 1972. Pp. 241-259."None>Grossman and Melmon, 1972</a>). Male patients may have papillary cystadenoma of the epididymis, an unusual tumor that is bilateral when it occurs in von Hippel-Lindau disease and is not familial when unilateral (<a href="#96" class="mim-tip-reference" title="Price, E. B., Jr. &lt;strong&gt;Papillary cystadenoma of the epididymis: a clinicopathologic analysis of 20 cases.&lt;/strong&gt; Arch. Path. 91: 456-470, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5103954/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5103954&lt;/a&gt;]" pmid="5103954">Price, 1971</a>). The experience of <a href="#69" class="mim-tip-reference" title="Lamiell, J. M. &lt;strong&gt;Personal Communication.&lt;/strong&gt; San Francisco, Calif. 9/1987."None>Lamiell (1987)</a> differed, however; 7 of 21 affected males in 1 kindred had an epididymal mass and 5 of these were unilateral. <a href="#120" class="mim-tip-reference" title="Tsuda, H., Fukushima, S., Takahashi, M., Hikosaka, Y., Hayashi, K. &lt;strong&gt;Familial bilateral papillary cystadenoma of the epididymis: report of three cases in siblings.&lt;/strong&gt; Cancer 37: 1831-1839, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1260690/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1260690&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1097-0142(197604)37:4&lt;1831::aid-cncr2820370430&gt;3.0.co;2-v&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1260690">Tsuda et al. (1976)</a> observed the occurrence of bilateral papillary cystadenoma of the epididymis in 3 brothers with VHL syndrome. Bilateral papillary cystadenomas of the broad ligament, presumably of mesonephric origin, is the probable homologous tumor of the female (<a href="#26" class="mim-tip-reference" title="Erbe, R. W. &lt;strong&gt;Cabot case.&lt;/strong&gt; New Eng. J. Med. 298: 95-101, 1978."None>Erbe, 1978</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5103954+1260690" 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 von Hippel-Lindau disease with pheochromocytoma, <a href="#1" class="mim-tip-reference" title="Atuk, N. O., McDonald, T., Wood, T., Carpenter, J. T., Walzak, M. P., Donaldson, M., Gillenwater, J. Y., Turner, S. M., Westfall, V. &lt;strong&gt;Familial pheochromocytoma, hypercalcemia, and von Hippel-Lindau disease: a ten-year study of a large family.&lt;/strong&gt; Medicine 58: 209-218, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/449657/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;449657&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00005792-197905000-00001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="449657">Atuk et al. (1979)</a> reported hypercalcemia which was corrected in all by removal of the tumor. In several patients, pheochromocytoma antedated development of retinal lesions. <a href="#28" class="mim-tip-reference" title="Fishman, R. S., Bartholomew, L. G. &lt;strong&gt;Severe pancreatic involvement in three generations in von Hippel-Lindau disease.&lt;/strong&gt; Mayo Clin. Proc. 54: 329-331, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/431135/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;431135&lt;/a&gt;]" pmid="431135">Fishman and Bartholomew (1979)</a> described 3 related patients with striking pancreatic involvement. One had exocrine pancreatic insufficiency. In an extensively affected kindred, <a href="#27" class="mim-tip-reference" title="Fill, W. L., Lamiell, J. M., Polk, N. O. &lt;strong&gt;The radiographic manifestations of von Hippel-Lindau disease.&lt;/strong&gt; Radiology 133: 289-295, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/573913/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;573913&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1148/133.2.289&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="573913">Fill et al. (1979)</a> found renal cell carcinoma in 16 of 42 cases and carcinoma of the pancreas in 4 of 42. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=573913+449657+431135" 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="#43" class="mim-tip-reference" title="Griffiths, D. F. R., Williams, G. T., Williams, E. D. &lt;strong&gt;Duodenal carcinoid tumours, phaeochromocytoma and neurofibromatosis: islet cell tumour, phaeochromocytoma and the von Hippel-Lindau complex: two distinctive neuroendocrine syndromes.&lt;/strong&gt; Quart. J. Med. 64: 769-782, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2897130/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2897130&lt;/a&gt;]" pmid="2897130">Griffiths et al. (1987)</a> found reports of 6 patients with von Hippel-Lindau syndrome, pheochromocytoma, and islet cell tumor. A further 11 patients showed pheochromocytoma and islet cell tumor. No patient with von Hippel-Lindau syndrome had a carcinoid tumor, which is a feature of neurofibromatosis with pheochromocytoma (see <a href="/entry/162200">162200</a>). No cases of neurofibromatosis had islet cell tumor. In Cardiff, Wales, 20 patients with cerebellar hemangioblastoma were seen between 1972 and 1985. In 8 of these, <a href="#56" class="mim-tip-reference" title="Huson, S. M., Harper, P. S., Hourihan, M. D., Cole, G., Weeks, R. D., Compston, D. A. S. &lt;strong&gt;Cerebellar haemangioblastoma and von Hippel-Lindau disease.&lt;/strong&gt; Brain 109: 1297-1310, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3790978/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3790978&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/brain/109.6.1297&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3790978">Huson et al. (1986)</a> subsequently established the diagnosis of von Hippel-Lindau disease. Although the diagnosis had not previously been considered, in retrospect, 7 of the 8 cases were known to be at risk for the syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3790978+2897130" 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="#58" class="mim-tip-reference" title="Jennings, A. M., Smith, C., Cole, D. R., Jennings, C., Shortland, J. R., Williams, J. L., Brown, C. B. &lt;strong&gt;Von Hippel-Lindau disease in a large British family: clinicopathological features and recommendations for screening and follow-up.&lt;/strong&gt; Quart. J. Med. 66: 233-249, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3200963/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3200963&lt;/a&gt;]" pmid="3200963">Jennings et al. (1988)</a> demonstrated the usefulness of family studies in determining asymptomatic lesions requiring treatment, such as renal cell carcinoma. They also reported the occurrence of a spermatic cord mesenchymal hamartoma in this disorder. <a href="#68" class="mim-tip-reference" title="Lamiell, J. M., Salazar, F. G., Hsia, Y. E. &lt;strong&gt;Von Hippel-Lindau disease affecting 43 members of a single kindred.&lt;/strong&gt; Medicine 68: 1-29, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2642584/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2642584&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00005792-198901000-00001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2642584">Lamiell et al. (1989)</a> identified 43 affected members in a large kindred, which was exceptional for absence of pheochromocytoma and erythrocythemia, for more renal and pancreatic cysts and malignancies, and for somewhat fewer eye or central nervous system lesions. Bilateral renal adenocarcinoma was found presymptomatically in 5 young subjects who had bilateral nephrectomy and hemodialysis. Three survived long-term after renal transplants. Five members of the family had pancreatic malignancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3200963+2642584" 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="#52" class="mim-tip-reference" title="Horbach, J. M. L. M., Brenninkmeyer, S. J., van de Velde, C. J. H., Nieuwenhuyzen Kruseman, A. C. &lt;strong&gt;A forme fruste of von Hippel-Lindau disease--a combination of adrenal pheochromocytoma and ipsilateral renal cell carcinoma: a case report.&lt;/strong&gt; Surgery 105: 436-441, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2646747/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2646747&lt;/a&gt;]" pmid="2646747">Horbach et al. (1989)</a> suggested that the combination of adrenal pheochromocytoma and ipsilateral renal cell carcinoma may represent a forme fruste of von Hippel-Lindau disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2646747" 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="#90" class="mim-tip-reference" title="Neumann, H. P. H., Wiestler, O. D. &lt;strong&gt;Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus.&lt;/strong&gt; Lancet 337: 1052-1054, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1673491/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1673491&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(91)91705-y&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1673491">Neumann and Wiestler (1991)</a> found a striking tendency for familial clustering of particular VHL features. Both angiomatosis retinae and hemangioblastoma of the CNS occurred in most families, whereas the occurrence of renal lesions and/or pancreatic cysts was mutually exclusive with pheochromocytoma. The authors interpreted these findings to indicate that the VHL locus is complex, with the existence of different mutations in different families or the occurrence of additional genetic lesions that cooperate with the VHL gene on chromosome 3p. They suggested a linear sequence of features as follows: pheochromocytoma, angiomatosis retinae, hemangioblastoma of the CNS, renal lesions, pancreatic cysts, and epididymal cystadenoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1673491" 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 the course of an evaluation of 41 families with this disorder from the United States and Canada, <a href="#37" class="mim-tip-reference" title="Glenn, G. M., Daniel, L. N., Choyke, P., Linehan, W. M., Oldfield, E., Gorin, M. B., Hosoe, S., Latif, F., Weiss, G., Walther, M., Lerman, M. I., Zbar, B. &lt;strong&gt;Von Hippel-Lindau (VHL) disease: distinct phenotypes suggest more than one mutant allele at the VHL locus.&lt;/strong&gt; Hum. Genet. 87: 207-210, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2066108/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2066108&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00204184&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2066108">Glenn et al. (1991)</a> found 1 large family with a distinctive phenotype: the most common disease manifestation was pheochromocytoma occurring in 57% (27 of 47) of affected members; few (4 of 47) had symptomatic spinal or cerebellar hemangioblastomas; no affected family member had renal cell carcinoma or pancreatic cysts. Genetic analysis demonstrated, however, that the disorder in this family was linked to the same markers found to be linked to typical VHL. The observations are clearly relevant to the descriptions of families with 'pure' pheochromocytoma (<a href="/entry/171300">171300</a>); they may be instances of allelism at the VHL locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2066108" 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="#61" class="mim-tip-reference" title="Keeler, L. L., III, Klauber, G. T. &lt;strong&gt;von Hippel-Lindau disease and renal cell carcinoma in a 16-year-old boy.&lt;/strong&gt; J. Urol. 147: 1588-1591, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1593692/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1593692&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-5347(17)37636-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1593692">Keeler and Klauber (1992)</a> described renal cell carcinoma in a 16-year-old boy, probably the youngest reported example of hypernephroma in VHL disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1593692" 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="#72" class="mim-tip-reference" title="Lenz, T., Thiede, H. M., Nussberger, J., Atlas, S. A., Distler, A., Schulte, K. L. &lt;strong&gt;Hyperreninemia and secondary hyperaldosteronism in a patient with pheochromocytoma and von Hippel-Lindau disease.&lt;/strong&gt; Nephron 62: 345-350, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1436350/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1436350&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000187071&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1436350">Lenz et al. (1992)</a> demonstrated that norepinephrine-producing adrenal pheochromocytoma in von Hippel-Lindau disease can produce the clinical syndrome of hypertension associated with severe hypokalemia and hyperreninemic hyperaldosteronism. The hyperreninemic hyperaldosteronism was rapidly improved by beta-blockade and was completely reversed by tumor removal. <a href="#62" class="mim-tip-reference" title="Kerr, D. J., Scheithauer, B. W., Miller, G. M., Ebersold, M. J., McPhee, T. J. &lt;strong&gt;Hemangioblastoma of the optic nerve: case report.&lt;/strong&gt; Neurosurgery 36: 573-581, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7753357/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7753357&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1227/00006123-199503000-00017&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7753357">Kerr et al. (1995)</a> described hemangioblastoma of the optic nerve in a 27-year-old woman with von Hippel-Lindau syndrome, the tenth such reported case. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7753357+1436350" 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="Davies, D. R., Norman, A. M., Whitehouse, R. W., Evans, D. G. R. &lt;strong&gt;Non-expression of von Hippel-Lindau phenotype in an obligate gene carrier.&lt;/strong&gt; Clin. Genet. 45: 104-106, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8004794/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8004794&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1994.tb04003.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8004794">Davies et al. (1994)</a> described a 65-year-old woman who was an obligate carrier of the gene for von Hippel-Lindau disease. Her father, 2 brothers, 2 sisters, and 3 sons had hemangioblastomas and renal carcinomas. Careful examination of the woman showed only a small benign renal cyst. Such cysts are very common in the general population. Therefore, obligate gene carriers may not exhibit any features of the disease beyond the age of 60 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8004794" 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>Using a VHL register set up in the northwest of England in 1990 containing information on 83 affected persons, <a href="#78" class="mim-tip-reference" title="Maddock, I. R., Moran, A., Maher, E. R., Teare, M. D., Norman, A., Payne, S. J., Whitehouse, R., Dodd, C., Lavin, M., Hartley, N., Super, M., Evans, D. G. R. &lt;strong&gt;A genetic register for von Hippel-Lindau disease.&lt;/strong&gt; J. Med. Genet. 33: 120-127, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8929948/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8929948&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.2.120&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8929948">Maddock et al. (1996)</a> studied population statistics, clinical features, age at onset, and survival. The mean age at onset of first symptoms was 26.25 years, with cerebellar hemangioblastoma being the most common presenting manifestation (34.9% of cases). The mean age at diagnosis of VHL was 30.87 years. Overall, 50 patients (60.2%) developed a cerebellar hemangioblastoma, 34 (41%) a retinal angioma, 21 (25.3%) a renal cell carcinoma, 12 (14.5%) a spinal hemangioblastoma, and 12 (14.5%) a pheochromocytoma. Mean age at death was 40.9 years with cerebellar hemangioblastoma being the most common cause (47.7% of deaths). In addition to the 83 clinically affected subjects, <a href="#78" class="mim-tip-reference" title="Maddock, I. R., Moran, A., Maher, E. R., Teare, M. D., Norman, A., Payne, S. J., Whitehouse, R., Dodd, C., Lavin, M., Hartley, N., Super, M., Evans, D. G. R. &lt;strong&gt;A genetic register for von Hippel-Lindau disease.&lt;/strong&gt; J. Med. Genet. 33: 120-127, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8929948/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8929948&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.2.120&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8929948">Maddock et al. (1996)</a> identified 3 obligate carriers who were considered to be lesion free on extensive screening tests. In the regionally based cancer registry, 14% of all CNS hemangioblastomas were found to occur as part of VHL, but investigations for VHL in apparently sporadic cases appeared to have been limited. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8929948" 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>Endolymphatic sac tumors (ELSTs) are highly vascular, benign, but locally aggressive neoplasms of the endolymphactic system that often destroy the surrounding temporal bone. They are very rare and generally occur sporadically, but occur with increased frequency in patients with VHL. <a href="#84" class="mim-tip-reference" title="Manski, T. J., Heffner, D. K., Glenn, G. M., Patronas, N. J., Pikus, A. T., Katz, D., Lebovics, R., Sledjeski, K., Choyke, P. L., Zbar, B., Linehan, W. M., Oldfield, E. H. &lt;strong&gt;Endolymphatic sac tumors: a source of morbid hearing loss in von Hippel-Lindau disease.&lt;/strong&gt; JAMA 277: 1461-1466, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9145719/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9145719&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/jama.277.18.1461&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9145719">Manski et al. (1997)</a> found MRI evidence of 15 ELSTs in 13 (11%) of 121 patients with VHL, but in none of 253 patients without evidence of VHL (P less than 0.001). Clinical findings in these 13 patients included hearing loss in 13, tinnitus in 12, vertigo in 8, and facial paresis in 1. Mean age at onset of hearing loss was 22 years (range, 12 to 50 years). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9145719" 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="#76" class="mim-tip-reference" title="Lonser, R. R., Kim, H. J., Butman, J. A., Vortmeyer, A. O., Choo, D. I., Oldfield, E. H. &lt;strong&gt;Tumors of the endolymphatic sac in von Hippel-Lindau disease.&lt;/strong&gt; New Eng. J. Med. 350: 2481-2486, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15190140/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15190140&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa040666&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15190140">Lonser et al. (2004)</a> described 3 cases of von Hippel-Lindau disease that illustrated the following features of endolymphatic sac tumors: morbid hearing loss due to a radiologically undetectable microscopic tumor in the endolymphatic sac or duct; initial symptoms caused by hemorrhage, endolymphatic hydrops, or both; an origin in the endolymphatic duct or sac; and molecular evidence of an association with von Hippel-Lindau disease. Complete surgical resection of the endolymphatic sac tumors is curative and can be performed with the preservation of hearing and the alleviation of vestibular symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15190140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Butman, J. A., Kim, H. J., Baggenstos, M., Ammerman, J. M., Dambrosia, J., Patsalides, A., Patronas, N. J., Oldfield, E. H., Lonser, R. R. &lt;strong&gt;Mechanisms of morbid hearing loss associated with tumors of the endolymphatic sac in von Hippel-Lindau disease.&lt;/strong&gt; JAMA 298: 41-48, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17609489/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17609489&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/jama.298.1.41&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17609489">Butman et al. (2007)</a> reported 35 VHL patients with ELSTs; 3 had bilateral tumors. Mean age at symptom onset was 31 years (range, 11 to 63 years). In additional to hearing loss, tinnitus, and vertigo, other features included aural fullness, aural pain, and facial nerve weakness. Detailed CT and MRI studies showed that 7 (18%) ears had otic capsule invasion, which was always associated with hearing loss. Tumors with otic capsule invasion were larger (2.2 cm) than those without capsule invasion (1.2 cm). However, there was not a significant association between tumor size and hearing loss. Intralabyrinthine hemorrhage was detected in 79% of ears with sudden hearing loss. <a href="#8" class="mim-tip-reference" title="Butman, J. A., Kim, H. J., Baggenstos, M., Ammerman, J. M., Dambrosia, J., Patsalides, A., Patronas, N. J., Oldfield, E. H., Lonser, R. R. &lt;strong&gt;Mechanisms of morbid hearing loss associated with tumors of the endolymphatic sac in von Hippel-Lindau disease.&lt;/strong&gt; JAMA 298: 41-48, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17609489/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17609489&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/jama.298.1.41&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17609489">Butman et al. (2007)</a> concluded that hearing loss associated with ELSTs can result from otic capsule invasion, intralabyrinthine hemorrhage, or endolymphatic hydrops. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17609489" 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="#57" class="mim-tip-reference" title="James, G. P. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Springfield, Ohio 8/15/1998."None>James (1998)</a> tabulated reports of 4 women with VHL and broad ligament papillary cystadenoma published between 1988 and 1994 (<a href="#36" class="mim-tip-reference" title="Gersell, D. J., King, T. C. &lt;strong&gt;Papillary cystadenoma of the mesosalpinx in von Hippel-Lindau disease.&lt;/strong&gt; Am. J. Surg. Path. 12: 145-149, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3341511/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3341511&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00000478-198802000-00008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3341511">Gersell and King, 1988</a>; <a href="#33" class="mim-tip-reference" title="Funk, K. C., Heiken, J. P. &lt;strong&gt;Papillary cystadenoma of the broad ligament in a patient with von Hippel-Lindau disease.&lt;/strong&gt; AJR Am. J. Roentgenol. 153: 527-528, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2763949/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2763949&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.2214/ajr.153.3.527&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2763949">Funk and Heiken, 1989</a>; <a href="#65" class="mim-tip-reference" title="Korn, W. T., Schatzki, S. C., DiSciullo, A. J., Scully, R. E. &lt;strong&gt;Papillary cystadenoma of the broad ligament in von Hippel-Lindau disease.&lt;/strong&gt; Am. J. Obstet. Gynec. 163: 596-598, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2386149/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2386149&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9378(90)91207-s&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2386149">Korn et al., 1990</a>; <a href="#34" class="mim-tip-reference" title="Gaffey, M. J., Mills, S. E., Boyd, J. C. &lt;strong&gt;Aggressive papillary tumor of middle ear/temporal bone and adnexal papillary cystadenoma.&lt;/strong&gt; Am. J. Surg. Path. 18: 1254-1260, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7977949/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7977949&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00000478-199412000-00009&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7977949">Gaffey et al., 1994</a>; <a href="#60" class="mim-tip-reference" title="Karsdorp, N., Elderson, A., Wittebol-Post, D., Hene, R. J., Vos, J., Feldberg, M. A. M., van Gils, A. P. G., Jansen-Schillhorn van Veen, J. M., Vroom, T. M., Hoppener, J. W. M., Lips, C. J. M. &lt;strong&gt;Von Hippel-Lindau disease: new strategies in early detection and treatment.&lt;/strong&gt; Am. J. Med. 97: 158-168, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8059782/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8059782&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(94)90026-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8059782">Karsdorp et al., 1994</a>) and added a fifth case. These are mesosalpinx cysts, which are the equivalent of epididymal cysts in the male. The cysts were unilateral in at least 3 of the 5 cases. They occurred along the full course of the mesonephric duct, in the mesosalpinx close to the ovary, over the uterine tubes, and near the vaginal fornix in a remnant of the Gartner duct (the female counterpart to the duct of the epididymis). At least 3 of the patients had multiple renal cysts and bilateral renal cell carcinoma. In the patient reported by <a href="#65" class="mim-tip-reference" title="Korn, W. T., Schatzki, S. C., DiSciullo, A. J., Scully, R. E. &lt;strong&gt;Papillary cystadenoma of the broad ligament in von Hippel-Lindau disease.&lt;/strong&gt; Am. J. Obstet. Gynec. 163: 596-598, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2386149/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2386149&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9378(90)91207-s&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2386149">Korn et al. (1990)</a>, screening for VHL after the papillary cystadenomas were diagnosed revealed pancreatic cysts and lesions of the cerebellum and kidney; renal cell carcinoma was diagnosed during follow-up surgery. The unilateral cyst in the patient reported by <a href="#34" class="mim-tip-reference" title="Gaffey, M. J., Mills, S. E., Boyd, J. C. &lt;strong&gt;Aggressive papillary tumor of middle ear/temporal bone and adnexal papillary cystadenoma.