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<title>
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Entry
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- #263400 - ERYTHROCYTOSIS, FAMILIAL, 2; ECYT2
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- OMIM
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<span class="h4">#263400</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/263400"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS133100"> <strong>Phenotypic Series</strong> </a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</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="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=19276&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=238557" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0060474" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/263400" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/OMIA001186/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0060474" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 238557<br />
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<strong>DO:</strong> 0060474<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
|
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263400
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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ERYTHROCYTOSIS, FAMILIAL, 2; ECYT2
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</h3>
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</div>
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<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">
|
|
POLYCYTHEMIA, VHL-DEPENDENT
|
|
</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">
|
|
POLYCYTHEMIA, CHUVASH TYPE, 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">
|
|
Erythrocytosis, familial, 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/263400"> 263400 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/263400" 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>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS133100" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<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/263400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/263400" 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 recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GROWTH </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Height </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Short stature (severe form) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5677937&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5677937</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422065006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422065006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237836003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237836003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237837007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237837007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E34.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E34.31</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R62.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R62.52</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.43" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.43</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Other </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Failure to thrive (severe form) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5677938&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5677938</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Vascular abnormalities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241657&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241657</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002597" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002597</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002597" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002597</a>]</span><br /> -
|
|
Vertebral hemangiomas <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849748</a>]</span><br /> -
|
|
Varicose veins <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128060009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128060009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399989005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399989005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12856003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12856003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I83.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I83.90</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042345&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042345</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002619" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002619</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002619" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002619</a>]</span><br /> -
|
|
Peripheral thrombosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849749&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849749</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002641" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002641</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002641" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002641</a>]</span><br /> -
|
|
Cerebral vascular events <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230690007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230690007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I63.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I63.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038454&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038454</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span><br /> -
|
|
Systemic hypotension <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45007003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45007003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I95" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I95</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I95.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I95.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/458" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">458</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/458.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">458.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020649&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020649</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002615" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002615</a>]</span><br /> -
|
|
Pulmonary hypertension (severe form) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5677939&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5677939</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/70995007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">70995007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I27.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I27.20</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002092" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002092</a>]</span><br />
|
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|
</span>
|
|
</div>
|
|
</div>
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</div>
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</div>
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Plethora <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/75246004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">75246004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0232370&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232370</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001050" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001050</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001050" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001050</a>]</span><br />
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</span>
|
|
</div>
|
|
</div>
|
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</div>
|
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|
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</div>
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Exercise intolerance (severe form) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5677935&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5677935</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267044007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267044007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003546" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003546</a>]</span><br /> -
|
|
Mitochondrial dysfunction (severe form) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5677936&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5677936</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003287" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003287</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
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|
|
</div>
|
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|
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</div>
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Headache <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25064002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25064002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R51.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R51.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R51</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/784.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018681&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018681</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002315</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002315</a>]</span><br /> -
|
|
Cerebral vascular events <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230690007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230690007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I63.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I63.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038454&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038454</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span><br /> -
|
|
Cerebral hemorrhage <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/274100004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">274100004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/431" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">431</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2937358&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2937358</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001342" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001342</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001342" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001342</a>]</span><br /> -
|
|
Delayed development (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> METABOLIC FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hypoglycemia (severe form) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5677940&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5677940</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237630007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237630007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271327008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271327008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302866003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302866003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1179458001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1179458001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E16.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E16.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/251.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">251.2</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001943</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">
|
|
|
|
- Erythrocytosis <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>]</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=C1527405&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1527405</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 /> -
|
|
Increased red blood cell mass <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853288&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853288</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001898" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001898</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001898" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001898</a>]</span><br /> -
|
|
Increased hematocrit <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165413005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165413005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239935&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239935</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001899" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001899</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001899" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001899</a>]</span><br /> -
|
|
Increased hemoglobin <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/131141003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">131141003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0549448&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0549448</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001900" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001900</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001900" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001900</a>]</span><br /> -
|
|
Decreased ferritin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0860972&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0860972</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Increased serum erythropoietin (EPO, <a href="/entry/133170">133170</a>) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241010&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241010</a>]</span><br /> -
|
|
Increased serum vascular endothelial growth factor (VEGF, <a href="/entry/192240">192240</a>)<br /> -
|
|
Increased serum plasminogen activator inhibitor-1 (PAI1, <a href="/entry/173360">173360</a>)<br /> -
|
|
Normal leukocyte and platelet counts <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849747&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849747</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Variable severity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861403&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861403</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span><br /> -
|
|
Variable age at onset (range birth to 22 years)<br /> -
|
|
The Chuvash form (associated with the R200W mutation) has a milder phenotype<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the VHL gene (VHL, <a href="/entry/608537#0014">608537.0014</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Erythrocytosis, familial
|
|
- <a href="/phenotypicSeries/PS133100">PS133100</a>
|
|
- 11 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1802?start=-3&limit=10&highlight=1802"> 1q42.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609820"> Erythrocytosis, familial, 3 </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">
|
|
<a href="/entry/609820"> 609820 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606425"> EGLN1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606425"> 606425 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/228?start=-3&limit=10&highlight=228"> 2p21 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611783"> Erythrocytosis, familial, 4 </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">
|
|
<a href="/entry/611783"> 611783 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603349"> EPAS1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603349"> 603349 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<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">
|
|
<a href="/entry/263400"> Erythrocytosis, familial, 2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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">
|
|
<a href="/entry/263400"> 263400 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608537"> VHL </a>
|
|
</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/7/515?start=-3&limit=10