&lt;/strong&gt; Am. J. Surg. Path. 18: 1254-1260, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7977949/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7977949&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00000478-199412000-00009&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7977949">Gaffey et al. (1994)</a> was preceded by the finding of a middle ear papillary tumor. The combined presentation of mesonephric cystadenoma and ear tumor was noted in reports of epididymal cysts in men (<a href="#96" class="mim-tip-reference" title="Price, E. B., Jr. &lt;strong&gt;Papillary cystadenoma of the epididymis: a clinicopathologic analysis of 20 cases.&lt;/strong&gt; Arch. Path. 91: 456-470, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5103954/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5103954&lt;/a&gt;]" pmid="5103954">Price, 1971</a>). <a href="#34" class="mim-tip-reference" title="Gaffey, M. J., Mills, S. E., Boyd, J. C. &lt;strong&gt;Aggressive papillary tumor of middle ear/temporal bone and adnexal papillary cystadenoma.&lt;/strong&gt; Am. J. Surg. Path. 18: 1254-1260, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7977949/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7977949&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00000478-199412000-00009&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7977949">Gaffey et al. (1994)</a> suggested that the ear tumor and the adnexal tumor may represent 'major visceral manifestations of VHL.' (Nomenclature: According to the VHL Family Alliance, a genetic support group, the approved terminology is 'adnexal papillary cystadenoma of probable mesonephric origin,' abbreviated APMO (<a href="#41" class="mim-tip-reference" title="Graff, J. W. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Brookline, Mass. 10/4/1998."None>Graff, 1998</a>).) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2763949+2386149+8059782+5103954+7977949+3341511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Fukino, K., Teramoto, A., Adachi, K., Takahashi, H., Emi, M. &lt;strong&gt;A family with hydrocephalus as a complication of cerebellar hemangioblastoma: identification of pro157leu mutation in the VHL gene.&lt;/strong&gt; J. Hum. Genet. 45: 47-51, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10697963/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10697963&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s100380050009&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10697963">Fukino et al. (2000)</a> described a Japanese VHL family in which 2 of the 3 affected members developed acute occlusive hydrocephalus that necessitated emergency surgery for ventricular shunting or drainage. In both cases, the occlusion of the cerebrospinal canal was caused by cerebellar hemangioblastoma. The 2 patients with hydrocephalus were sisters aged 8 and 19 at the time of development of obstructive hydrocephalus. They inherited VHL from their mother, who also suffered from cerebellar hemangioblastoma requiring surgery as well as from retinal angiomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10697963" 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="#86" class="mim-tip-reference" title="McCabe, C. M., Flynn, H. W., Jr., Shields, C. L., Shields, J. A., Regillo, C. D., McDonald, H. R., Berrocal, M. H., Gass, J. D. M., Mieler, W. F. &lt;strong&gt;Juxtapapillary capillary hemangiomas: clinical features and visual acuity outcomes.&lt;/strong&gt; Ophthalmology 107: 2240-2249, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11097604/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11097604&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0161-6420(00)00422-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11097604">McCabe et al. (2000)</a> described the clinical features, association with von Hippel-Lindau disease, and visual acuity outcomes of patients with juxtapapillary capillary hemangioma, on or adjacent to the optic nerve. Because of their location, a hamartoma on the lesions could potentially be misdiagnosed as papilledema, papillitis, choroidal neovascularization, or choroiditis. Endophytic, exophytic, and sessile forms were described. On long-term follow-up, visual acuity generally worsened. Patients with VHL and juxtapapillary hemangioma more often presented at a younger age, had tumors with an endophytic growth pattern, and had bilateral, multiple tumors. Tumor treatment with laser photocoagulation resulted in variable visual acuity outcomes in the patients reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11097604" 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="#99" class="mim-tip-reference" title="Raja, D., Benz, M. S., Murray, T. G., Escalona-Benz, E. M., Markoe, A. &lt;strong&gt;Salvage external beam radiotherapy of retinal capillary hemangiomas secondary to von Hippel-Lindau disease: visual and anatomic outcomes.&lt;/strong&gt; Ophthalmology 111: 150-153, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14711727/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14711727&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ophtha.2003.04.003&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14711727">Raja et al. (2004)</a> reported that external beam radiotherapy (EBRT) was a useful option in the treatment of retinal hemangiomas secondary to VHL disease that progressed despite standard therapy. EBRT led to improvement of visual acuity, reduction in tumor volume, and stabilization of retinal detachment in most patients treated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14711727" 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="Eisenhofer, G., Walther, M. M., Huynh, T.-T., Li, S.-T., Bornstein, S. R., Vortmeyer, A., Mannelli, M., Goldstein, D. S., Linehan, W. M., Lenders, J. W. M., Pacak, K. &lt;strong&gt;Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 1999-2008, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11344198/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11344198&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.5.7496&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11344198">Eisenhofer et al. (2001)</a> examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in MEN2 (<a href="/entry/171400">171400</a>) and VHL to underlying differences in the expression of tyrosine hydroxylase (TH; <a href="/entry/191290">191290</a>), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT; <a href="/entry/171190">171190</a>), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN2 patients and 30 VHL patients with adrenal pheochromocytomas. MEN2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than VHL patients. MEN2 patients all had elevated plasma concentrations of the epinephrine metabolite metanephrine, whereas VHL patients showed specific increases in the norepinephrine metabolite normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN2 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11344198" 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="#115" class="mim-tip-reference" title="Taouli, B., Ghouadni, M., Correas, J.-M., Hammel, P., Couvelard, A., Richard, S., Vilgrain, V. &lt;strong&gt;Spectrum of abdominal imaging findings in von Hippel-Lindau disease.&lt;/strong&gt; AJR Am. J. Roentgenol. 181: 1049-1054, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14500227/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14500227&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.2214/ajr.181.4.1811049&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14500227">Taouli et al. (2003)</a> discussed abdominal imaging findings, including pictorial images, from more than 150 patients with VHL syndrome. The most common findings were renal and pancreatic masses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14500227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a prospective study of 406 VHL patients from 199 families seen at 1 institution in a 12-year period, Chew (2005) found that 205 of the patients had ocular involvement. Patients with complete deletion of the VHL gene were less likely to have ocular involvement than those with partial deletion, missense, or nonsense mutations (9% vs 45%; p less than 0.0001). <a href="#15" class="mim-tip-reference" title="Chew, E. Y. &lt;strong&gt;Ocular manifestations of von Hippel-Lindau disease: clinical and genetic investigations.&lt;/strong&gt; Trans. Am. Ophthal. Soc. 103: 495-511, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17057815/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17057815&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17057815[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;]" pmid="17057815">Chew (2005)</a> identified a previously unreported ocular feature, retinal neovascularization, in 17 patients. <a href="#15" class="mim-tip-reference" title="Chew, E. Y. &lt;strong&gt;Ocular manifestations of von Hippel-Lindau disease: clinical and genetic investigations.&lt;/strong&gt; Trans. Am. Ophthal. Soc. 103: 495-511, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17057815/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17057815&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17057815[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;]" pmid="17057815">Chew (2005)</a> also found 11 cases of intraorbital/intracranial hemangioblastoma, previously reported to be rare in VHL, accounting for 5.3% of all vision-threatening lesions in this study group. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17057815" 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 surgically excised retinal hemangioblastomas associated with von Hippel-Lindau disease, <a href="#73" class="mim-tip-reference" title="Liang, X., Shen, D., Huang, Y., Yin, C., Bojanowski, C. M., Zhuang, Z., Chan, C.-C. &lt;strong&gt;Molecular pathology and CXCR4 expression in surgically excised retinal hemangioblastomas associated with von Hippel-Lindau disease.&lt;/strong&gt; Ophthalmology 114: 147-156, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17070589/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17070589&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17070589[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ophtha.2006.05.068&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17070589">Liang et al. (2007)</a> demonstrated high levels of VEGF (<a href="/entry/192240">192240</a>) and CXCR4 (<a href="/entry/162643">162643</a>) mRNA and protein but low levels of CXCL12 (<a href="/entry/600835">600835</a>). Increased expression of VEGF and CXCR4 was also detected in more active hemangioblastomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17070589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Binderup, M. L. M., Budtz-Jorgensen, E., Bisgaard, M. L. &lt;strong&gt;Risk of new tumors in von Hippel-Lindau patients depends on age and genotype.&lt;/strong&gt; Genet. Med. 18: 89-97, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25834951/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25834951&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2015.44&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25834951">Binderup et al. (2016)</a> performed a retrospective analysis of a national cohort study that included 52 VHL mutation carriers. The analysis spanned a total of 799 person-years. From birth to time of the report, 581 manifestations were diagnosed during 2,583 examinations in the study subjects. The rate of new tumor development varied significantly with age and was highest at 30 to 34 years (0.4 new tumors/year). Tumor location further influenced the rate. The risk of retinal tumors was highest in subjects during the teenage years but was highest for cerebellar tumors in subjects during their 30s. Truncating VHL mutation carriers had a significantly higher manifestation rate compared with missense mutation carriers (hazard ratio = 1.85, 95% confidence interval 1.06-3.24, p = 0.031). The authors concluded that the rate of new manifestation development is not constant throughout the life span of VHL patients. They recommended careful retinal surveillance during the teenage years and increased cerebellar surveillance in adulthood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25834951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="pathogenesis" class="mim-anchor"></a>
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<strong>Pathogenesis</strong>
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<p>Interfamilial differences in predisposition to pheochromocytoma in VHL reflect allelic heterogeneity such that there is a strong association between missense mutations and risk of pheochromocytoma. <a href="#98" class="mim-tip-reference" title="Prowse, A. H., Webster, A. R., Richards, F. M., Richard, S., Olschwang, S., Resche, F., Affara, N. A., Maher, E. R. &lt;strong&gt;Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors.&lt;/strong&gt; Am. J. Hum. Genet. 60: 765-771, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9106522/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9106522&lt;/a&gt;]" pmid="9106522">Prowse et al. (1997)</a> investigated the mechanism of tumorigenesis in VHL tumors to determine whether there were differences between tumor types or classes of germline mutations. They studied 53 tumors (30 renal cell carcinomas, 15 hemangioblastomas, 5 pheochromocytomas, and 3 pancreatic tumors) from 33 patients (27 kindreds) with VHL. Overall, 51% of 45 informative tumors showed LOH at the VHL locus. In 11 cases, it was possible to distinguish between loss of the wildtype and mutant alleles, and in each case the wildtype allele was lost. LOH was detected in all tumor types and occurred in the presence of both germline missense mutations and other types of germline mutation associated with a low risk of pheochromocytoma. Intragenic somatic mutations were detected in 3 tumors (all hemangioblastomas) and in 2 of these could be shown to occur in the wildtype allele. Their study provided the first example of homozygous inactivation of the VHL gene by small intragenic mutations in this type of tumor. Hypermethylation of the VHL gene was detected in 33% (6 of 18) of tumors without LOH, including 2 renal cell carcinomas and 4 hemangioblastomas. <a href="#98" class="mim-tip-reference" title="Prowse, A. H., Webster, A. R., Richards, F. M., Richard, S., Olschwang, S., Resche, F., Affara, N. A., Maher, E. R. &lt;strong&gt;Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors.&lt;/strong&gt; Am. J. Hum. Genet. 60: 765-771, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9106522/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9106522&lt;/a&gt;]" pmid="9106522">Prowse et al. (1997)</a> stated that although hypermethylation of the VHL gene had been reported previously in nonfamilial RCC and although methylation of tumor-suppressor genes had been implicated in the pathogenesis of other sporadic cancers, this was the first report of somatic methylation in a familial cancer syndrome. <a href="#47" class="mim-tip-reference" title="Herman, J. G., Latif, F., Weng, Y., Lerman, M. I., Zbar, B., Liu, S., Samid, D., Duan, D.-S. R., Guarra, J. R., Linehan, W. M., Baylin, S. B. &lt;strong&gt;Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinomas.&lt;/strong&gt; Proc. Nat. Acad. Sci. 91: 9700-9704, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7937876/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7937876&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.91.21.9700&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7937876">Herman et al. (1994)</a> observed hypermethylation of the VHL gene in 19% of sporadic RCCs. <a href="#122" class="mim-tip-reference" title="Versteeg, R. &lt;strong&gt;Aberrant methylation in cancer. (Editorial)&lt;/strong&gt; Am. J. Hum. Genet. 60: 751-754, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9106519/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9106519&lt;/a&gt;]" pmid="9106519">Versteeg (1997)</a> provided a general discussion of aberrant methylation in cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9106522+7937876+9106519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By using comparative genomic hybridization (CGH), <a href="#77" class="mim-tip-reference" title="Lui, W. O., Chen, J., Glasker, S., Bender, B. U., Madura, C., Khoo, S. K., Kort, E., Larsson, C., Neumann, H. P. H., Teh, B. T. &lt;strong&gt;Selective loss of chromosome 11 in pheochromocytomas associated with the VHL syndrome.&lt;/strong&gt; Oncogene 21: 1117-1122, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11850829/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11850829&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.onc.1205149&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11850829">Lui et al. (2002)</a> characterized the genetic profiles of 36 VHL-related pheochromocytomas. They found loss of chromosome 3 or chromosome 11 in 34 tumors (94%) and 31 tumors (86%), respectively. There was significant concordance of deletions in chromosomes 3 and 11, suggesting that they are involved in 2 different but necessary and complementary genetic pathways. The loss of chromosome 11 appeared to be specific for VHL-related pheochromocytoma as it was not present in any of the 10 VHL-related CNS hemangioblastomas studied and was significantly less common when compared with sporadic and MEN2-related pheochromocytomas. The authors stated that this was the first report of a novel consistent genetic alteration that is selected and specific for VHL-related pheochromocytoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11850829" 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="#81" class="mim-tip-reference" title="Maher, E. R., Iselius, L., Yates, J. R. W., Littler, M., Benjamin, C., Harris, R., Sampson, J., Williams, A., Ferguson-Smith, M. A., Morton, N. &lt;strong&gt;Von Hippel-Lindau disease: a genetic study.&lt;/strong&gt; J. Med. Genet. 28: 443-447, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1895313/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1895313&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.28.7.443&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1895313">Maher et al. (1991)</a> estimated the point prevalence of heterozygotes in East Anglia to be 1 in 53,000, with an estimated birth incidence of 1 in 36,000 live births. Reproductive fitness was 0.83. Direct and indirect estimates of the mutation rate were 4.4 per million gametes per generation and 2.32 per million gametes per generation, respectively. No significant association was found between parental age or birth order and new mutations. In the Freiburg district of Germany, <a href="#90" class="mim-tip-reference" title="Neumann, H. P. H., Wiestler, O. D. &lt;strong&gt;Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus.&lt;/strong&gt; Lancet 337: 1052-1054, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1673491/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1673491&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0140-6736(91)91705-y&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1673491">Neumann and Wiestler (1991)</a> calculated the prevalence of this disorder to be 1 in 38,951. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1895313+1673491" 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="#78" class="mim-tip-reference" title="Maddock, I. R., Moran, A., Maher, E. R., Teare, M. D., Norman, A., Payne, S. J., Whitehouse, R., Dodd, C., Lavin, M., Hartley, N., Super, M., Evans, D. G. R. &lt;strong&gt;A genetic register for von Hippel-Lindau disease.&lt;/strong&gt; J. Med. Genet. 33: 120-127, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8929948/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8929948&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.2.120&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8929948">Maddock et al. (1996)</a> reported on a VHL register set up in the northwest of England in 1990. There was information on 83 affected persons. In addition, the effectiveness of the screening program used and the occurrence of CNS hemangioblastomas in the general populations were examined. The diagnostic point prevalence of heterozygotes in the region was 1 in 85,000 persons, with an estimated birth incidence of 1 in 45,500 live births. The mutation rate was estimated directly to be 1.4 x 10(-6)/gene/generation (1 in 714,200). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8929948" 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="#130" class="mim-tip-reference" title="Wu, P., Zhang, N., Wang, X., Ning, X., Li, T., Bu, D., Gong, K. &lt;strong&gt;Family history of von Hippel-Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients.&lt;/strong&gt; J. Hum. Genet. 57: 238-243, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22357542/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22357542&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/jhg.2012.10&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22357542">Wu et al. (2012)</a> identified mutations in the VHL gene in 12 (75%) of 16 Chinese probands with clinically diagnosed VHL syndrome. PCR-direct sequencing detected 12 mutations, 1 of which was novel, in 12 patients (75%). Use of universal primer quantitative fluorescent multiplex PCR (UPQFM-PCR) enabled detection of 2 large deletions in 2 (12.5%) patients. The 2 remaining patients carried atypical variations in the VHL gene that could not definitively be called pathogenic. Nine (56.3%) probands did not have a family history of the disorder, suggesting a high frequency of de novo mutations among Chinese patients. Clinically, 15 families were classified as type 1 (without pheochromocytoma) and 1 as type 2 (with pheochromocytoma). The most common manifestations were CNS hemangioblastoma, clear cell renal cell carcinoma, and pancreatic cysts and tumors. Combining this information with previous reports of Chinese VHL patients indicated that the clinical features and spectrum of VHL mutations among the Chinese are comparable to those found in large-scale investigations from other countries. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22357542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Diagnosis</strong>
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<p><a href="#109" class="mim-tip-reference" title="Seizinger, B. R., Smith, D. I., Filling-Katz, M. R., Neumann, H., Green, J. S., Choyke, P. L., Anderson, K. M., Freiman, R. N., Klauck, S. M., Whaley, J., Decker, H.-J. H., Hsia, Y. E., Collins, D., Halperin, J., Lamiell, J. M., Oostra, B., Waziri, M. H., Gorin, M. B., Scherer, G., Drabkin, H. A., Aronin, N., Schinzel, A., Martuza, R. L., Gusella, J. F., Haines, J. L. &lt;strong&gt;Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 88: 2864-2868, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2011596/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2011596&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.88.7.2864&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2011596">Seizinger et al. (1991)</a> pointed out that visceral cysts of the kidney, pancreas, and epididymis occur not only as features of VHL but also in the general population, and that the presence of such cysts, unaccompanied by other more typical lesions such as retinal and cerebellar hemangioblastoma, may represent a major diagnostic problem. The application of flanking markers for the VHL gene for presymptomatic diagnostic testing confirmed that epididymal cysts are indeed not suitable as a diagnostic criterion. The genetic studies suggested that VHL with or without pheochromocytomas is caused by defects within the same gene. Renal cell carcinoma occurs as part of VHL; a second more proximal region of chromosome 3, 3p14.2, is responsible for 'pure familial renal cell carcinoma' (<a href="/entry/144700">144700</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2011596" 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="#124" class="mim-tip-reference" title="Webster, A. R., Maher, E. R., Bird, A. C., Moore, A. T. &lt;strong&gt;Risk of multisystem disease in isolated ocular angioma (haemangioblastoma).&lt;/strong&gt; J. Med. Genet. 37: 62-63, 2000. Note: Erratum: 37: 399 only, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10691410/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10691410&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.37.1.62&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10691410">Webster et al. (2000)</a> calculated the likelihood of VHL in an individual presenting with a single ocular angioma conditional upon the age of presentation, results of DNA analysis, family history of VHL, and results of systemic screening, and produced a risk estimate table for individuals with combinations of these variables. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10691410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="Hes, F. J., Hoppener, J. W. M., Lips, C. J. M. &lt;strong&gt;Pheochromocytoma in Von Hippel-Lindau disease.&lt;/strong&gt; J. Clin. Endocr. Metab. 88: 969-974, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12629069/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12629069&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2002-021466&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12629069">Hes et al. (2003)</a> noted that in the presence of a positive family history, VHL disease can be diagnosed clinically in a patient with at least 1 typical VHL tumor. Typical VHL tumors are retinal, spinal, and cerebellar hemangioblastoma; renal cell carcinoma; and pheochromocytoma. Endolymphatic sac tumors and multiple pancreatic cysts suggest a positive carriership in the presence of a positive VHL family history because they are uncommon in the general population. In contrast, renal and epididymal cysts occur very frequently in the general population and are, as sole manifestations, not reliable indicators for VHL disease. In patients with a negative family history of VHL-associated tumors, a diagnosis of VHL disease can also be made on the basis of 2 or more hemangioblastomas or a single hemangioblastoma in association with a visceral manifestation (e.g., pheochromocytoma or renal cell carcinoma). <a href="#48" class="mim-tip-reference" title="Hes, F. J., Hoppener, J. W. M., Lips, C. J. M. &lt;strong&gt;Pheochromocytoma in Von Hippel-Lindau disease.&lt;/strong&gt; J. Clin. Endocr. Metab. 88: 969-974, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12629069/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12629069&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2002-021466&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12629069">Hes et al. (2003)</a> suggested the following criteria for eligibility for VHL gene mutation analysis: a patient with classic VHL disease (meeting clinical diagnostic criteria) and/or first-degree family members; a person from a family in which a germline VHL gene mutation has been identified (presymptomatic test); a VHL-suspected patient, i.e., one with multicentric tumors in 1 organ, bilateral tumors, 2 organ systems affected, or 1 VHL-associated tumor at a young age (less than 50 years for hemangioblastoma and pheochromocytoma or less than 30 years for renal cell carcinoma); or a patient from a family with hemangioblastoma, renal cell carcinoma, or pheochromocytoma only. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12629069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Mutation Analysis</em></strong></p><p>
Using DNA polymorphic markers, <a href="#38" class="mim-tip-reference" title="Glenn, G. M., Linehan, W. M., Hosoe, S., Latif, F., Yao, M., Choyke, P., Gorin, M. B., Chew, E., Oldfield, E., Manolatos, C., Orcutt, M. L., Walther, M. M., Weiss, G. H., Tory, K., Jensson, O., Lerman, M. I., Zbar, B. &lt;strong&gt;Screening for von Hippel-Lindau disease by DNA polymorphism analysis.&lt;/strong&gt; JAMA 267: 1226-1231, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1347089/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1347089&lt;/a&gt;]" pmid="1347089">Glenn et al. (1992)</a> studied 16 families with VHL disease. Of 48 asymptomatic persons at risk of developing this illness because of an affected parent or sib, DNA polymorphism analysis predicted that 9 were carriers of the disease gene and 33 had the wildtype allele. The test was not informative in 6 persons. All 9 persons predicted to carry the VHL gene had evidence of occult disease on clinical examination. There was no clinical evidence of VHL disease in 32 of 33 persons predicted to carry the wildtype allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1347089" 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>Richards et al. (<a href="#102" class="mim-tip-reference" title="Richards, F. M., Maher, E. R., Latif, F., Phipps, M. E., Tory, K., Lush, M., Crossey, P. A., Oostra, B., Enblad, P., Gustavson, K. H., Green, J., Turner, G., Yates, J. R. W., Linehan, W. M., Affara, N. A., Lerman, M., Zbar, B., Ferguson-Smith, M. A. &lt;strong&gt;Detailed genetic mapping of the von Hippel-Lindau disease tumour suppressor gene.&lt;/strong&gt; J. Med. Genet. 30: 104-107, 1993. Note: Erratum: J. Med. Genet. 30: 528 only, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8445612/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8445612&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.30.2.104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8445612">1993</a>, <a href="#101" class="mim-tip-reference" title="Richards, F. M., Crossey, P. A., Phipps, M. E., Foster, K., Latif, F., Evans, G., Sampson, J., Lerman, M. I., Zbar, B., Affara, N. A., Ferguson-Smith, M. A., Maher, E. R. &lt;strong&gt;Detailed mapping of germline deletions of the von Hippel-Lindau disease tumour suppressor gene.&lt;/strong&gt; Hum. Molec. Genet. 3: 595-598, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8069305/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8069305&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/3.4.595&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8069305">1994</a>) found that large germline deletions could be detected by Southern analysis and pulsed field gel electrophoresis in 19% and 3% of VHL patients, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8445612+8069305" 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>To determine whether the pheochromocytoma-associated syndromes VHL and MEN2 play a role in the development of thoracic functioning paragangliomas, <a href="#2" class="mim-tip-reference" title="Bender, B. U., Altehofer, C., Januszewicz, A., Gartner, R., Schmidt, H., Hoffmann, M. M., Heidemann, P. H., Neumann, H. P. H. &lt;strong&gt;Functioning thoracic paraganglioma: association with Von Hippel-Lindau syndrome.&lt;/strong&gt; J. Clin. Endocr. Metab. 82: 3356-3360, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9329368/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9329368&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.82.10.4050&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9329368">Bender et al. (1997)</a> analyzed germline DNA from 5 unselected patients with this tumor for mutations in the genes that predispose to VHL and MEN2. Molecular and clinical data revealed that 3 (60%) had VHL, with 2 different germline mutations of the VHL gene, but no individual was affected by MEN2. Two of these 3 patients with VHL did not show any additional VHL-associated lesions. <a href="#2" class="mim-tip-reference" title="Bender, B. U., Altehofer, C., Januszewicz, A., Gartner, R., Schmidt, H., Hoffmann, M. M., Heidemann, P. H., Neumann, H. P. H. &lt;strong&gt;Functioning thoracic paraganglioma: association with Von Hippel-Lindau syndrome.&lt;/strong&gt; J. Clin. Endocr. Metab. 82: 3356-3360, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9329368/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9329368&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.82.10.4050&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9329368">Bender et al. (1997)</a> suggested that VHL should be considered in the differential diagnosis of thoracic pheochromocytoma, and that in VHL patients suspected of a catecholamine-secreting tumor, thoracic localization should be considered if an adrenal pheochromocytoma cannot be detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9329368" 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="#95" class="mim-tip-reference" title="Pack, S. D., Zbar, B., Pak, E., Ault, D. O., Humphrey, J. S., Pham, T., Hurley, K., Weil, R. J., Park, W.-S., Kuzmin, I., Stolle, C., Glenn, G., Liotta, L. A., Lerman, M. I., Klausner, R. D., Linehan, W. M., Zhuang, Z. &lt;strong&gt;Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.&lt;/strong&gt; Cancer Res. 59: 5560-5564, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10554035/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10554035&lt;/a&gt;]" pmid="10554035">Pack et al. (1999)</a> stated that the reported frequency of detection of VHL germline mutations had varied from 39 to 80%. <a href="#114" class="mim-tip-reference" title="Stolle, C., Glenn, G., Zbar, B., Humphrey, J. S., Choyke, P., Walther, M., Pack, S., Hurley, K., Audrey, C., Klausner, R., Linehan, W. M. &lt;strong&gt;Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene.&lt;/strong&gt; Hum. Mutat. 12: 417-423, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9829911/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9829911&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1998)12:6&lt;417::AID-HUMU8&gt;3.0.CO;2-K&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9829911">Stolle et al. (1998)</a> found that a quantitative Southern blotting procedure improved this frequency. <a href="#95" class="mim-tip-reference" title="Pack, S. D., Zbar, B., Pak, E., Ault, D. O., Humphrey, J. S., Pham, T., Hurley, K., Weil, R. J., Park, W.-S., Kuzmin, I., Stolle, C., Glenn, G., Liotta, L. A., Lerman, M. I., Klausner, R. D., Linehan, W. M., Zhuang, Z. &lt;strong&gt;Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.&lt;/strong&gt; Cancer Res. 59: 5560-5564, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10554035/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10554035&lt;/a&gt;]" pmid="10554035">Pack et al. (1999)</a> reported the use of fluorescence in situ hybridization as a method to detect and characterize VHL germline deletions. They reexamined a group of VHL patients shown previously by SSCP and sequencing analysis not to harbor point mutations in the VHL locus. They found constitutional deletions in 29 of 30 VHL patients in this group, using cosmid and P1 probes that covered the VHL locus. They then tested 6 phenotypically normal offspring from 4 of these VHL families: 2 were found to carry the deletion and the other 4 were deletion-free. In addition, germline mosaicism of the VHL gene was identified in 1 family. Thus, FISH was found to be a simple and reliable method to detect VHL germline deletions and to be practically useful in cases where other methods of screening fail to detect abnormalities in the VHL gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9829911+10554035" 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="#49" class="mim-tip-reference" title="Hes, F. J., McKee, S., Taphoorn, M. J. B., Rehal, P., van der Luijt, R. B., McMahon, R., van der Smagt, J. J., Dow, D., Zewald, R. A., Whittaker, J., Lips, C. J. M., MacDonald, F., Pearson, P. L., Maher, E. R. &lt;strong&gt;Cryptic von Hippel-Lindau disease: germline mutations in patients with haemangioblastoma only.&lt;/strong&gt; J. Med. Genet. 37: 939-943, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11106358/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11106358&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.37.12.939&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11106358">Hes et al. (2000)</a> performed mutation analysis of the VHL gene in 84 patients presenting with a single CNS hemangioblastoma and 4 with multiple hemangioblastomas, but no other features of VHL. A VHL germline mutation was found in 3 of 69 (4.3%) of those with single hemangioblastomas presenting at less than 50 years of age (3 of 84 (3.6%) in total) and 2 of the 4 patients with multiple hemangioblastomas. A VHL mutation was found in a 44-year-old woman presenting with a single cerebellar hemangioblastoma, in 4 clinically unaffected relatives, and in 2 single cases presenting at 29 and 36 years. <a href="#49" class="mim-tip-reference" title="Hes, F. J., McKee, S., Taphoorn, M. J. B., Rehal, P., van der Luijt, R. B., McMahon, R., van der Smagt, J. J., Dow, D., Zewald, R. A., Whittaker, J., Lips, C. J. M., MacDonald, F., Pearson, P. L., Maher, E. R. &lt;strong&gt;Cryptic von Hippel-Lindau disease: germline mutations in patients with haemangioblastoma only.&lt;/strong&gt; J. Med. Genet. 37: 939-943, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11106358/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11106358&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.37.12.939&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11106358">Hes et al. (2000)</a> recommended that in addition to conventional clinical and radiologic investigations, VHL mutation analysis be offered to those presenting with CNS hemangioblastomas before the age of 50 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11106358" 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="#110" class="mim-tip-reference" title="Sgambati, M. T., Stolle, C., Choyke, P. L., Walther, M. M., Zbar, B., Linehan, W. M., Glenn, G. M. &lt;strong&gt;Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents.&lt;/strong&gt; Am. J. Hum. Genet. 66: 84-91, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10631138/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10631138&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10631138[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302726&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10631138">Sgambati et al. (2000)</a> presented 2 cases of VHL mosaicism. In each of 2 families, standard testing methods (Southern blot analysis and direct sequencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysis of the affected parents' blood detected the VHL gene mutation in a portion of their peripheral blood lymphocytes. In one case, detection of the deleted allele was by FISH, and, in the second case, a 3-bp deletion was detected by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. <a href="#110" class="mim-tip-reference" title="Sgambati, M. T., Stolle, C., Choyke, P. L., Walther, M. M., Zbar, B., Linehan, W. M., Glenn, G. M. &lt;strong&gt;Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents.&lt;/strong&gt; Am. J. Hum. Genet. 66: 84-91, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10631138/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10631138&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10631138[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302726&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10631138">Sgambati et al. (2000)</a> concluded that mosaicism in VHL is important to search for and recognize when an individual without a family history of VHL has VHL. Patients diagnosed without family histories of the disease have been reported in as many as 23% of kindreds. Identification of individuals potentially mosaic for VHL will affect counseling of families, and these individuals should themselves be included in clinical screening programs for occult disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10631138" 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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<div>
<a id="cytogenetics" class="mim-anchor"></a>
<h4 href="#mimCytogeneticsFold" id="mimCytogeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Cytogenetics</strong>
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<p><a href="#63" class="mim-tip-reference" title="Kiechle-Schwarz, M., Neumann, H. P. H., Decker, H.-J. H., Dietrich, C., Wullich, B., Schempp, W. &lt;strong&gt;Cytogenetic studies on three pheochromocytomas derived from patients with von Hippel-Lindau syndrome.&lt;/strong&gt; Hum. Genet. 82: 127-130, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2722187/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2722187&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00284043&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2722187">Kiechle-Schwarz et al. (1989)</a> found rearrangements resulting in partial or total trisomy of chromosome 3p in 3 cell clones from pheochromocytomas derived from patients with von Hippel-Lindau syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2722187" 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="#66" class="mim-tip-reference" title="Kovacs, G., Kung, H. &lt;strong&gt;Nonhomologous chromatid exchange in hereditary and sporadic renal cell carcinomas.&lt;/strong&gt; Proc. Nat. Acad. Sci. 88: 194-198, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1986366/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1986366&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.88.1.194&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1986366">Kovacs and Kung (1991)</a> analyzed the DNA from 28 nonpapillary renal cell carcinomas arising in 2 patients with VHL disease. They used both karyotypic and RFLP analyses for evidence of allelic recombination on chromosomes 3 and 5. Two distinct breakpoint clusters were identified, each associated with different karyotypic alterations. The first type involves a breakpoint at chromosome 3p13, with the common nonreciprocal translocations occurring between 3p and 5q or 1q, resulting in the net loss of 3p and gain of 5q or 1q segments. In the second form of translocation, which was less common, the breakpoint on 3p and on the partner chromosome is near the centromere at bands p11 or q11. This kind of rearrangement was observed in 10 tumors with a nonrandom involvement of chromosome 3. In each case the derivative chromosome carrying the translocated 3p segment was preferentially eliminated from the tumor cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1986366" 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>
</span>
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</div>
<div>
<a id="mapping" class="mim-anchor"></a>
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
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<strong>Mapping</strong>
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</h4>
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<p><a href="#39" class="mim-tip-reference" title="Go, R. C. P., Lamiell, J. M., Hsia, Y. E., Yuen, J. W.-M., Paik, Y. &lt;strong&gt;Segregation and linkage analyses of von Hippel Lindau disease among 220 descendants from one kindred.&lt;/strong&gt; Am. J. Hum. Genet. 36: 131-142, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6582782/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6582782&lt;/a&gt;]" pmid="6582782">Go et al. (1984)</a> found no linkage of VHL with any of 31 marker loci by studying 41 affected persons among 220 descendants of an ancestral couple. <a href="#126" class="mim-tip-reference" title="Wells, R. A., Reeders, S. T., Green, J., Johnson, G. J., Robson, K. J. H. &lt;strong&gt;Linkage studies of von Hippel-Lindau syndrome using multiple-locus hypervariable DNA probes. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 46: 714, 1987."None>Wells et al. (1987)</a> found linkage with a segregating minisatellite band at a recombination fraction of 0.15 (lod score of about 3.0). In studies of 9 families, <a href="#108" class="mim-tip-reference" title="Seizinger, B. R., Rouleau, G. A., Ozelius, L. J., Lane, A. H., Farmer, G. E., Lamiell, J. M., Haines, J., Yuen, J. W., Collins, D., Majoor-Krakauer, D., Bonner, T., Mathew, C, and 19 others. &lt;strong&gt;Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma.&lt;/strong&gt; Nature 332: 268-269, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2894613/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2894613&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/332268a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2894613">Seizinger et al. (1988)</a> found linkage with RAF1 (<a href="/entry/164760">164760</a>) on chromosome 3; the combined maximum lod score was 4.38 at theta = 0.11 (1 lod unit confidence interval, the approximate equivalent of 95% confidence interval, of theta = 0.04 to 0.23). The finding of recombination between VHL and RAF1 indicated that the site of the VHL mutation is not in the RAF1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6582782+2894613" 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="#107" class="mim-tip-reference" title="Seizinger, B. R., Farmer, G., Haines, J., Anderson, K., Whaley, J., Hettlich, C., Decker, J., Rouleau, G., Smith, D., Drabkin, H., Filling-Katz, M., Neumann, H., Collins, D., Hsia, E., Green, J., Waziri, M., Gusella, J., Li, F. &lt;strong&gt;Isolating the gene(s) for von Hippel-Lindau disease and renal cell carcinoma. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 45 (suppl.): A32, 1989."None>Seizinger et al. (1989)</a> reported a multipoint linkage analysis of the VHL gene using a battery of polymorphic markers in the region 3p26-p25. <a href="#121" class="mim-tip-reference" title="Vance, J. M., Small, K. W., Jones, M. A., Stajich, J. M., Yamaoka, L. H., Roses, A. D., Hung, W.-Y., Pericak-Vance, M. A. &lt;strong&gt;Confirmation of linkage in von Hippel-Lindau disease.&lt;/strong&gt; Genomics 6: 565-567, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2328994/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2328994&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0888-7543(90)90488-g&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2328994">Vance et al. (1990)</a> confirmed the linkage of VHL to 3p. <a href="#54" class="mim-tip-reference" title="Hosoe, S., Brauch, H., Latif, F., Glenn, G., Daniel, L., Bale, S., Choyke, P., Gorin, M., Oldfield, E., Berman, A., Goodman, J., Orcutt, M. L., Hampsch, K., Delisio, J., Modi, W., McBride, W., Anglard, P., Weiss, G., Walther, M. M., Linehan, W. M., Lerman, M. I., Zbar, B. &lt;strong&gt;Localization of the von Hippel-Lindau disease gene to a small region of chromosome 3.&lt;/strong&gt; Genomics 8: 634-640, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2276737/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2276737&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0888-7543(90)90249-t&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2276737">Hosoe et al. (1990)</a> concluded that VHL is located between RAF1 (3p25) and D3S18 (3p26). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2276737+2328994" 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="#79" class="mim-tip-reference" title="Maher, E. R., Bentley, E., Yates, J. R. W., Barton, D., Jennings, A., Fellows, I. W., Ponder, M. A., Ponder, B. A. J., Benjamin, C., Harris, R., Ferguson-Smith, M. A. &lt;strong&gt;Mapping of von Hippel-Lindau disease to chromosome 3p confirmed by genetic linkage analysis.&lt;/strong&gt; J. Neurol. Sci. 100: 27-30, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1982450/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1982450&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0022-510x(90)90008-b&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1982450">Maher et al. (1990)</a> confirmed the assignment to 3p by linkage studies in 12 British families. They suggested that the VHL locus is telomeric to the THRB gene (<a href="/entry/190160">190160</a>). No evidence for genetic heterogeneity was found. <a href="#109" class="mim-tip-reference" title="Seizinger, B. R., Smith, D. I., Filling-Katz, M. R., Neumann, H., Green, J. S., Choyke, P. L., Anderson, K. M., Freiman, R. N., Klauck, S. M., Whaley, J., Decker, H.-J. H., Hsia, Y. E., Collins, D., Halperin, J., Lamiell, J. M., Oostra, B., Waziri, M. H., Gorin, M. B., Scherer, G., Drabkin, H. A., Aronin, N., Schinzel, A., Martuza, R. L., Gusella, J. F., Haines, J. L. &lt;strong&gt;Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease.&lt;/strong&gt; Proc. Nat. Acad. Sci. 88: 2864-2868, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2011596/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2011596&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.88.7.2864&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2011596">Seizinger et al. (1991)</a> reported the location of the VHL locus at 3p26-p25 on the basis of studies in 28 pedigrees comprising 164 affected persons. By multipoint linkage analysis, <a href="#80" class="mim-tip-reference" title="Maher, E. R., Bentley, E., Yates, J. R. W., Latif, F., Lerman, M., Zbar, B., Affara, N. A., Ferguson-Smith, M. A. &lt;strong&gt;Mapping of the von Hippel-Lindau disease locus to a small region of chromosome 3p by genetic linkage analysis.&lt;/strong&gt; Genomics 10: 957-960, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1680799/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1680799&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0888-7543(91)90185-h&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1680799">Maher et al. (1991)</a> demonstrated flanking markers. They found no evidence of locus heterogeneity; families with and without pheochromocytoma showed linkage to D3S18 with which no recombination was observed (maximum lod score = 6.6 at theta = 0.0; CI, 0.00-0.06). By multipoint linkage analysis, <a href="#102" class="mim-tip-reference" title="Richards, F. M., Maher, E. R., Latif, F., Phipps, M. E., Tory, K., Lush, M., Crossey, P. A., Oostra, B., Enblad, P., Gustavson, K. H., Green, J., Turner, G., Yates, J. R. W., Linehan, W. M., Affara, N. A., Lerman, M., Zbar, B., Ferguson-Smith, M. A. &lt;strong&gt;Detailed genetic mapping of the von Hippel-Lindau disease tumour suppressor gene.&lt;/strong&gt; J. Med. Genet. 30: 104-107, 1993. Note: Erratum: J. Med. Genet. 30: 528 only, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8445612/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8445612&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.30.2.104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8445612">Richards et al. (1993)</a> narrowed the target region for isolation of the VHL disease gene by positional cloning techniques to a 4-cM interval between D3S1250 and D3S18. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2011596+1680799+1982450+8445612" 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="#103" class="mim-tip-reference" title="Richards, F. M., Phipps, M. E., Latif, F., Yao, M., Crossey, P. A., Foster, K., Linehan, W. M., Affara, N. A., Lerman, M. I., Zbar, B., Ferguson-Smith, M. A., Maher, E. R. &lt;strong&gt;Mapping the von Hippel-Lindau disease tumour suppressor gene: identification of germline deletions by pulsed field gel electrophoresis.&lt;/strong&gt; Hum. Molec. Genet. 2: 879-882, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8364570/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8364570&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/2.7.879&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8364570">Richards et al. (1993)</a> constructed a long-range physical map around D3S601, which had been shown to be tightly linked to the VHL locus, and screened 91 VHL patients from 80 kindreds for germline rearrangements using pulsed field gel electrophoresis. Two patients were found to have germline deletions within this region, approximately 120 kb and 50 kb, respectively, telomeric to D3S601. The results established the position of the VHL locus with respect to D3S601, refined its localization to a small region of approximately 50 kb, and excluded the plasma membrane Ca(2+)-transporting ATPase-2 gene (<a href="/entry/108733">108733</a>) as the site of the VHL mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8364570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p>In 28 of 221 kindreds with von Hippel-Lindau syndrome, <a href="#70" class="mim-tip-reference" title="Latif, F., Tory, K., Gnarra, J., Yao, M., Duh, F.-M., Orcutt, M. L., Stackhouse, T., Kuzmin, I., Modi, W., Geil, L., Schmidt, L., Zhou, F., Li, H., Wei, M. H., Chen, F., Glenn, G., Choyke, P., Walther, M. M., Weng, Y., Duan, D.-S. R., Dean, M., Glavac, D., Richards, F. M., Crossey, P. A., Ferguson-Smith, M. A., Le Paslier, D., Chumakov, I., Cohen, D., Chinault, A. C., Maher, E. R., Linehan, W. M., Zbar, B., Lerman, M. I. &lt;strong&gt;Identification of the von Hippel-Lindau disease tumor suppressor gene.&lt;/strong&gt; Science 260: 1317-1320, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8493574/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8493574&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.8493574&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8493574">Latif et al. (1993)</a> identified rearrangements of the VHL gene. Eighteen of these rearrangements were due to deletion in the VHL gene: 1 of these was an in-frame 3-nucleotide deletion (<a href="/entry/608537#0001">608537.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8493574" 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 55 of 94 unrelated VHL kindreds, <a href="#20" class="mim-tip-reference" title="Crossey, P. A., Foster, K., Richards, F. M., Phipps, M. E., Latif, F., Tory, K., Jones, M. H., Bentley, E., Kumar, R., Lerman, M. I., Zbar, B., Affara, N. A., Ferguson-Smith, M. A., Maher, E. R. &lt;strong&gt;Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours.&lt;/strong&gt; Hum. Genet. 93: 53-58, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8270255/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8270255&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00218913&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8270255">Crossey et al. (1994)</a> identified 40 different mutations in the VHL gene. The 2 most frequent mutations were arg238-to-gln (<a href="/entry/608537#0005">608537.0005</a>) and arg238-to-trp (<a href="/entry/608537#0003">608537.0003</a>), which were detected in 5 and 4 unrelated kindreds, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8270255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Ciotti, P., Garuti, A., Gulli, R., Ballestrero, A., Bellone, E., Mandich, P. &lt;strong&gt;Germline mutations in the von Hippel-Lindau gene in Italian patients.&lt;/strong&gt; Europ. J. Med. Genet. 52: 311-314, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19464396/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19464396&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ejmg.2009.05.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19464396">Ciotti et al. (2009)</a> identified mutations in the VHL gene in 9 (100%) of 9 unrelated families and in 16 (88.9%) of 18 isolated patients presenting with the classic phenotype of VHL syndrome. VHL mutations were also found in 2 (66.7%) of 3 patients who met the diagnostic criteria for VHL syndrome, but who also had multiple cerebellar hemangioblastomas. Of those with mutations, 6 (22%) of 27 were found to have complete or partial deletions of the gene. No VHL mutations were found in 13 additional patients who did not meet the full diagnostic criteria of the disorder, but who had some suggestive features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19464396" 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 6 patients from a family (F8) with von Hippel-Lindau syndrome, <a href="#71" class="mim-tip-reference" title="Lenglet, M., Robriquet, F., Schwarz, K., Camps, C., Couturier, A., Hoogewijs, D., Buffet, A., Knight, S. J. L., Gad, S., Couve, S., Chesnel, F., Pacault, M., and 39 others. &lt;strong&gt;Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.&lt;/strong&gt; Blood 132: 469-483, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29891534/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29891534&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2018-03-838235&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29891534">Lenglet et al. (2018)</a> identified a heterozygous complex mutation in the cryptic exon 1-prime (E1-prime) of the VHL gene (<a href="/entry/608537#0032">608537.0032</a>). The mutations, which occurred on the same allele, were found by a combination of microsatellite analysis and gene sequencing and segregated with the disorder in the family. The mutations were predicted to result in leu128-to-val (L128V) and leu138-to-pro (L138P) substitutions in the newly identified X1 VHL protein isoform. Analysis of patient cells and tumor tissue showed upregulation of isoforms containing exons 1 and E1-prime, predicted to result in premature termination that would likely be degraded by nonsense-mediated mRNA. There was also lower expression of other wildtype VHL isoforms. Minigene assays in various cell lines showed a synergistic effect of the 2 mutations on abnormal splicing; the expression of E1-prime-containing isoforms was higher for mutations associated with cancer than with erythrocytosis (see <a href="/entry/263400">263400</a>). The authors postulated downregulation of VHL isoforms as a pathogenic mechanism. Sequencing of tumor tissue from these patients did not identify VHL loss of heterozygosity, indicating that somatic VHL deletion may not be a prerequisite for developing cancer in patients with this genotype. The patients had classic features of the disorder, including hemangioblastoma, clear cell renal carcinoma, and pheochromocytoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29891534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifiers of VHL</em></strong></p><p>
To assess the influence of variation in CCND1 (<a href="/entry/168461">168461</a>) on the retinal, renal, and central nervous system (CNS) manifestations of von Hippel-Lindau disease (<a href="/entry/193300">193300</a>), <a href="#132" class="mim-tip-reference" title="Zatyka, M., Morrissey, C., Kuzmin, I., Lerman, M. I., Latif, F., Richards, F. M., Maher, E. R. &lt;strong&gt;Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter.&lt;/strong&gt; J. Med. Genet. 39: 463-472, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12114475/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12114475&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.39.7.463&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12114475">Zatyka et al. (2002)</a> genotyped 118 patients for the codon 242 G-A SNP (<a href="/entry/168461#0001">168461.0001</a>). The number of retinal angiomas was significantly higher in individuals harboring the G allele compared with AA homozygotes (p of 0.04). Possession of 1 or more G alleles was associated with earlier diagnosis of CNS hemangioblastoma by almost 2-fold, although the difference did not attain statistical significance (p of 0.05). A similar analysis for onset of renal cell carcinoma showed no evidence of an association with CCND1 genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12114475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a retrospective analysis of 123 patients from 55 families with VHL, including 13 with complete germline deletion of the VHL gene and 42 with partial gene deletions, <a href="#85" class="mim-tip-reference" title="Maranchie, J. K., Afonso, A., Albert, P. S., Kalyandrug, S., Phillips, J. L., Zhou, S., Peterson, J., Ghadimi, B. M., Hurley, K., Riss, J., Vasselli, J. R., Ried, T., Zbar, B., Choyke, P., Walther, M. M., Klausner, R. D., Linehan, W. M. &lt;strong&gt;Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location.&lt;/strong&gt; Hum. Mutat. 23: 40-46, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14695531/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14695531&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10302&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14695531">Maranchie et al. (2004)</a> observed a paradoxically lower prevalence of renal cell carcinoma in those with complete gene deletions. RCC occurred more frequently in patients with partial germline VHL deletions relative to complete deletions (48.9% vs 22.6%, p = 0.007). This striking phenotypic dichotomy was not seen for cystic renal lesions or for CNS (p = 0.22), pancreas (p = 0.72), or pheochromocytoma (p = 0.34). Deletion mapping demonstrated that development of RCC had an even greater correlation with retention of HSPC300 (C3ORF10; <a href="/entry/611183">611183</a>), located within the 30-kb region of 3p immediately telomeric to the VHL gene (52.3% vs 18.9%, p less than 0.001), suggesting the presence of a neighboring gene or genes critical to the development and maintenance of RCC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14695531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Cascon, A., Escobar, B., Montero-Conde, C., Rodriguez-Antona, C., Ruiz-Llorente, S., Osorio, A., Mercadillo, F., Leton, R., Campos, J. M., Garcia-Sagredo, J. M., Benitez, J., Malumbres, M., Robledo, M. &lt;strong&gt;Loss of the actin regulator HSPC300 results in clear cell renal cell carcinoma protection in Von Hippel-Lindau patients.&lt;/strong&gt; Hum. Mutat. 28: 613-621, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17311301/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17311301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20496&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17311301">Cascon et al. (2007)</a> found that 6 of 8 VHL patients without RCC had large germline deletion of the VHL gene including deletion of HSPC300. In contrast, 9 of the 10 with RCC had retention of the HSPC300 gene. Analysis of 9 sporadic RCC tumors showed that all retained an HSPC300 allele. <a href="#11" class="mim-tip-reference" title="Cascon, A., Escobar, B., Montero-Conde, C., Rodriguez-Antona, C., Ruiz-Llorente, S., Osorio, A., Mercadillo, F., Leton, R., Campos, J. M., Garcia-Sagredo, J. M., Benitez, J., Malumbres, M., Robledo, M. &lt;strong&gt;Loss of the actin regulator HSPC300 results in clear cell renal cell carcinoma protection in Von Hippel-Lindau patients.&lt;/strong&gt; Hum. Mutat. 28: 613-621, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17311301/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17311301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20496&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17311301">Cascon et al. (2007)</a> concluded that loss of the HSPC300 gene confers protection against renal clear cell carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17311301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="genotypePhenotypeCorrelations" class="mim-anchor"></a>
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<p>Although pheochromocytoma occurs in only about 7% of VHL patients, marked interfamilial differences are often observed. Examining the relationship between VHL gene mutations and phenotype in 65 VHL kindreds, <a href="#21" class="mim-tip-reference" title="Crossey, P. A., Richards, F. M., Foster, K., Green, J. S., Prowse, A., Latif, F., Lerman, M. I., Zbar, B., Affara, N. A., Ferguson-Smith, M. A., Maher, E. R. &lt;strong&gt;Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype.&lt;/strong&gt; Hum. Molec. Genet. 3: 1303-1308, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7987306/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7987306&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/3.8.1303&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7987306">Crossey et al. (1994)</a> found that large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma but in only 2 of 12 families with pheochromocytoma (P less than 0.01). Of 12 families with pheochromocytoma, 10 had missense mutations compared with 13 of 53 kindreds without pheochromocytoma (P less than 0.001). In particular, the arg238-to-trp and arg238-to-gln mutations were associated with a high risk (62%) of pheochromocytoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7987306" 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="Chen, F., Kishida, T., Yao, M., Hustad, T., Glavac, D., Dean, M., Gnarra, J. R., Orcutt, M. L., Duh, F. M., Glenn, G., Green, J., Hsia, Y. E., Lamiell, J., Li, H., Wei, M. H., Schmidt, L., Tory, K., Kuzman, I., Stackhouse, T., Latif, F., Linehan, W. M., Lerman, M., Zbar, B. &lt;strong&gt;Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype.&lt;/strong&gt; Hum. Mutat. 5: 66-75, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7728151/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7728151&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.1380050109&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7728151">Chen et al. (1995)</a> identified germline mutations in 85 of 114 VHL families (75%). They found that the types of mutations responsible for VHL without pheochromocytoma (VHL type 1) differed from those responsible for VHL with pheochromocytoma (VHL type 2). Microdeletions/insertions, nonsense mutations, or deletions were found in 56% of families with VHL type 1; missense mutations accounted for 96% of those responsible for VHL type 2. Specific mutations in codon 238 accounted for 43% of the mutations responsible for VHL type 2 (see <a href="/entry/608537#0003">608537.0003</a>-<a href="/entry/608537#0005">608537.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7728151" 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="#133" class="mim-tip-reference" title="Zbar, B., Kishida, T., Chen, F., Schmidt, L., Maher, E. R., Richards, F. M., Crossey, P. A., Webster, A. R., Affara, N. A., Ferguson-Smith, M. A., Brauch, H., Glavac, D., and 14 others. &lt;strong&gt;Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.&lt;/strong&gt; Hum. Mutat. 8: 348-357, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8956040/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8956040&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1996)8:4&lt;348::AID-HUMU8&gt;3.0.CO;2-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8956040">Zbar et al. (1996)</a> performed germline mutation analysis in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300 (63%) of the families tested; a total of 137 distinct intragenic germline mutations were detected. Most (124 of 137) of the mutations occurred in 1 or 2 families; a few occurred in 4 or more families. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produce similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced 3 distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma (e.g., <a href="/entry/608537#0003">608537.0003</a>), and (3) pheochromocytoma alone (e.g., <a href="/entry/608537#0012">608537.0012</a>). <a href="#133" class="mim-tip-reference" title="Zbar, B., Kishida, T., Chen, F., Schmidt, L., Maher, E. R., Richards, F. M., Crossey, P. A., Webster, A. R., Affara, N. A., Ferguson-Smith, M. A., Brauch, H., Glavac, D., and 14 others. &lt;strong&gt;Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.&lt;/strong&gt; Hum. Mutat. 8: 348-357, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8956040/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8956040&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1996)8:4&lt;348::AID-HUMU8&gt;3.0.CO;2-3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8956040">Zbar et al. (1996)</a> provided a catalog of VHL germline mutations with associated phenotype information. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8956040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with von Hippel-Lindau syndrome due to a 505T-C transition (<a href="/entry/608537#0009">608537.0009</a>) in the VHL gene, <a href="#106" class="mim-tip-reference" title="Schimke, R. N., Collins, D. L., Rothberg, P. G. &lt;strong&gt;Functioning carotid paraganglioma in the von Hippel-Lindau syndrome. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 80: 533-534, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9880225/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9880225&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19981228)80:5&lt;533::aid-ajmg21&gt;3.0.co;2-c&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9880225">Schimke et al. (1998)</a> found a secretory carotid body paraganglioma, the first such instance; a nonfunctional malignant carotid body tumor had been described in a patient with VHL by <a href="#55" class="mim-tip-reference" title="Hull, M. T., Roth, L. M., Glover, J. L., Walker, P. D. &lt;strong&gt;Metastatic carotid body paraganglioma in von Hippel-Lindau disease: an electron microscopic study.&lt;/strong&gt; Arch. Path. Lab. Med. 106: 235-239, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6896135/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6896135&lt;/a&gt;]" pmid="6896135">Hull et al. (1982)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6896135+9880225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Gallou, C., Joly, D., Mejean, A., Staroz, F., Martin, N., Tarlet, G., Orfanelli, M. T., Bouvier, R., Droz, D., Chretien, Y., Marechal, J. M., Richard, S., Junien, C., Beroud, C. &lt;strong&gt;Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC.&lt;/strong&gt; Hum. Mutat. 13: 464-475, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10408776/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10408776&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1999)13:6&lt;464::AID-HUMU6&gt;3.0.CO;2-A&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10408776">Gallou et al. (1999)</a> analyzed the occurrence of RCC in VHL families, based on the nature of the VHL mutations. They observed RCC in at least 1 member of the VHL families in 77% of cases with mutations leading to truncated proteins, and in 55% of cases with missense mutations (P less than 0.05). Thus, mutations resulting in truncated proteins may carry a higher risk of RCC in VHL patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10408776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Bradley, J. F., Collins, D. L., Schimke, R. N., Parrott, H. N., Rothberg, P. G. &lt;strong&gt;Two distinct phenotypes caused by two different missense mutations in the same codon of the VHL gene.&lt;/strong&gt; Am. J. Med. Genet. 87: 163-167, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10533030/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10533030&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19991119)87:2&lt;163::aid-ajmg7&gt;3.0.co;2-a&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10533030">Bradley et al. (1999)</a> described a family with VHL disease and a mutation in the VHL protein (<a href="/entry/608537#0017">608537.0017</a>). Of 13 affected individuals, 7 had renal cell carcinoma and 1 had pheochromocytoma. The authors contrasted this family with 2 families reported by <a href="#14" class="mim-tip-reference" title="Chen, F., Slife, L., Kishida, T., Mulvihill, J., Tisherman, S. E., Zbar, B. &lt;strong&gt;Genotype-phenotype correlation in von Hippel-Lindau disease: identification of a mutation associated with VHL type 2A.&lt;/strong&gt; J. Med. Genet. 33: 716-717, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8863170/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8863170&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.8.716&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8863170">Chen et al. (1996)</a> that had a mutation at the same position but causing a different amino acid change (<a href="/entry/608537#0012">608537.0012</a>). In these families, 19 of 22 affected individuals had pheochromocytoma and none had renal cell carcinoma. <a href="#5" class="mim-tip-reference" title="Bradley, J. F., Collins, D. L., Schimke, R. N., Parrott, H. N., Rothberg, P. G. &lt;strong&gt;Two distinct phenotypes caused by two different missense mutations in the same codon of the VHL gene.&lt;/strong&gt; Am. J. Med. Genet. 87: 163-167, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10533030/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10533030&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19991119)87:2&lt;163::aid-ajmg7&gt;3.0.co;2-a&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10533030">Bradley et al. (1999)</a> concluded that different amino acid changes at the same position can cause very distinct clinical phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10533030+8863170" 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="#50" class="mim-tip-reference" title="Hes, F., Zewald, R., Peeters, T., Sijmons, R., Links, T., Verheij, J., Matthijs, G., Legius, E., Mortier, G., van der Torren, K., Rosman, M., Lips, C., Pearson, P., van der Luijt, R. &lt;strong&gt;Genotype-phenotype correlations in families with deletions in the von Hippel-Lindau (VHL) gene.&lt;/strong&gt; Hum. Genet. 106: 425-431, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10830910/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10830910&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004390000265&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10830910">Hes et al. (2000)</a> described 5 VHL families in which direct sequencing of the coding region of the VHL gene failed to identify the family-specific mutation. Further molecular analysis revealed deletions involving the VHL gene in each of these families. In 4 families, partial deletions of 1 or more exons were detected by Southern blot analysis. In the fifth family, FISH analysis demonstrated the deletion of the entire VHL gene. The data supported the previously established observation that families with a germline deletion have a low risk for pheochromocytoma. Further unraveling of the genotype-phenotype correlations in VHL disease revealed that families with a full or partial deletion of the VHL gene exhibited a phenotype with a preponderance of central nervous system hemangioblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10830910" 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="#30" class="mim-tip-reference" title="Friedrich, C. A. &lt;strong&gt;Genotype/phenotype correlation in von Hippel-Lindau syndrome.&lt;/strong&gt; Hum. Molec. Genet. 10: 763-767, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11257110/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11257110&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.7.763&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11257110">Friedrich (2001)</a> reviewed genotype/phenotype correlations in von Hippel-Lindau syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11257110" 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="#51" class="mim-tip-reference" title="Hoffman, M. A., Ohh, M., Yang, H., Kico, J. M., Ivan, M., Kaelin, W. G., Jr. &lt;strong&gt;von Hippel-Lindau, protein mutants linked to type 2C VHL disease preserve the ability to downregulated HIF.&lt;/strong&gt; Hum. Molec. Genet. 10: 1019-1027, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11331612/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11331612&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.10.1019&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11331612">Hoffman et al. (2001)</a> noted that a type 2C VHL mutant, L188V (<a href="/entry/608537#0014">608537.0014</a>), which had been associated with a pheochromocytoma-only phenotype (and had been shown to retain the ability to promote HIF (<a href="/entry/603348">603348</a>) ubiquitylation), retained the ability to suppress cyclin D1 (CCND1; <a href="/entry/168461">168461</a>) expression, suggesting that loss of VHL-mediated suppression of cyclin D1 is not necessary for pheochromocytoma development in VHL disease. Other studies had suggested that (1) genetic modifiers influence the phenotypic expression of VHL disease (<a href="#125" class="mim-tip-reference" title="Webster, A. R., Richards, F. M., MacRonald, F. E., Moore, A. T., Maher, E. R. &lt;strong&gt;An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects.&lt;/strong&gt; Am. J. Hum. Genet. 63: 1025-1035, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9758595/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9758595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302037&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9758595">Webster et al., 1998</a>); and (2) polymorphic variation at the CCND1 codon 242 A/G SNP (<a href="/entry/168461#0001">168461.0001</a>) may influence cancer susceptibility or prognosis in some situations. Therefore, <a href="#132" class="mim-tip-reference" title="Zatyka, M., Morrissey, C., Kuzmin, I., Lerman, M. I., Latif, F., Richards, F. M., Maher, E. R. &lt;strong&gt;Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter.&lt;/strong&gt; J. Med. Genet. 39: 463-472, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12114475/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12114475&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.39.7.463&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12114475">Zatyka et al. (2002)</a> analyzed the relationship between CCND1 genotype and phenotypic expression of VHL disease. They found an association between the G allele and multiple retinal angiomas (p = 0.04), and risk of central nervous system hemangioblastoma (p = 0.05). The findings suggested that a variety of HIF-independent mechanisms may contribute to the tumor suppressor activity of the VHL protein and that polymorphic variation at one VHL protein target influences the phenotypic expression of VHL disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9758595+11331612+12114475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 573 individuals with VHL syndrome from 200 unrelated families, <a href="#93" class="mim-tip-reference" title="Ong, K. R., Woodward, E. R., Killick, P., Lim, C., Macdonald, F., Maher, E. R. &lt;strong&gt;Genotype-phenotype correlations in von Hippel-Lindau disease.&lt;/strong&gt; Hum. Mutat. 28: 143-149, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17024664/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17024664&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20385&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17024664">Ong et al. (2007)</a> found that age at disease onset was significantly earlier, and age-related risks of retinal angiomas and RCC were higher in individuals with nonsense or frameshift mutations compared to those with deletions or missense mutations. The results also confirmed the association of pheochromocytomas with missense mutations, particularly those that resulted in surface amino acid substitutions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17024664" 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="#129" class="mim-tip-reference" title="Wong, W. T., Agron, E., Coleman, H. R., Reed, G. F., Csaky, K., Peterson, J., Glenn, G., Linehan, W. M., Albert, P., Chew, E. Y. &lt;strong&gt;Genotype-phenotype correlation in von Hippel-Lindau disease with retinal angiomatosis.&lt;/strong&gt; Arch. Ophthal. 125: 239-245, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17296901/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17296901&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17296901[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archopht.125.2.239&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17296901">Wong et al. (2007)</a> characterized the germline mutations found in 335 patients with VHL disease associated with retinal capillary hemangioblastomas (RCHs) and sought to establish genotype-phenotype correlations between genotype category (amino acid substitutions, protein-truncating mutations, and complete deletions) and ocular phenotype. The prevalence of RCHs was lowest (14.5%) among patients with complete deletions; the overall prevalence of retinal angiomatosis was 37.2%. Genotype category had no correlation with unilaterality or bilaterality of ocular disease or with the number or extent of peripheral RCHs. The prevalence of RCHs at the juxtapapillary location was lower among patients with protein-truncating mutations than in patients with amino acid substitutions. Complete deletions were associated with the highest mean visual acuity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17296901" 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="#29" class="mim-tip-reference" title="Franke, G., Bausch, B., Hoffmann, M. M., Cybulla, M., Wilhelm, C., Kohlhase, J., Scherer, G., Neumann, H. P. H. &lt;strong&gt;Alu-Alu recombination underlies the vast majority of large VHL germline deletions: molecular characterization and genotype-phenotype correlations in VHL patients.&lt;/strong&gt; Hum. Mutat. 30: 776-786, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19280651/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19280651&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20948&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19280651">Franke et al. (2009)</a> identified germline deletions in the VHL gene ranging from 0.5 to 250 kb in 54 families with VHL syndrome. In 28 of these families, at least 1 additional gene was deleted including FANCD2 (<a href="/entry/227646">227646</a>), HSPC300 (C3ORF10;<a href="/entry/611183">611183</a>), and IRAK2 (<a href="/entry/603304">603304</a>). The precise breakpoints were determined in 33 index patients. Of the 66 breakpoints, 90% occurred in Alu elements, indicating that Alu-mediated recombination is a major mechanism for germline deletions of the VHL gene. Among all 54 families with VHL syndrome resulting from germline deletions of the VHL gene, <a href="#29" class="mim-tip-reference" title="Franke, G., Bausch, B., Hoffmann, M. M., Cybulla, M., Wilhelm, C., Kohlhase, J., Scherer, G., Neumann, H. P. H. &lt;strong&gt;Alu-Alu recombination underlies the vast majority of large VHL germline deletions: molecular characterization and genotype-phenotype correlations in VHL patients.&lt;/strong&gt; Hum. Mutat. 30: 776-786, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19280651/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19280651&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20948&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19280651">Franke et al. (2009)</a> found a higher occurrence of renal cell carcinomas and CNS hemangioblastomas compared to patients with other types of mutations. There was an independent association between renal cell carcinoma and retinal angiomas and retention of the HSPC300 gene, which confirmed the findings of <a href="#11" class="mim-tip-reference" title="Cascon, A., Escobar, B., Montero-Conde, C., Rodriguez-Antona, C., Ruiz-Llorente, S., Osorio, A., Mercadillo, F., Leton, R., Campos, J. M., Garcia-Sagredo, J. M., Benitez, J., Malumbres, M., Robledo, M. &lt;strong&gt;Loss of the actin regulator HSPC300 results in clear cell renal cell carcinoma protection in Von Hippel-Lindau patients.&lt;/strong&gt; Hum. Mutat. 28: 613-621, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17311301/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17311301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20496&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17311301">Cascon et al. (2007)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17311301+19280651" 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="#88" class="mim-tip-reference" title="McNeill, A., Rattenberry, E., Barber, R., Killick, P., MacDonald, F., Maher, E. R. &lt;strong&gt;Genotype-phenotype correlations in VHL exon deletions.&lt;/strong&gt; Am. J. Med. Genet. 149A: 2147-2151, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19764026/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19764026&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33023&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19764026">McNeill et al. (2009)</a> reviewed the molecular and clinical characteristics of 127 individuals from 62 kindreds with germline deletions in the VHL gene. Large VHL gene deletions associated with a contiguous loss of HSPC300 (10 patients) were associated with a significantly lower lifetime risk of RCC than deletions that did not involve HSPC300 (42 patients). The age-related risk of RCC at age 60 was 0% in the first group and 72% in the second group. Patients with exon 1 VHL deletions and retention of FANCD2 were excluded as the status of HSPC300 was uncertain. The risks of hemangioblastomas and pheochromocytomas were similar in both groups. These findings further supported the growing body of evidence indicating that patients with VHL syndrome caused by large VHL deletions that include the HSPC300 gene have a specific subtype of VHL syndrome with protection from RCC, which <a href="#88" class="mim-tip-reference" title="McNeill, A., Rattenberry, E., Barber, R., Killick, P., MacDonald, F., Maher, E. R. &lt;strong&gt;Genotype-phenotype correlations in VHL exon deletions.&lt;/strong&gt; Am. J. Med. Genet. 149A: 2147-2151, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19764026/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19764026&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33023&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19764026">McNeill et al. (2009)</a> proposed be named VHL type 1B. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19764026" 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="#75" class="mim-tip-reference" title="Liu, S.-J., Wang, J.-Y., Peng, S.-H., Li, T., Ning, X.-H., Hong, B.-A., Liu, J.-Y., Wu, P.-J., Zhou, B.-W., Zhou, J.-C., Qi, N.-N., Peng, X., Zhang, J.-F., Ma, K.-F., Cai, L., Gong, K. &lt;strong&gt;Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-alpha binding site in VHL protein.&lt;/strong&gt; Genet. Med. 20: 1266-1273, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29595810/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29595810&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2017.261&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29595810">Liu et al. (2018)</a> recruited 339 VHL patients and grouped them based on mutation types: HIF-alpha binding site missense (HM) mutations, non-HIF-alpha binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared. Missense mutations conferred an increased risk of pheochromocytoma compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group but was similar between HM and TR groups. Patients in the nHM group had a higher risk of pheochromocytoma and lower risks of central nervous system hemangioblastoma (CHB), renal cell carcinoma, and pancreatic tumor than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival and CHB-specific survival than HMTR mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29595810" 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="#22" class="mim-tip-reference" title="Cushing, H., Bailey, P. &lt;strong&gt;Hemangiomas of cerebellum and retina (Lindau&#x27;s disease), with the report of a case.&lt;/strong&gt; Arch. Ophthal. 57: 447-463, 1928."None>Cushing and Bailey (1928)</a> pointed out that <a href="#74" class="mim-tip-reference" title="Lindau, A. &lt;strong&gt;Zur Frage der Angiomatosis Retinae und Ihrer Hirncomplikation.&lt;/strong&gt; Acta Ophthal. 4: 193-226, 1927."None>Lindau (1927)</a> was mainly responsible for showing the connection between retinal angiomas and CNS lesions. They reported the rather long-term follow-up of a patient named Frank McA. who had the full syndrome. The family history of involvement in several generations was obtained by John F. Fulton (1899-1960), Yale neurophysiologist who worked with Cushing for a year in the 1920s, and drawings of the fundus lesions were obtained by W. H. Wilmer of Johns Hopkins. As pointed out by <a href="#22" class="mim-tip-reference" title="Cushing, H., Bailey, P. &lt;strong&gt;Hemangiomas of cerebellum and retina (Lindau&#x27;s disease), with the report of a case.&lt;/strong&gt; Arch. Ophthal. 57: 447-463, 1928."None>Cushing and Bailey (1928)</a>, Treacher <a href="#18" class="mim-tip-reference" title="Collins, E. T. &lt;strong&gt;Intra-ocular growths (two cases, brother and sister, with peculiar vascular new growth, probably primarily retinal, affecting both eyes).&lt;/strong&gt; Trans. Ophthal. Soc. U.K. 14: 141-149, 1894."None>Collins (1894)</a> was the first to recognize the angiomatous nature of the retinal lesions; he reported brother and sister. Then, <a href="#123" class="mim-tip-reference" title="von Hippel, E. &lt;strong&gt;Ueber eine sehr seltene Erkrankung der Netzhaut.&lt;/strong&gt; Albrecht von Graefes Arch. Ophthal. 59: 83-106, 1904."None>von Hippel (1904)</a> reported his 2 patients. In his biography of Cushing, <a href="#32" class="mim-tip-reference" title="Fulton, J. F. &lt;strong&gt;Harvey Cushing: A Biography.&lt;/strong&gt; Springfield, Illinois: Charles C Thomas (pub.) 1946. P. 579."None>Fulton (1946)</a> gave an interesting account of the 'young Swedish pathologist named Arvid Lindau (who) had attracted Cushing's attention in 1927 [<a href="#74" class="mim-tip-reference" title="Lindau, A. &lt;strong&gt;Zur Frage der Angiomatosis Retinae und Ihrer Hirncomplikation.&lt;/strong&gt; Acta Ophthal. 4: 193-226, 1927."None>Lindau, 1927</a>] through his description of an important new disease entity, which Cushing appropriately christened Lindau's disease.'</p><p><a href="#89" class="mim-tip-reference" title="Melmon, K. L., Rosen, S. W. &lt;strong&gt;Lindau&#x27;s disease: review of the literature and study of a large kindred.&lt;/strong&gt; Am. J. Med. 36: 595-617, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14142412/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14142412&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(64)90107-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14142412">Melmon and Rosen (1964)</a> reviewed the literature and reported studies of an extensively affected kindred. They pointed out that von Hippel's first publication on this subject concerned 2 patients, Otto Meyer and Otto Mobius by name, who figured in several later publications as well. Following this historic lead, <a href="#89" class="mim-tip-reference" title="Melmon, K. L., Rosen, S. W. &lt;strong&gt;Lindau&#x27;s disease: review of the literature and study of a large kindred.&lt;/strong&gt; Am. J. Med. 36: 595-617, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14142412/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14142412&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(64)90107-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14142412">Melmon and Rosen (1964)</a> gave the full name of each of their patients beginning with the proband Bruno Bernardini. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14142412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="seeAlso" class="mim-anchor"></a>
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<strong>See Also:</strong>
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<a href="#Brown1973" class="mim-tip-reference" title="Brown, D. G., Hilal, S. K., Tenner, M. S. &lt;strong&gt;Wyburn-Mason syndrome.&lt;/strong&gt; Arch. Neurol. 28: 67-68, 1973.">Brown et al. (1973)</a>; <a href="#Cahill1942" class="mim-tip-reference" title="Cahill, G. F., Melicow, M. M., Guerry, D. &lt;strong&gt;The renal lesions in von Hippel-Lindau&#x27;s disease.&lt;/strong&gt; Trans. Am. Assoc. Genitourinary Surg. 35: 271-281, 1942.">Cahill et al. (1942)</a>; <a href="#Chapman1962" class="mim-tip-reference" title="Chapman, R. C., Diaz-Perez, R. &lt;strong&gt;Pheochromocytoma associated with cerebellar hemangioblastoma.&lt;/strong&gt; JAMA 182: 1014-1017, 1962.">Chapman and Diaz-Perez
(1962)</a>; <a href="#Christoferson1961" class="mim-tip-reference" title="Christoferson, L. A., Gustafson, M. B., Petersen, A. G. &lt;strong&gt;Von Hippel-Lindau&#x27;s disease.&lt;/strong&gt; JAMA 178: 280-282, 1961.">Christoferson et al. (1961)</a>; <a href="#Corn2003" class="mim-tip-reference" title="Corn, P. G., McDonald, E. R., III, Herman, J. G., El-Deiry, W. S. &lt;strong&gt;Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein.&lt;/strong&gt; Nature Genet. 35: 229-237, 2003.">Corn et al. (2003)</a>; <a href="#Decker1988" class="mim-tip-reference" title="Decker, H.-J. H., Neumann, H. P. H., Walter, T. A., Sandberg, A. A. &lt;strong&gt;3p involvement in a renal cell carcinoma in von Hippel-Lindau syndrome: region of tumor breakpoint clustering on 3p?&lt;/strong&gt; Cancer Genet. Cytogenet. 33: 59-65, 1988.">Decker et
al. (1988)</a>; <a href="#Green1986" class="mim-tip-reference" title="Green, J. S., Bowmer, M. I., Johnson, G. J. &lt;strong&gt;Von Hippel-Lindau disease in a Newfoundland kindred.&lt;/strong&gt; Canad. Med. Assoc. J. 134: 133-138 and 146, 1986.">Green et al. (1986)</a>; <a href="#Hagler1971" class="mim-tip-reference" title="Hagler, W. S., Hyman, B. N., Waters, W. C., III. &lt;strong&gt;Von Hippel&#x27;s angiomatosis retinae and pheochromocytoma.&lt;/strong&gt; Trans. Am. Acad. Ophthal. Otolaryng. 75: 1022-1034, 1971.">Hagler et al. (1971)</a>; <a href="#Hennessy1967" class="mim-tip-reference" title="Hennessy, T. G., Stern, W. E., Herrick, S. E. &lt;strong&gt;Cerebellar hemangioblastoma: erythropoietic activity by radioion assay.&lt;/strong&gt; J. Nucl. Med. 8: 601-606, 1967.">Hennessy et
al. (1967)</a>; <a href="#Horton1976" class="mim-tip-reference" title="Horton, W. A., Wong, V., Eldridge, R. &lt;strong&gt;Von Hippel-Lindau disease--clinical and pathological manifestations in 9 families with 50 affected members.&lt;/strong&gt; Arch. Intern. Med. 136: 769-777, 1976.">Horton et al. (1976)</a>; <a href="#Kaplan1961" class="mim-tip-reference" title="Kaplan, C., Sayre, G. P., Greene, L. F. &lt;strong&gt;Bilateral nephrogenic carcinomas in Lindau-von Hippel disease.&lt;/strong&gt; J. Urol. 86: 36-42, 1961.">Kaplan et al. (1961)</a>; <a href="#King1987" class="mim-tip-reference" title="King, C. R., Schimke, R. N., Arthur, T., Davoren, B., Collins, D. &lt;strong&gt;Proximal 3p deletion in renal cell carcinoma cells from a patient with von Hippel-Lindau disease.&lt;/strong&gt; Cancer Genet. Cytogenet. 27: 345-348, 1987.">King et al.
(1987)</a>; <a href="#Maher1990" class="mim-tip-reference" title="Maher, E. R., Yates, J. R. W., Ferguson-Smith, M. A. &lt;strong&gt;Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma.&lt;/strong&gt; J. Med. Genet. 27: 311-314, 1990.">Maher et al. (1990)</a>; <a href="#Mahon2001" class="mim-tip-reference" title="Mahon, P. C., Hirota, K., Semenza, G. L. &lt;strong&gt;FIH-1: a novel protein that interacts with HIF-1-alpha and VHL to mediate repression of HIF-1 transcriptional activity.&lt;/strong&gt; Genes Dev. 15: 2675-2686, 2001.">Mahon et al. (2001)</a>; <a href="#Nibbelink1969" class="mim-tip-reference" title="Nibbelink, D. W., Peters, B. H., McCormick, W. F. &lt;strong&gt;On the association of pheochromocytoma and cerebellar hemangioblastoma.&lt;/strong&gt; Neurology 19: 455-460, 1969.">Nibbelink et al.
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[<a href="https://doi.org/10.1007/BF00223868" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1973.00490190085013" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20496" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/jama.1962.03050490038008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380050109" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1254" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00218913" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0888-7543(90)90249-t" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.8493574" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.21219" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00427365" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/3.4.595" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.30.2.104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/2.7.879" target="_blank">Full Text</a>]
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Taouli, B., Ghouadni, M., Correas, J.-M., Hammel, P., Couvelard, A., Richard, S., Vilgrain, V.
<strong>Spectrum of abdominal imaging findings in von Hippel-Lindau disease.</strong>
AJR Am. J. Roentgenol. 181: 1049-1054, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14500227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14500227</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14500227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.2214/ajr.181.4.1811049" target="_blank">Full Text</a>]
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<a id="Thomas1961" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Thomas, M., Burnside, R. M.
<strong>Von Hippel-Lindau disease.</strong>
Am. J. Ophthal. 51: 140-146, 1961.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13776516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13776516</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13776516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0002-9394(61)91321-6" target="_blank">Full Text</a>]
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<a id="Tisherman1962" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Tisherman, S. E., Gregg, F. J., Danowski, T. S.
<strong>Familial pheochromocytoma .</strong>
JAMA 182: 152-156, 1962.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13985160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13985160</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13985160" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/jama.1962.03050410048010" target="_blank">Full Text</a>]
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<a id="118" class="mim-anchor"></a>
<a id="Tisherman1993" class="mim-anchor"></a>
<div class="">
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Tisherman, S. E., Tisherman, B. G., Tisherman, S. A., Dunmire, S., Levey, G. S., Mulvihill, J. J.
<strong>Three-decade investigation of familial pheochromocytoma: an allele of von Hippel-Lindau disease?</strong>
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<a id="119" class="mim-anchor"></a>
<a id="Tory1989" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Tory, K., Brauch, H., Linehan, M., Barba, D., Oldfield, E., Filling-Katz, M., Seizinger, B., Nakamura, Y., White, R., Marshall, F. F., Lerman, M. I., Zbar, B.
<strong>Specific genetic change in tumors associated with von Hippel-Lindau disease.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2738940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2738940</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2738940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/jnci/81.14.1097" target="_blank">Full Text</a>]
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Tsuda, H., Fukushima, S., Takahashi, M., Hikosaka, Y., Hayashi, K.
<strong>Familial bilateral papillary cystadenoma of the epididymis: report of three cases in siblings.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1260690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1260690</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1260690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/1097-0142(197604)37:4&lt;1831::aid-cncr2820370430&gt;3.0.co;2-v" target="_blank">Full Text</a>]
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<a id="Vance1990" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2328994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2328994</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2328994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0888-7543(90)90488-g" target="_blank">Full Text</a>]
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<strong>Aberrant methylation in cancer. (Editorial)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9106519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9106519</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9106519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Ueber eine sehr seltene Erkrankung der Netzhaut.</strong>
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Webster, A. R., Maher, E. R., Bird, A. C., Moore, A. T.
<strong>Risk of multisystem disease in isolated ocular angioma (haemangioblastoma).</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10691410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10691410</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10691410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.37.1.62" target="_blank">Full Text</a>]
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<a id="Webster1998" class="mim-anchor"></a>
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Webster, A. R., Richards, F. M., MacRonald, F. E., Moore, A. T., Maher, E. R.
<strong>An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects.</strong>
Am. J. Hum. Genet. 63: 1025-1035, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9758595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9758595</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9758595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/302037" target="_blank">Full Text</a>]
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Wells, R. A., Reeders, S. T., Green, J., Johnson, G. J., Robson, K. J. H.
<strong>Linkage studies of von Hippel-Lindau syndrome using multiple-locus hypervariable DNA probes. (Abstract)</strong>
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Wesolowski, D. P., Ellwood, R. A., Schwab, R. E., Farah, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7197999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7197999</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7197999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1259/0007-1285-54-647-982" target="_blank">Full Text</a>]
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Wise, K. S., Gibson, J. A.
<strong>Von Hippel-Lindau's disease and phaeochromocytoma.</strong>
Brit. Med. J. 1: 441, 1971.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5101347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5101347</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5101347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/bmj.1.5746.441" target="_blank">Full Text</a>]
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<a id="Wong2007" class="mim-anchor"></a>
<div class="">
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Wong, W. T., Agron, E., Coleman, H. R., Reed, G. F., Csaky, K., Peterson, J., Glenn, G., Linehan, W. M., Albert, P., Chew, E. Y.
<strong>Genotype-phenotype correlation in von Hippel-Lindau disease with retinal angiomatosis.</strong>
Arch. Ophthal. 125: 239-245, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17296901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17296901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17296901[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=17296901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archopht.125.2.239" target="_blank">Full Text</a>]
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<a id="Wu2012" class="mim-anchor"></a>
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Wu, P., Zhang, N., Wang, X., Ning, X., Li, T., Bu, D., Gong, K.
<strong>Family history of von Hippel-Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients.</strong>
J. Hum. Genet. 57: 238-243, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22357542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22357542</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22357542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/jhg.2012.10" target="_blank">Full Text</a>]
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Wyburn-Mason, R.
<strong>Arteriovenous aneurysm of mid-brain and retina, facial naevi and mental changes.</strong>
Brain 66: 163-203, 1943.
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Zatyka, M., Morrissey, C., Kuzmin, I., Lerman, M. I., Latif, F., Richards, F. M., Maher, E. R.
<strong>Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114475</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12114475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.39.7.463" target="_blank">Full Text</a>]
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<a id="Zbar1996" class="mim-anchor"></a>
<div class="">
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Zbar, B., Kishida, T., Chen, F., Schmidt, L., Maher, E. R., Richards, F. M., Crossey, P. A., Webster, A. R., Affara, N. A., Ferguson-Smith, M. A., Brauch, H., Glavac, D., and 14 others.
<strong>Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.</strong>
Hum. Mutat. 8: 348-357, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8956040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8956040</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8956040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:4&lt;348::AID-HUMU8&gt;3.0.CO;2-3" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 06/04/2020
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Cassandra L. Kniffin - updated : 02/28/2020<br>Ada Hamosh - updated : 2/24/2016<br>Cassandra L. Kniffin - updated : 11/7/2012<br>Cassandra L. Kniffin - updated : 10/25/2010<br>Cassandra L. Kniffin - updated : 10/15/2010<br>Cassandra L. Kniffin - updated : 8/30/2010<br>Cassandra L. Kniffin - updated : 8/18/2009<br>Cassandra L. Kniffin - updated : 4/4/2008<br>Cassandra L. Kniffin - updated : 7/10/2007<br>Jane Kelly - updated : 5/30/2007<br>Cassandra L. Kniffin - updated : 4/2/2007<br>Jane Kelly - updated : 3/23/2007<br>Jane Kelly - updated : 12/7/2006<br>Victor A. McKusick - updated : 9/26/2006<br>Victor A. McKusick - updated : 6/23/2004<br>Jane Kelly - updated : 6/4/2004<br>Cassandra L. Kniffin - updated : 6/2/2004<br>Cassandra L. Kniffin - reorganized : 3/23/2004<br>John A. Phillips, III - updated : 2/12/2004<br>Victor A. McKusick - updated : 2/3/2004<br>George E. Tiller - updated : 11/13/2003<br>Patricia A. Hartz - updated : 11/7/2003<br>Victor A. McKusick - updated : 10/21/2003<br>Ada Hamosh - updated : 9/23/2003<br>Victor A. McKusick - updated : 8/8/2003<br>Victor A. McKusick - updated : 5/16/2003<br>John A. Phillips, III - updated : 4/8/2003<br>Victor A. McKusick - updated : 1/10/2003<br>Patricia A. Hartz - updated : 12/26/2002<br>Victor A. McKusick - updated : 11/4/2002<br>Victor A. McKusick - updated : 9/20/2002<br>Victor A. McKusick - updated : 9/9/2002<br>Ada Hamosh - updated : 8/14/2002<br>Victor A. McKusick - updated : 8/9/2002<br>Michael J. Wright - updated : 7/29/2002<br>Ada Hamosh - updated : 7/17/2002<br>Victor A. McKusick - updated : 7/1/2002<br>Victor A. McKusick - updated : 3/14/2002<br>Paul J. Converse - updated : 1/14/2002<br>Jane Kelly - updated : 12/14/2001<br>Stylianos E. Antonarakis - updated : 10/31/2001<br>George E. Tiller - updated : 10/9/2001<br>John A. Phillips, III - updated : 7/11/2001<br>John A. Phillips, III - updated : 7/5/2001<br>George E. Tiller - updated : 6/19/2001<br>Ada Hamosh - updated : 4/30/2001<br>Jane Kelly - updated : 4/4/2001<br>Victor A. McKusick - updated : 3/6/2001<br>Michael J. Wright - updated : 2/8/2001<br>Michael J. Wright - updated : 1/9/2001<br>Victor A. McKusick - updated : 5/12/2000<br>Victor A. McKusick - updated : 1/13/2000<br>Stylianos E. Antonarakis - updated : 1/7/2000<br>Victor A. McKusick - updated : 1/4/2000<br>Sonja A. Rasmussen - updated : 12/8/1999<br>Rebekah S. Rasooly - updated : 7/27/1999<br>Victor A. McKusick - updated : 6/25/1999<br>Ada Hamosh - updated : 5/19/1999<br>Victor A. McKusick - updated : 1/15/1999<br>Victor A. McKusick - updated : 12/3/1998<br>Victor A. McKusick - updated : 11/2/1998<br>Victor A. McKusick - updated : 10/19/1998<br>Victor A. McKusick - updated : 10/15/1998<br>Victor A. McKusick - updated : 8/11/1998<br>Stylianos E. Antonarakis - updated : 8/3/1998<br>Victor A. McKusick - updated : 3/6/1998<br>John A. Phillips, III - updated : 12/25/1997<br>Victor A. McKusick - updated : 1/13/1998<br>Victor A. McKusick - updated : 12/18/1997<br>Victor A. McKusick - updated : 10/9/1997<br>Victor A. McKusick - updated : 9/19/1997<br>Victor A. McKusick - updated : 8/12/1997<br>Victor A. McKusick - updated : 6/12/1997<br>Iosif W. Lurie - updated : 8/10/1996<br>Moyra Smith - Updated : 5/25/1996<br>Moyra Smith - updated : 4/6/1996<br>Orest Hurko - updated : 6/13/1995
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Victor A. McKusick : 6/2/1986
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carol : 11/13/2024
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<strong>#</strong> 193300
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VON HIPPEL-LINDAU SYNDROME; VHLS
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<em>Alternative titles; symbols</em>
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VHL
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Other entities represented in this entry:
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VON HIPPEL-LINDAU SYNDROME, MODIFIERS OF, INCLUDED
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<strong>SNOMEDCT:</strong> 46659004; &nbsp;
<strong>ICD10CM:</strong> Q85.83; &nbsp;
<strong>ORPHA:</strong> 892; &nbsp;
<strong>DO:</strong> 14175; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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3p25.3
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von Hippel-Lindau syndrome
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193300
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Autosomal dominant
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3
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VHL
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608537
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11q13.3
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{von Hippel-Lindau syndrome, modifier of}
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193300
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Autosomal dominant
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3
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CCND1
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168461
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because von Hippel-Lindau syndrome (VHLS) is caused by heterozygous mutation in the VHL gene (608537) on chromosome 3p25.</p><p>Evidence suggests that variation in the cyclin D1 gene (CCND1; 168461) on chromosome 11q13 may modify the phenotype.</p><p>Homozygous or compound heterozygous mutations in the VHL gene cause familial erythrocytosis-2 (ECYT2; 263400).</p>
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<strong>Description</strong>
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<p>Von Hippel-Lindau syndrome (VHLS) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors.</p><p>Neumann and Wiestler (1991) classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma). Brauch et al. (1995) further subdivided VHL type 2 into type 2A (with pheochromocytoma) and type 2B (with pheochromocytoma and renal cell carcinoma). Hoffman et al. (2001) noted that VHL type 2C refers to patients with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma. McNeill et al. (2009) proposed that patients with VHL syndrome caused by large VHL deletions that include the HSPC300 gene (C3ORF10; 611183) have a specific subtype of VHL syndrome characterized by protection from renal cell carcinoma, which the authors proposed be named VHL type 1B. </p><p>Nordstrom-O'Brien et al. (2010) provided a review of the genetics of von Hippel-Lindau disease. </p>
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<strong>Clinical Features</strong>
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<p>The cardinal features of von Hippel-Lindau syndrome are angiomata of the retina and hemangioblastoma of the cerebellum. Hemangioma of the spinal cord has also been observed. Pheochromocytoma occurs in some patients. The combination of hypertension with angioma may lead to subarachnoid hemorrhage. Hypernephroma-like renal tumors occur in some patients. Polycythemia may be due to either the hemangioblastoma of the cerebellum or the hypernephroma. Hemangiomas of the adrenals, lungs, and liver, and multiple cysts of the pancreas and kidneys, have been observed in some instances.</p><p>Although there were many earlier reports of this syndrome (see HISTORY), Melmon and Rosen (1964) introduced the term 'von Hippel-Landau' syndrome and described a large kindred with multiple features of the disorder. The condition of arteriovenous aneurysm of retina and midbrain with facial nevus, described by Bonnet et al. (1938) and by Wyburn-Mason (1943), is of uncertain relationship to this condition. Metastatic renal cancer occurs in some instances (Kranes and Balogh, 1966). Goldberg and Duke (1968) examined the eyes of an affected 51-year-old black male whose mother died of cerebellar tumor at age 26 years. The same case was described by McKusick (1961). In addition to the association of tumors of the brain and adrenal medulla that occurs in neurofibromatosis and in von Hippel-Lindau disease, cerebellar tumors sometimes produce paroxysmal hypertension similar to that of pheochromocytoma. Urinary catecholamines are normal in such cases (Cameron and Doig, 1970). </p><p>Cysts and 'hypernephroid' tumors of the epididymis have been described in VHL patients (Grossman and Melmon, 1972). Male patients may have papillary cystadenoma of the epididymis, an unusual tumor that is bilateral when it occurs in von Hippel-Lindau disease and is not familial when unilateral (Price, 1971). The experience of Lamiell (1987) differed, however; 7 of 21 affected males in 1 kindred had an epididymal mass and 5 of these were unilateral. Tsuda et al. (1976) observed the occurrence of bilateral papillary cystadenoma of the epididymis in 3 brothers with VHL syndrome. Bilateral papillary cystadenomas of the broad ligament, presumably of mesonephric origin, is the probable homologous tumor of the female (Erbe, 1978). </p><p>In von Hippel-Lindau disease with pheochromocytoma, Atuk et al. (1979) reported hypercalcemia which was corrected in all by removal of the tumor. In several patients, pheochromocytoma antedated development of retinal lesions. Fishman and Bartholomew (1979) described 3 related patients with striking pancreatic involvement. One had exocrine pancreatic insufficiency. In an extensively affected kindred, Fill et al. (1979) found renal cell carcinoma in 16 of 42 cases and carcinoma of the pancreas in 4 of 42. </p><p>Griffiths et al. (1987) found reports of 6 patients with von Hippel-Lindau syndrome, pheochromocytoma, and islet cell tumor. A further 11 patients showed pheochromocytoma and islet cell tumor. No patient with von Hippel-Lindau syndrome had a carcinoid tumor, which is a feature of neurofibromatosis with pheochromocytoma (see 162200). No cases of neurofibromatosis had islet cell tumor. In Cardiff, Wales, 20 patients with cerebellar hemangioblastoma were seen between 1972 and 1985. In 8 of these, Huson et al. (1986) subsequently established the diagnosis of von Hippel-Lindau disease. Although the diagnosis had not previously been considered, in retrospect, 7 of the 8 cases were known to be at risk for the syndrome. </p><p>Jennings et al. (1988) demonstrated the usefulness of family studies in determining asymptomatic lesions requiring treatment, such as renal cell carcinoma. They also reported the occurrence of a spermatic cord mesenchymal hamartoma in this disorder. Lamiell et al. (1989) identified 43 affected members in a large kindred, which was exceptional for absence of pheochromocytoma and erythrocythemia, for more renal and pancreatic cysts and malignancies, and for somewhat fewer eye or central nervous system lesions. Bilateral renal adenocarcinoma was found presymptomatically in 5 young subjects who had bilateral nephrectomy and hemodialysis. Three survived long-term after renal transplants. Five members of the family had pancreatic malignancy. </p><p>Horbach et al. (1989) suggested that the combination of adrenal pheochromocytoma and ipsilateral renal cell carcinoma may represent a forme fruste of von Hippel-Lindau disease. </p><p>Neumann and Wiestler (1991) found a striking tendency for familial clustering of particular VHL features. Both angiomatosis retinae and hemangioblastoma of the CNS occurred in most families, whereas the occurrence of renal lesions and/or pancreatic cysts was mutually exclusive with pheochromocytoma. The authors interpreted these findings to indicate that the VHL locus is complex, with the existence of different mutations in different families or the occurrence of additional genetic lesions that cooperate with the VHL gene on chromosome 3p. They suggested a linear sequence of features as follows: pheochromocytoma, angiomatosis retinae, hemangioblastoma of the CNS, renal lesions, pancreatic cysts, and epididymal cystadenoma. </p><p>In the course of an evaluation of 41 families with this disorder from the United States and Canada, Glenn et al. (1991) found 1 large family with a distinctive phenotype: the most common disease manifestation was pheochromocytoma occurring in 57% (27 of 47) of affected members; few (4 of 47) had symptomatic spinal or cerebellar hemangioblastomas; no affected family member had renal cell carcinoma or pancreatic cysts. Genetic analysis demonstrated, however, that the disorder in this family was linked to the same markers found to be linked to typical VHL. The observations are clearly relevant to the descriptions of families with 'pure' pheochromocytoma (171300); they may be instances of allelism at the VHL locus. </p><p>Keeler and Klauber (1992) described renal cell carcinoma in a 16-year-old boy, probably the youngest reported example of hypernephroma in VHL disease. </p><p>Lenz et al. (1992) demonstrated that norepinephrine-producing adrenal pheochromocytoma in von Hippel-Lindau disease can produce the clinical syndrome of hypertension associated with severe hypokalemia and hyperreninemic hyperaldosteronism. The hyperreninemic hyperaldosteronism was rapidly improved by beta-blockade and was completely reversed by tumor removal. Kerr et al. (1995) described hemangioblastoma of the optic nerve in a 27-year-old woman with von Hippel-Lindau syndrome, the tenth such reported case. </p><p>Davies et al. (1994) described a 65-year-old woman who was an obligate carrier of the gene for von Hippel-Lindau disease. Her father, 2 brothers, 2 sisters, and 3 sons had hemangioblastomas and renal carcinomas. Careful examination of the woman showed only a small benign renal cyst. Such cysts are very common in the general population. Therefore, obligate gene carriers may not exhibit any features of the disease beyond the age of 60 years. </p><p>Using a VHL register set up in the northwest of England in 1990 containing information on 83 affected persons, Maddock et al. (1996) studied population statistics, clinical features, age at onset, and survival. The mean age at onset of first symptoms was 26.25 years, with cerebellar hemangioblastoma being the most common presenting manifestation (34.9% of cases). The mean age at diagnosis of VHL was 30.87 years. Overall, 50 patients (60.2%) developed a cerebellar hemangioblastoma, 34 (41%) a retinal angioma, 21 (25.3%) a renal cell carcinoma, 12 (14.5%) a spinal hemangioblastoma, and 12 (14.5%) a pheochromocytoma. Mean age at death was 40.9 years with cerebellar hemangioblastoma being the most common cause (47.7% of deaths). In addition to the 83 clinically affected subjects, Maddock et al. (1996) identified 3 obligate carriers who were considered to be lesion free on extensive screening tests. In the regionally based cancer registry, 14% of all CNS hemangioblastomas were found to occur as part of VHL, but investigations for VHL in apparently sporadic cases appeared to have been limited. </p><p>Endolymphatic sac tumors (ELSTs) are highly vascular, benign, but locally aggressive neoplasms of the endolymphactic system that often destroy the surrounding temporal bone. They are very rare and generally occur sporadically, but occur with increased frequency in patients with VHL. Manski et al. (1997) found MRI evidence of 15 ELSTs in 13 (11%) of 121 patients with VHL, but in none of 253 patients without evidence of VHL (P less than 0.001). Clinical findings in these 13 patients included hearing loss in 13, tinnitus in 12, vertigo in 8, and facial paresis in 1. Mean age at onset of hearing loss was 22 years (range, 12 to 50 years). </p><p>Lonser et al. (2004) described 3 cases of von Hippel-Lindau disease that illustrated the following features of endolymphatic sac tumors: morbid hearing loss due to a radiologically undetectable microscopic tumor in the endolymphatic sac or duct; initial symptoms caused by hemorrhage, endolymphatic hydrops, or both; an origin in the endolymphatic duct or sac; and molecular evidence of an association with von Hippel-Lindau disease. Complete surgical resection of the endolymphatic sac tumors is curative and can be performed with the preservation of hearing and the alleviation of vestibular symptoms. </p><p>Butman et al. (2007) reported 35 VHL patients with ELSTs; 3 had bilateral tumors. Mean age at symptom onset was 31 years (range, 11 to 63 years). In additional to hearing loss, tinnitus, and vertigo, other features included aural fullness, aural pain, and facial nerve weakness. Detailed CT and MRI studies showed that 7 (18%) ears had otic capsule invasion, which was always associated with hearing loss. Tumors with otic capsule invasion were larger (2.2 cm) than those without capsule invasion (1.2 cm). However, there was not a significant association between tumor size and hearing loss. Intralabyrinthine hemorrhage was detected in 79% of ears with sudden hearing loss. Butman et al. (2007) concluded that hearing loss associated with ELSTs can result from otic capsule invasion, intralabyrinthine hemorrhage, or endolymphatic hydrops. </p><p>James (1998) tabulated reports of 4 women with VHL and broad ligament papillary cystadenoma published between 1988 and 1994 (Gersell and King, 1988; Funk and Heiken, 1989; Korn et al., 1990; Gaffey et al., 1994; Karsdorp et al., 1994) and added a fifth case. These are mesosalpinx cysts, which are the equivalent of epididymal cysts in the male. The cysts were unilateral in at least 3 of the 5 cases. They occurred along the full course of the mesonephric duct, in the mesosalpinx close to the ovary, over the uterine tubes, and near the vaginal fornix in a remnant of the Gartner duct (the female counterpart to the duct of the epididymis). At least 3 of the patients had multiple renal cysts and bilateral renal cell carcinoma. In the patient reported by Korn et al. (1990), screening for VHL after the papillary cystadenomas were diagnosed revealed pancreatic cysts and lesions of the cerebellum and kidney; renal cell carcinoma was diagnosed during follow-up surgery. The unilateral cyst in the patient reported by Gaffey et al. (1994) was preceded by the finding of a middle ear papillary tumor. The combined presentation of mesonephric cystadenoma and ear tumor was noted in reports of epididymal cysts in men (Price, 1971). Gaffey et al. (1994) suggested that the ear tumor and the adnexal tumor may represent 'major visceral manifestations of VHL.' (Nomenclature: According to the VHL Family Alliance, a genetic support group, the approved terminology is 'adnexal papillary cystadenoma of probable mesonephric origin,' abbreviated APMO (Graff, 1998).) </p><p>Fukino et al. (2000) described a Japanese VHL family in which 2 of the 3 affected members developed acute occlusive hydrocephalus that necessitated emergency surgery for ventricular shunting or drainage. In both cases, the occlusion of the cerebrospinal canal was caused by cerebellar hemangioblastoma. The 2 patients with hydrocephalus were sisters aged 8 and 19 at the time of development of obstructive hydrocephalus. They inherited VHL from their mother, who also suffered from cerebellar hemangioblastoma requiring surgery as well as from retinal angiomas. </p><p>McCabe et al. (2000) described the clinical features, association with von Hippel-Lindau disease, and visual acuity outcomes of patients with juxtapapillary capillary hemangioma, on or adjacent to the optic nerve. Because of their location, a hamartoma on the lesions could potentially be misdiagnosed as papilledema, papillitis, choroidal neovascularization, or choroiditis. Endophytic, exophytic, and sessile forms were described. On long-term follow-up, visual acuity generally worsened. Patients with VHL and juxtapapillary hemangioma more often presented at a younger age, had tumors with an endophytic growth pattern, and had bilateral, multiple tumors. Tumor treatment with laser photocoagulation resulted in variable visual acuity outcomes in the patients reported. </p><p>Raja et al. (2004) reported that external beam radiotherapy (EBRT) was a useful option in the treatment of retinal hemangiomas secondary to VHL disease that progressed despite standard therapy. EBRT led to improvement of visual acuity, reduction in tumor volume, and stabilization of retinal detachment in most patients treated. </p><p>Eisenhofer et al. (2001) examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in MEN2 (171400) and VHL to underlying differences in the expression of tyrosine hydroxylase (TH; 191290), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT; 171190), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN2 patients and 30 VHL patients with adrenal pheochromocytomas. MEN2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than VHL patients. MEN2 patients all had elevated plasma concentrations of the epinephrine metabolite metanephrine, whereas VHL patients showed specific increases in the norepinephrine metabolite normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN2 patients. </p><p>Taouli et al. (2003) discussed abdominal imaging findings, including pictorial images, from more than 150 patients with VHL syndrome. The most common findings were renal and pancreatic masses. </p><p>In a prospective study of 406 VHL patients from 199 families seen at 1 institution in a 12-year period, Chew (2005) found that 205 of the patients had ocular involvement. Patients with complete deletion of the VHL gene were less likely to have ocular involvement than those with partial deletion, missense, or nonsense mutations (9% vs 45%; p less than 0.0001). Chew (2005) identified a previously unreported ocular feature, retinal neovascularization, in 17 patients. Chew (2005) also found 11 cases of intraorbital/intracranial hemangioblastoma, previously reported to be rare in VHL, accounting for 5.3% of all vision-threatening lesions in this study group. </p><p>In surgically excised retinal hemangioblastomas associated with von Hippel-Lindau disease, Liang et al. (2007) demonstrated high levels of VEGF (192240) and CXCR4 (162643) mRNA and protein but low levels of CXCL12 (600835). Increased expression of VEGF and CXCR4 was also detected in more active hemangioblastomas. </p><p>Binderup et al. (2016) performed a retrospective analysis of a national cohort study that included 52 VHL mutation carriers. The analysis spanned a total of 799 person-years. From birth to time of the report, 581 manifestations were diagnosed during 2,583 examinations in the study subjects. The rate of new tumor development varied significantly with age and was highest at 30 to 34 years (0.4 new tumors/year). Tumor location further influenced the rate. The risk of retinal tumors was highest in subjects during the teenage years but was highest for cerebellar tumors in subjects during their 30s. Truncating VHL mutation carriers had a significantly higher manifestation rate compared with missense mutation carriers (hazard ratio = 1.85, 95% confidence interval 1.06-3.24, p = 0.031). The authors concluded that the rate of new manifestation development is not constant throughout the life span of VHL patients. They recommended careful retinal surveillance during the teenage years and increased cerebellar surveillance in adulthood. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Interfamilial differences in predisposition to pheochromocytoma in VHL reflect allelic heterogeneity such that there is a strong association between missense mutations and risk of pheochromocytoma. Prowse et al. (1997) investigated the mechanism of tumorigenesis in VHL tumors to determine whether there were differences between tumor types or classes of germline mutations. They studied 53 tumors (30 renal cell carcinomas, 15 hemangioblastomas, 5 pheochromocytomas, and 3 pancreatic tumors) from 33 patients (27 kindreds) with VHL. Overall, 51% of 45 informative tumors showed LOH at the VHL locus. In 11 cases, it was possible to distinguish between loss of the wildtype and mutant alleles, and in each case the wildtype allele was lost. LOH was detected in all tumor types and occurred in the presence of both germline missense mutations and other types of germline mutation associated with a low risk of pheochromocytoma. Intragenic somatic mutations were detected in 3 tumors (all hemangioblastomas) and in 2 of these could be shown to occur in the wildtype allele. Their study provided the first example of homozygous inactivation of the VHL gene by small intragenic mutations in this type of tumor. Hypermethylation of the VHL gene was detected in 33% (6 of 18) of tumors without LOH, including 2 renal cell carcinomas and 4 hemangioblastomas. Prowse et al. (1997) stated that although hypermethylation of the VHL gene had been reported previously in nonfamilial RCC and although methylation of tumor-suppressor genes had been implicated in the pathogenesis of other sporadic cancers, this was the first report of somatic methylation in a familial cancer syndrome. Herman et al. (1994) observed hypermethylation of the VHL gene in 19% of sporadic RCCs. Versteeg (1997) provided a general discussion of aberrant methylation in cancer. </p><p>By using comparative genomic hybridization (CGH), Lui et al. (2002) characterized the genetic profiles of 36 VHL-related pheochromocytomas. They found loss of chromosome 3 or chromosome 11 in 34 tumors (94%) and 31 tumors (86%), respectively. There was significant concordance of deletions in chromosomes 3 and 11, suggesting that they are involved in 2 different but necessary and complementary genetic pathways. The loss of chromosome 11 appeared to be specific for VHL-related pheochromocytoma as it was not present in any of the 10 VHL-related CNS hemangioblastomas studied and was significantly less common when compared with sporadic and MEN2-related pheochromocytomas. The authors stated that this was the first report of a novel consistent genetic alteration that is selected and specific for VHL-related pheochromocytoma. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Maher et al. (1991) estimated the point prevalence of heterozygotes in East Anglia to be 1 in 53,000, with an estimated birth incidence of 1 in 36,000 live births. Reproductive fitness was 0.83. Direct and indirect estimates of the mutation rate were 4.4 per million gametes per generation and 2.32 per million gametes per generation, respectively. No significant association was found between parental age or birth order and new mutations. In the Freiburg district of Germany, Neumann and Wiestler (1991) calculated the prevalence of this disorder to be 1 in 38,951. </p><p>Maddock et al. (1996) reported on a VHL register set up in the northwest of England in 1990. There was information on 83 affected persons. In addition, the effectiveness of the screening program used and the occurrence of CNS hemangioblastomas in the general populations were examined. The diagnostic point prevalence of heterozygotes in the region was 1 in 85,000 persons, with an estimated birth incidence of 1 in 45,500 live births. The mutation rate was estimated directly to be 1.4 x 10(-6)/gene/generation (1 in 714,200). </p><p>Wu et al. (2012) identified mutations in the VHL gene in 12 (75%) of 16 Chinese probands with clinically diagnosed VHL syndrome. PCR-direct sequencing detected 12 mutations, 1 of which was novel, in 12 patients (75%). Use of universal primer quantitative fluorescent multiplex PCR (UPQFM-PCR) enabled detection of 2 large deletions in 2 (12.5%) patients. The 2 remaining patients carried atypical variations in the VHL gene that could not definitively be called pathogenic. Nine (56.3%) probands did not have a family history of the disorder, suggesting a high frequency of de novo mutations among Chinese patients. Clinically, 15 families were classified as type 1 (without pheochromocytoma) and 1 as type 2 (with pheochromocytoma). The most common manifestations were CNS hemangioblastoma, clear cell renal cell carcinoma, and pancreatic cysts and tumors. Combining this information with previous reports of Chinese VHL patients indicated that the clinical features and spectrum of VHL mutations among the Chinese are comparable to those found in large-scale investigations from other countries. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Seizinger et al. (1991) pointed out that visceral cysts of the kidney, pancreas, and epididymis occur not only as features of VHL but also in the general population, and that the presence of such cysts, unaccompanied by other more typical lesions such as retinal and cerebellar hemangioblastoma, may represent a major diagnostic problem. The application of flanking markers for the VHL gene for presymptomatic diagnostic testing confirmed that epididymal cysts are indeed not suitable as a diagnostic criterion. The genetic studies suggested that VHL with or without pheochromocytomas is caused by defects within the same gene. Renal cell carcinoma occurs as part of VHL; a second more proximal region of chromosome 3, 3p14.2, is responsible for 'pure familial renal cell carcinoma' (144700). </p><p>Webster et al. (2000) calculated the likelihood of VHL in an individual presenting with a single ocular angioma conditional upon the age of presentation, results of DNA analysis, family history of VHL, and results of systemic screening, and produced a risk estimate table for individuals with combinations of these variables. </p><p>Hes et al. (2003) noted that in the presence of a positive family history, VHL disease can be diagnosed clinically in a patient with at least 1 typical VHL tumor. Typical VHL tumors are retinal, spinal, and cerebellar hemangioblastoma; renal cell carcinoma; and pheochromocytoma. Endolymphatic sac tumors and multiple pancreatic cysts suggest a positive carriership in the presence of a positive VHL family history because they are uncommon in the general population. In contrast, renal and epididymal cysts occur very frequently in the general population and are, as sole manifestations, not reliable indicators for VHL disease. In patients with a negative family history of VHL-associated tumors, a diagnosis of VHL disease can also be made on the basis of 2 or more hemangioblastomas or a single hemangioblastoma in association with a visceral manifestation (e.g., pheochromocytoma or renal cell carcinoma). Hes et al. (2003) suggested the following criteria for eligibility for VHL gene mutation analysis: a patient with classic VHL disease (meeting clinical diagnostic criteria) and/or first-degree family members; a person from a family in which a germline VHL gene mutation has been identified (presymptomatic test); a VHL-suspected patient, i.e., one with multicentric tumors in 1 organ, bilateral tumors, 2 organ systems affected, or 1 VHL-associated tumor at a young age (less than 50 years for hemangioblastoma and pheochromocytoma or less than 30 years for renal cell carcinoma); or a patient from a family with hemangioblastoma, renal cell carcinoma, or pheochromocytoma only. </p><p><strong><em>Mutation Analysis</em></strong></p><p>
Using DNA polymorphic markers, Glenn et al. (1992) studied 16 families with VHL disease. Of 48 asymptomatic persons at risk of developing this illness because of an affected parent or sib, DNA polymorphism analysis predicted that 9 were carriers of the disease gene and 33 had the wildtype allele. The test was not informative in 6 persons. All 9 persons predicted to carry the VHL gene had evidence of occult disease on clinical examination. There was no clinical evidence of VHL disease in 32 of 33 persons predicted to carry the wildtype allele. </p><p>Richards et al. (1993, 1994) found that large germline deletions could be detected by Southern analysis and pulsed field gel electrophoresis in 19% and 3% of VHL patients, respectively. </p><p>To determine whether the pheochromocytoma-associated syndromes VHL and MEN2 play a role in the development of thoracic functioning paragangliomas, Bender et al. (1997) analyzed germline DNA from 5 unselected patients with this tumor for mutations in the genes that predispose to VHL and MEN2. Molecular and clinical data revealed that 3 (60%) had VHL, with 2 different germline mutations of the VHL gene, but no individual was affected by MEN2. Two of these 3 patients with VHL did not show any additional VHL-associated lesions. Bender et al. (1997) suggested that VHL should be considered in the differential diagnosis of thoracic pheochromocytoma, and that in VHL patients suspected of a catecholamine-secreting tumor, thoracic localization should be considered if an adrenal pheochromocytoma cannot be detected. </p><p>Pack et al. (1999) stated that the reported frequency of detection of VHL germline mutations had varied from 39 to 80%. Stolle et al. (1998) found that a quantitative Southern blotting procedure improved this frequency. Pack et al. (1999) reported the use of fluorescence in situ hybridization as a method to detect and characterize VHL germline deletions. They reexamined a group of VHL patients shown previously by SSCP and sequencing analysis not to harbor point mutations in the VHL locus. They found constitutional deletions in 29 of 30 VHL patients in this group, using cosmid and P1 probes that covered the VHL locus. They then tested 6 phenotypically normal offspring from 4 of these VHL families: 2 were found to carry the deletion and the other 4 were deletion-free. In addition, germline mosaicism of the VHL gene was identified in 1 family. Thus, FISH was found to be a simple and reliable method to detect VHL germline deletions and to be practically useful in cases where other methods of screening fail to detect abnormalities in the VHL gene. </p><p>Hes et al. (2000) performed mutation analysis of the VHL gene in 84 patients presenting with a single CNS hemangioblastoma and 4 with multiple hemangioblastomas, but no other features of VHL. A VHL germline mutation was found in 3 of 69 (4.3%) of those with single hemangioblastomas presenting at less than 50 years of age (3 of 84 (3.6%) in total) and 2 of the 4 patients with multiple hemangioblastomas. A VHL mutation was found in a 44-year-old woman presenting with a single cerebellar hemangioblastoma, in 4 clinically unaffected relatives, and in 2 single cases presenting at 29 and 36 years. Hes et al. (2000) recommended that in addition to conventional clinical and radiologic investigations, VHL mutation analysis be offered to those presenting with CNS hemangioblastomas before the age of 50 years. </p><p>Sgambati et al. (2000) presented 2 cases of VHL mosaicism. In each of 2 families, standard testing methods (Southern blot analysis and direct sequencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysis of the affected parents' blood detected the VHL gene mutation in a portion of their peripheral blood lymphocytes. In one case, detection of the deleted allele was by FISH, and, in the second case, a 3-bp deletion was detected by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. Sgambati et al. (2000) concluded that mosaicism in VHL is important to search for and recognize when an individual without a family history of VHL has VHL. Patients diagnosed without family histories of the disease have been reported in as many as 23% of kindreds. Identification of individuals potentially mosaic for VHL will affect counseling of families, and these individuals should themselves be included in clinical screening programs for occult disease. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Cytogenetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Kiechle-Schwarz et al. (1989) found rearrangements resulting in partial or total trisomy of chromosome 3p in 3 cell clones from pheochromocytomas derived from patients with von Hippel-Lindau syndrome. </p><p>Kovacs and Kung (1991) analyzed the DNA from 28 nonpapillary renal cell carcinomas arising in 2 patients with VHL disease. They used both karyotypic and RFLP analyses for evidence of allelic recombination on chromosomes 3 and 5. Two distinct breakpoint clusters were identified, each associated with different karyotypic alterations. The first type involves a breakpoint at chromosome 3p13, with the common nonreciprocal translocations occurring between 3p and 5q or 1q, resulting in the net loss of 3p and gain of 5q or 1q segments. In the second form of translocation, which was less common, the breakpoint on 3p and on the partner chromosome is near the centromere at bands p11 or q11. This kind of rearrangement was observed in 10 tumors with a nonrandom involvement of chromosome 3. In each case the derivative chromosome carrying the translocated 3p segment was preferentially eliminated from the tumor cells. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Go et al. (1984) found no linkage of VHL with any of 31 marker loci by studying 41 affected persons among 220 descendants of an ancestral couple. Wells et al. (1987) found linkage with a segregating minisatellite band at a recombination fraction of 0.15 (lod score of about 3.0). In studies of 9 families, Seizinger et al. (1988) found linkage with RAF1 (164760) on chromosome 3; the combined maximum lod score was 4.38 at theta = 0.11 (1 lod unit confidence interval, the approximate equivalent of 95% confidence interval, of theta = 0.04 to 0.23). The finding of recombination between VHL and RAF1 indicated that the site of the VHL mutation is not in the RAF1 gene. </p><p>Seizinger et al. (1989) reported a multipoint linkage analysis of the VHL gene using a battery of polymorphic markers in the region 3p26-p25. Vance et al. (1990) confirmed the linkage of VHL to 3p. Hosoe et al. (1990) concluded that VHL is located between RAF1 (3p25) and D3S18 (3p26). </p><p>Maher et al. (1990) confirmed the assignment to 3p by linkage studies in 12 British families. They suggested that the VHL locus is telomeric to the THRB gene (190160). No evidence for genetic heterogeneity was found. Seizinger et al. (1991) reported the location of the VHL locus at 3p26-p25 on the basis of studies in 28 pedigrees comprising 164 affected persons. By multipoint linkage analysis, Maher et al. (1991) demonstrated flanking markers. They found no evidence of locus heterogeneity; families with and without pheochromocytoma showed linkage to D3S18 with which no recombination was observed (maximum lod score = 6.6 at theta = 0.0; CI, 0.00-0.06). By multipoint linkage analysis, Richards et al. (1993) narrowed the target region for isolation of the VHL disease gene by positional cloning techniques to a 4-cM interval between D3S1250 and D3S18. </p><p>Richards et al. (1993) constructed a long-range physical map around D3S601, which had been shown to be tightly linked to the VHL locus, and screened 91 VHL patients from 80 kindreds for germline rearrangements using pulsed field gel electrophoresis. Two patients were found to have germline deletions within this region, approximately 120 kb and 50 kb, respectively, telomeric to D3S601. The results established the position of the VHL locus with respect to D3S601, refined its localization to a small region of approximately 50 kb, and excluded the plasma membrane Ca(2+)-transporting ATPase-2 gene (108733) as the site of the VHL mutation. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In 28 of 221 kindreds with von Hippel-Lindau syndrome, Latif et al. (1993) identified rearrangements of the VHL gene. Eighteen of these rearrangements were due to deletion in the VHL gene: 1 of these was an in-frame 3-nucleotide deletion (608537.0001). </p><p>In 55 of 94 unrelated VHL kindreds, Crossey et al. (1994) identified 40 different mutations in the VHL gene. The 2 most frequent mutations were arg238-to-gln (608537.0005) and arg238-to-trp (608537.0003), which were detected in 5 and 4 unrelated kindreds, respectively. </p><p>Ciotti et al. (2009) identified mutations in the VHL gene in 9 (100%) of 9 unrelated families and in 16 (88.9%) of 18 isolated patients presenting with the classic phenotype of VHL syndrome. VHL mutations were also found in 2 (66.7%) of 3 patients who met the diagnostic criteria for VHL syndrome, but who also had multiple cerebellar hemangioblastomas. Of those with mutations, 6 (22%) of 27 were found to have complete or partial deletions of the gene. No VHL mutations were found in 13 additional patients who did not meet the full diagnostic criteria of the disorder, but who had some suggestive features. </p><p>In 6 patients from a family (F8) with von Hippel-Lindau syndrome, Lenglet et al. (2018) identified a heterozygous complex mutation in the cryptic exon 1-prime (E1-prime) of the VHL gene (608537.0032). The mutations, which occurred on the same allele, were found by a combination of microsatellite analysis and gene sequencing and segregated with the disorder in the family. The mutations were predicted to result in leu128-to-val (L128V) and leu138-to-pro (L138P) substitutions in the newly identified X1 VHL protein isoform. Analysis of patient cells and tumor tissue showed upregulation of isoforms containing exons 1 and E1-prime, predicted to result in premature termination that would likely be degraded by nonsense-mediated mRNA. There was also lower expression of other wildtype VHL isoforms. Minigene assays in various cell lines showed a synergistic effect of the 2 mutations on abnormal splicing; the expression of E1-prime-containing isoforms was higher for mutations associated with cancer than with erythrocytosis (see 263400). The authors postulated downregulation of VHL isoforms as a pathogenic mechanism. Sequencing of tumor tissue from these patients did not identify VHL loss of heterozygosity, indicating that somatic VHL deletion may not be a prerequisite for developing cancer in patients with this genotype. The patients had classic features of the disorder, including hemangioblastoma, clear cell renal carcinoma, and pheochromocytoma. </p><p><strong><em>Modifiers of VHL</em></strong></p><p>
To assess the influence of variation in CCND1 (168461) on the retinal, renal, and central nervous system (CNS) manifestations of von Hippel-Lindau disease (193300), Zatyka et al. (2002) genotyped 118 patients for the codon 242 G-A SNP (168461.0001). The number of retinal angiomas was significantly higher in individuals harboring the G allele compared with AA homozygotes (p of 0.04). Possession of 1 or more G alleles was associated with earlier diagnosis of CNS hemangioblastoma by almost 2-fold, although the difference did not attain statistical significance (p of 0.05). A similar analysis for onset of renal cell carcinoma showed no evidence of an association with CCND1 genotype. </p><p>In a retrospective analysis of 123 patients from 55 families with VHL, including 13 with complete germline deletion of the VHL gene and 42 with partial gene deletions, Maranchie et al. (2004) observed a paradoxically lower prevalence of renal cell carcinoma in those with complete gene deletions. RCC occurred more frequently in patients with partial germline VHL deletions relative to complete deletions (48.9% vs 22.6%, p = 0.007). This striking phenotypic dichotomy was not seen for cystic renal lesions or for CNS (p = 0.22), pancreas (p = 0.72), or pheochromocytoma (p = 0.34). Deletion mapping demonstrated that development of RCC had an even greater correlation with retention of HSPC300 (C3ORF10; 611183), located within the 30-kb region of 3p immediately telomeric to the VHL gene (52.3% vs 18.9%, p less than 0.001), suggesting the presence of a neighboring gene or genes critical to the development and maintenance of RCC. </p><p>Cascon et al. (2007) found that 6 of 8 VHL patients without RCC had large germline deletion of the VHL gene including deletion of HSPC300. In contrast, 9 of the 10 with RCC had retention of the HSPC300 gene. Analysis of 9 sporadic RCC tumors showed that all retained an HSPC300 allele. Cascon et al. (2007) concluded that loss of the HSPC300 gene confers protection against renal clear cell carcinoma. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Although pheochromocytoma occurs in only about 7% of VHL patients, marked interfamilial differences are often observed. Examining the relationship between VHL gene mutations and phenotype in 65 VHL kindreds, Crossey et al. (1994) found that large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma but in only 2 of 12 families with pheochromocytoma (P less than 0.01). Of 12 families with pheochromocytoma, 10 had missense mutations compared with 13 of 53 kindreds without pheochromocytoma (P less than 0.001). In particular, the arg238-to-trp and arg238-to-gln mutations were associated with a high risk (62%) of pheochromocytoma. </p><p>Chen et al. (1995) identified germline mutations in 85 of 114 VHL families (75%). They found that the types of mutations responsible for VHL without pheochromocytoma (VHL type 1) differed from those responsible for VHL with pheochromocytoma (VHL type 2). Microdeletions/insertions, nonsense mutations, or deletions were found in 56% of families with VHL type 1; missense mutations accounted for 96% of those responsible for VHL type 2. Specific mutations in codon 238 accounted for 43% of the mutations responsible for VHL type 2 (see 608537.0003-608537.0005). </p><p>Zbar et al. (1996) performed germline mutation analysis in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300 (63%) of the families tested; a total of 137 distinct intragenic germline mutations were detected. Most (124 of 137) of the mutations occurred in 1 or 2 families; a few occurred in 4 or more families. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produce similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced 3 distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma (e.g., 608537.0003), and (3) pheochromocytoma alone (e.g., 608537.0012). Zbar et al. (1996) provided a catalog of VHL germline mutations with associated phenotype information. </p><p>In a patient with von Hippel-Lindau syndrome due to a 505T-C transition (608537.0009) in the VHL gene, Schimke et al. (1998) found a secretory carotid body paraganglioma, the first such instance; a nonfunctional malignant carotid body tumor had been described in a patient with VHL by Hull et al. (1982). </p><p>Gallou et al. (1999) analyzed the occurrence of RCC in VHL families, based on the nature of the VHL mutations. They observed RCC in at least 1 member of the VHL families in 77% of cases with mutations leading to truncated proteins, and in 55% of cases with missense mutations (P less than 0.05). Thus, mutations resulting in truncated proteins may carry a higher risk of RCC in VHL patients. </p><p>Bradley et al. (1999) described a family with VHL disease and a mutation in the VHL protein (608537.0017). Of 13 affected individuals, 7 had renal cell carcinoma and 1 had pheochromocytoma. The authors contrasted this family with 2 families reported by Chen et al. (1996) that had a mutation at the same position but causing a different amino acid change (608537.0012). In these families, 19 of 22 affected individuals had pheochromocytoma and none had renal cell carcinoma. Bradley et al. (1999) concluded that different amino acid changes at the same position can cause very distinct clinical phenotypes. </p><p>Hes et al. (2000) described 5 VHL families in which direct sequencing of the coding region of the VHL gene failed to identify the family-specific mutation. Further molecular analysis revealed deletions involving the VHL gene in each of these families. In 4 families, partial deletions of 1 or more exons were detected by Southern blot analysis. In the fifth family, FISH analysis demonstrated the deletion of the entire VHL gene. The data supported the previously established observation that families with a germline deletion have a low risk for pheochromocytoma. Further unraveling of the genotype-phenotype correlations in VHL disease revealed that families with a full or partial deletion of the VHL gene exhibited a phenotype with a preponderance of central nervous system hemangioblastoma. </p><p>Friedrich (2001) reviewed genotype/phenotype correlations in von Hippel-Lindau syndrome. </p><p>Hoffman et al. (2001) noted that a type 2C VHL mutant, L188V (608537.0014), which had been associated with a pheochromocytoma-only phenotype (and had been shown to retain the ability to promote HIF (603348) ubiquitylation), retained the ability to suppress cyclin D1 (CCND1; 168461) expression, suggesting that loss of VHL-mediated suppression of cyclin D1 is not necessary for pheochromocytoma development in VHL disease. Other studies had suggested that (1) genetic modifiers influence the phenotypic expression of VHL disease (Webster et al., 1998); and (2) polymorphic variation at the CCND1 codon 242 A/G SNP (168461.0001) may influence cancer susceptibility or prognosis in some situations. Therefore, Zatyka et al. (2002) analyzed the relationship between CCND1 genotype and phenotypic expression of VHL disease. They found an association between the G allele and multiple retinal angiomas (p = 0.04), and risk of central nervous system hemangioblastoma (p = 0.05). The findings suggested that a variety of HIF-independent mechanisms may contribute to the tumor suppressor activity of the VHL protein and that polymorphic variation at one VHL protein target influences the phenotypic expression of VHL disease. </p><p>In a study of 573 individuals with VHL syndrome from 200 unrelated families, Ong et al. (2007) found that age at disease onset was significantly earlier, and age-related risks of retinal angiomas and RCC were higher in individuals with nonsense or frameshift mutations compared to those with deletions or missense mutations. The results also confirmed the association of pheochromocytomas with missense mutations, particularly those that resulted in surface amino acid substitutions. </p><p>Wong et al. (2007) characterized the germline mutations found in 335 patients with VHL disease associated with retinal capillary hemangioblastomas (RCHs) and sought to establish genotype-phenotype correlations between genotype category (amino acid substitutions, protein-truncating mutations, and complete deletions) and ocular phenotype. The prevalence of RCHs was lowest (14.5%) among patients with complete deletions; the overall prevalence of retinal angiomatosis was 37.2%. Genotype category had no correlation with unilaterality or bilaterality of ocular disease or with the number or extent of peripheral RCHs. The prevalence of RCHs at the juxtapapillary location was lower among patients with protein-truncating mutations than in patients with amino acid substitutions. Complete deletions were associated with the highest mean visual acuity. </p><p>Franke et al. (2009) identified germline deletions in the VHL gene ranging from 0.5 to 250 kb in 54 families with VHL syndrome. In 28 of these families, at least 1 additional gene was deleted including FANCD2 (227646), HSPC300 (C3ORF10;611183), and IRAK2 (603304). The precise breakpoints were determined in 33 index patients. Of the 66 breakpoints, 90% occurred in Alu elements, indicating that Alu-mediated recombination is a major mechanism for germline deletions of the VHL gene. Among all 54 families with VHL syndrome resulting from germline deletions of the VHL gene, Franke et al. (2009) found a higher occurrence of renal cell carcinomas and CNS hemangioblastomas compared to patients with other types of mutations. There was an independent association between renal cell carcinoma and retinal angiomas and retention of the HSPC300 gene, which confirmed the findings of Cascon et al. (2007). </p><p>McNeill et al. (2009) reviewed the molecular and clinical characteristics of 127 individuals from 62 kindreds with germline deletions in the VHL gene. Large VHL gene deletions associated with a contiguous loss of HSPC300 (10 patients) were associated with a significantly lower lifetime risk of RCC than deletions that did not involve HSPC300 (42 patients). The age-related risk of RCC at age 60 was 0% in the first group and 72% in the second group. Patients with exon 1 VHL deletions and retention of FANCD2 were excluded as the status of HSPC300 was uncertain. The risks of hemangioblastomas and pheochromocytomas were similar in both groups. These findings further supported the growing body of evidence indicating that patients with VHL syndrome caused by large VHL deletions that include the HSPC300 gene have a specific subtype of VHL syndrome with protection from RCC, which McNeill et al. (2009) proposed be named VHL type 1B. </p><p>Liu et al. (2018) recruited 339 VHL patients and grouped them based on mutation types: HIF-alpha binding site missense (HM) mutations, non-HIF-alpha binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared. Missense mutations conferred an increased risk of pheochromocytoma compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group but was similar between HM and TR groups. Patients in the nHM group had a higher risk of pheochromocytoma and lower risks of central nervous system hemangioblastoma (CHB), renal cell carcinoma, and pancreatic tumor than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival and CHB-specific survival than HMTR mutations. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Cushing and Bailey (1928) pointed out that Lindau (1927) was mainly responsible for showing the connection between retinal angiomas and CNS lesions. They reported the rather long-term follow-up of a patient named Frank McA. who had the full syndrome. The family history of involvement in several generations was obtained by John F. Fulton (1899-1960), Yale neurophysiologist who worked with Cushing for a year in the 1920s, and drawings of the fundus lesions were obtained by W. H. Wilmer of Johns Hopkins. As pointed out by Cushing and Bailey (1928), Treacher Collins (1894) was the first to recognize the angiomatous nature of the retinal lesions; he reported brother and sister. Then, von Hippel (1904) reported his 2 patients. In his biography of Cushing, Fulton (1946) gave an interesting account of the 'young Swedish pathologist named Arvid Lindau (who) had attracted Cushing's attention in 1927 [Lindau, 1927] through his description of an important new disease entity, which Cushing appropriately christened Lindau's disease.'</p><p>Melmon and Rosen (1964) reviewed the literature and reported studies of an extensively affected kindred. They pointed out that von Hippel's first publication on this subject concerned 2 patients, Otto Meyer and Otto Mobius by name, who figured in several later publications as well. Following this historic lead, Melmon and Rosen (1964) gave the full name of each of their patients beginning with the proband Bruno Bernardini. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Brown et al. (1973); Cahill et al. (1942); Chapman and Diaz-Perez
(1962); Christoferson et al. (1961); Corn et al. (2003); Decker et
al. (1988); Green et al. (1986); Hagler et al. (1971); Hennessy et
al. (1967); Horton et al. (1976); Kaplan et al. (1961); King et al.
(1987); Maher et al. (1990); Mahon et al. (2001); Nibbelink et al.
(1969); Otenasek and Silver (1961); Probst et al. (1978); Rho (1969);
Sander et al. (1970); Schechterman (1961); Sharp and Platt (1971);
Shokeir (1970); Silver (1954); Thomas and Burnside (1961); Tisherman
et al. (1962); Tisherman et al. (1993); Tory et al. (1989);
Wesolowski et al. (1981); Wise and Gibson (1971)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
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<strong>Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma.</strong>
Nature 332: 268-269, 1988.
[PubMed: 2894613]
[Full Text: https://doi.org/10.1038/332268a0]
</p>
</li>
<li>
<p class="mim-text-font">
Seizinger, B. R., Smith, D. I., Filling-Katz, M. R., Neumann, H., Green, J. S., Choyke, P. L., Anderson, K. M., Freiman, R. N., Klauck, S. M., Whaley, J., Decker, H.-J. H., Hsia, Y. E., Collins, D., Halperin, J., Lamiell, J. M., Oostra, B., Waziri, M. H., Gorin, M. B., Scherer, G., Drabkin, H. A., Aronin, N., Schinzel, A., Martuza, R. L., Gusella, J. F., Haines, J. L.
<strong>Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease.</strong>
Proc. Nat. Acad. Sci. 88: 2864-2868, 1991.
[PubMed: 2011596]
[Full Text: https://doi.org/10.1073/pnas.88.7.2864]
</p>
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Sgambati, M. T., Stolle, C., Choyke, P. L., Walther, M. M., Zbar, B., Linehan, W. M., Glenn, G. M.
<strong>Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents.</strong>
Am. J. Hum. Genet. 66: 84-91, 2000.
[PubMed: 10631138]
[Full Text: https://doi.org/10.1086/302726]
</p>
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<li>
<p class="mim-text-font">
Sharp, W. V., Platt, R. L.
<strong>Familial pheochromocytoma: association with von-Hippel-Lindau&#x27;s disease.</strong>
Angiology 22: 141-146, 1971.
[PubMed: 5549682]
[Full Text: https://doi.org/10.1177/000331977102200305]
</p>
</li>
<li>
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Shokeir, M. H. K.
<strong>Von Hippel-Lindau syndrome: a report on three kindreds.</strong>
J. Med. Genet. 7: 155-157, 1970.
[PubMed: 5519602]
[Full Text: https://doi.org/10.1136/jmg.7.2.155]
</p>
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<li>
<p class="mim-text-font">
Silver, M. L.
<strong>Hereditary vascular tumors of the nervous system.</strong>
J. Am. Med. Assoc. 156: 1053-1056, 1954.
[PubMed: 13201444]
[Full Text: https://doi.org/10.1001/jama.1954.02950110015006]
</p>
</li>
<li>
<p class="mim-text-font">
Stolle, C., Glenn, G., Zbar, B., Humphrey, J. S., Choyke, P., Walther, M., Pack, S., Hurley, K., Audrey, C., Klausner, R., Linehan, W. M.
<strong>Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene.</strong>
Hum. Mutat. 12: 417-423, 1998.
[PubMed: 9829911]
[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)12:6&lt;417::AID-HUMU8&gt;3.0.CO;2-K]
</p>
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<p class="mim-text-font">
Taouli, B., Ghouadni, M., Correas, J.-M., Hammel, P., Couvelard, A., Richard, S., Vilgrain, V.
<strong>Spectrum of abdominal imaging findings in von Hippel-Lindau disease.</strong>
AJR Am. J. Roentgenol. 181: 1049-1054, 2003.
[PubMed: 14500227]
[Full Text: https://doi.org/10.2214/ajr.181.4.1811049]
</p>
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<p class="mim-text-font">
Thomas, M., Burnside, R. M.
<strong>Von Hippel-Lindau disease.</strong>
Am. J. Ophthal. 51: 140-146, 1961.
[PubMed: 13776516]
[Full Text: https://doi.org/10.1016/0002-9394(61)91321-6]
</p>
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Tisherman, S. E., Gregg, F. J., Danowski, T. S.
<strong>Familial pheochromocytoma .</strong>
JAMA 182: 152-156, 1962.
[PubMed: 13985160]
[Full Text: https://doi.org/10.1001/jama.1962.03050410048010]
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Tisherman, S. E., Tisherman, B. G., Tisherman, S. A., Dunmire, S., Levey, G. S., Mulvihill, J. J.
<strong>Three-decade investigation of familial pheochromocytoma: an allele of von Hippel-Lindau disease?</strong>
Arch. Intern. Med. 153: 2550-2556, 1993.
[PubMed: 8239848]
</p>
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<li>
<p class="mim-text-font">
Tory, K., Brauch, H., Linehan, M., Barba, D., Oldfield, E., Filling-Katz, M., Seizinger, B., Nakamura, Y., White, R., Marshall, F. F., Lerman, M. I., Zbar, B.
<strong>Specific genetic change in tumors associated with von Hippel-Lindau disease.</strong>
J. Nat. Cancer Inst. 81: 1097-1101, 1989.
[PubMed: 2738940]
[Full Text: https://doi.org/10.1093/jnci/81.14.1097]
</p>
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<p class="mim-text-font">
Tsuda, H., Fukushima, S., Takahashi, M., Hikosaka, Y., Hayashi, K.
<strong>Familial bilateral papillary cystadenoma of the epididymis: report of three cases in siblings.</strong>
Cancer 37: 1831-1839, 1976.
[PubMed: 1260690]
[Full Text: https://doi.org/10.1002/1097-0142(197604)37:4&lt;1831::aid-cncr2820370430&gt;3.0.co;2-v]
</p>
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<p class="mim-text-font">
Vance, J. M., Small, K. W., Jones, M. A., Stajich, J. M., Yamaoka, L. H., Roses, A. D., Hung, W.-Y., Pericak-Vance, M. A.
<strong>Confirmation of linkage in von Hippel-Lindau disease.</strong>
Genomics 6: 565-567, 1990.
[PubMed: 2328994]
[Full Text: https://doi.org/10.1016/0888-7543(90)90488-g]
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Versteeg, R.
<strong>Aberrant methylation in cancer. (Editorial)</strong>
Am. J. Hum. Genet. 60: 751-754, 1997.
[PubMed: 9106519]
</p>
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<p class="mim-text-font">
von Hippel, E.
<strong>Ueber eine sehr seltene Erkrankung der Netzhaut.</strong>
Albrecht von Graefes Arch. Ophthal. 59: 83-106, 1904.
</p>
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<p class="mim-text-font">
Webster, A. R., Maher, E. R., Bird, A. C., Moore, A. T.
<strong>Risk of multisystem disease in isolated ocular angioma (haemangioblastoma).</strong>
J. Med. Genet. 37: 62-63, 2000. Note: Erratum: 37: 399 only, 2000.
[PubMed: 10691410]
[Full Text: https://doi.org/10.1136/jmg.37.1.62]
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Webster, A. R., Richards, F. M., MacRonald, F. E., Moore, A. T., Maher, E. R.
<strong>An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects.</strong>
Am. J. Hum. Genet. 63: 1025-1035, 1998.
[PubMed: 9758595]
[Full Text: https://doi.org/10.1086/302037]
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Wells, R. A., Reeders, S. T., Green, J., Johnson, G. J., Robson, K. J. H.
<strong>Linkage studies of von Hippel-Lindau syndrome using multiple-locus hypervariable DNA probes. (Abstract)</strong>
Cytogenet. Cell Genet. 46: 714, 1987.
</p>
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Wesolowski, D. P., Ellwood, R. A., Schwab, R. E., Farah, J.
<strong>Hippel-Lindau syndrome in identical twins.</strong>
Brit. J. Radiol. 54: 982-986, 1981.
[PubMed: 7197999]
[Full Text: https://doi.org/10.1259/0007-1285-54-647-982]
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Wise, K. S., Gibson, J. A.
<strong>Von Hippel-Lindau&#x27;s disease and phaeochromocytoma.</strong>
Brit. Med. J. 1: 441, 1971.
[PubMed: 5101347]
[Full Text: https://doi.org/10.1136/bmj.1.5746.441]
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Wong, W. T., Agron, E., Coleman, H. R., Reed, G. F., Csaky, K., Peterson, J., Glenn, G., Linehan, W. M., Albert, P., Chew, E. Y.
<strong>Genotype-phenotype correlation in von Hippel-Lindau disease with retinal angiomatosis.</strong>
Arch. Ophthal. 125: 239-245, 2007.
[PubMed: 17296901]
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Wu, P., Zhang, N., Wang, X., Ning, X., Li, T., Bu, D., Gong, K.
<strong>Family history of von Hippel-Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients.</strong>
J. Hum. Genet. 57: 238-243, 2012.
[PubMed: 22357542]
[Full Text: https://doi.org/10.1038/jhg.2012.10]
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<li>
<p class="mim-text-font">
Wyburn-Mason, R.
<strong>Arteriovenous aneurysm of mid-brain and retina, facial naevi and mental changes.</strong>
Brain 66: 163-203, 1943.
</p>
</li>
<li>
<p class="mim-text-font">
Zatyka, M., Morrissey, C., Kuzmin, I., Lerman, M. I., Latif, F., Richards, F. M., Maher, E. R.
<strong>Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter.</strong>
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[PubMed: 12114475]
[Full Text: https://doi.org/10.1136/jmg.39.7.463]
</p>
</li>
<li>
<p class="mim-text-font">
Zbar, B., Kishida, T., Chen, F., Schmidt, L., Maher, E. R., Richards, F. M., Crossey, P. A., Webster, A. R., Affara, N. A., Ferguson-Smith, M. A., Brauch, H., Glavac, D., and 14 others.
<strong>Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.</strong>
Hum. Mutat. 8: 348-357, 1996.
[PubMed: 8956040]
[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)8:4&lt;348::AID-HUMU8&gt;3.0.CO;2-3]
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Ada Hamosh - updated : 06/04/2020<br>Cassandra L. Kniffin - updated : 02/28/2020<br>Ada Hamosh - updated : 2/24/2016<br>Cassandra L. Kniffin - updated : 11/7/2012<br>Cassandra L. Kniffin - updated : 10/25/2010<br>Cassandra L. Kniffin - updated : 10/15/2010<br>Cassandra L. Kniffin - updated : 8/30/2010<br>Cassandra L. Kniffin - updated : 8/18/2009<br>Cassandra L. Kniffin - updated : 4/4/2008<br>Cassandra L. Kniffin - updated : 7/10/2007<br>Jane Kelly - updated : 5/30/2007<br>Cassandra L. Kniffin - updated : 4/2/2007<br>Jane Kelly - updated : 3/23/2007<br>Jane Kelly - updated : 12/7/2006<br>Victor A. McKusick - updated : 9/26/2006<br>Victor A. McKusick - updated : 6/23/2004<br>Jane Kelly - updated : 6/4/2004<br>Cassandra L. Kniffin - updated : 6/2/2004<br>Cassandra L. Kniffin - reorganized : 3/23/2004<br>John A. Phillips, III - updated : 2/12/2004<br>Victor A. McKusick - updated : 2/3/2004<br>George E. Tiller - updated : 11/13/2003<br>Patricia A. Hartz - updated : 11/7/2003<br>Victor A. McKusick - updated : 10/21/2003<br>Ada Hamosh - updated : 9/23/2003<br>Victor A. McKusick - updated : 8/8/2003<br>Victor A. McKusick - updated : 5/16/2003<br>John A. Phillips, III - updated : 4/8/2003<br>Victor A. McKusick - updated : 1/10/2003<br>Patricia A. Hartz - updated : 12/26/2002<br>Victor A. McKusick - updated : 11/4/2002<br>Victor A. McKusick - updated : 9/20/2002<br>Victor A. McKusick - updated : 9/9/2002<br>Ada Hamosh - updated : 8/14/2002<br>Victor A. McKusick - updated : 8/9/2002<br>Michael J. Wright - updated : 7/29/2002<br>Ada Hamosh - updated : 7/17/2002<br>Victor A. McKusick - updated : 7/1/2002<br>Victor A. McKusick - updated : 3/14/2002<br>Paul J. Converse - updated : 1/14/2002<br>Jane Kelly - updated : 12/14/2001<br>Stylianos E. Antonarakis - updated : 10/31/2001<br>George E. Tiller - updated : 10/9/2001<br>John A. Phillips, III - updated : 7/11/2001<br>John A. Phillips, III - updated : 7/5/2001<br>George E. Tiller - updated : 6/19/2001<br>Ada Hamosh - updated : 4/30/2001<br>Jane Kelly - updated : 4/4/2001<br>Victor A. McKusick - updated : 3/6/2001<br>Michael J. Wright - updated : 2/8/2001<br>Michael J. Wright - updated : 1/9/2001<br>Victor A. McKusick - updated : 5/12/2000<br>Victor A. McKusick - updated : 1/13/2000<br>Stylianos E. Antonarakis - updated : 1/7/2000<br>Victor A. McKusick - updated : 1/4/2000<br>Sonja A. Rasmussen - updated : 12/8/1999<br>Rebekah S. Rasooly - updated : 7/27/1999<br>Victor A. McKusick - updated : 6/25/1999<br>Ada Hamosh - updated : 5/19/1999<br>Victor A. McKusick - updated : 1/15/1999<br>Victor A. McKusick - updated : 12/3/1998<br>Victor A. McKusick - updated : 11/2/1998<br>Victor A. McKusick - updated : 10/19/1998<br>Victor A. McKusick - updated : 10/15/1998<br>Victor A. McKusick - updated : 8/11/1998<br>Stylianos E. Antonarakis - updated : 8/3/1998<br>Victor A. McKusick - updated : 3/6/1998<br>John A. Phillips, III - updated : 12/25/1997<br>Victor A. McKusick - updated : 1/13/1998<br>Victor A. McKusick - updated : 12/18/1997<br>Victor A. McKusick - updated : 10/9/1997<br>Victor A. McKusick - updated : 9/19/1997<br>Victor A. McKusick - updated : 8/12/1997<br>Victor A. McKusick - updated : 6/12/1997<br>Iosif W. Lurie - updated : 8/10/1996<br>Moyra Smith - Updated : 5/25/1996<br>Moyra Smith - updated : 4/6/1996<br>Orest Hurko - updated : 6/13/1995
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Victor A. McKusick : 6/2/1986
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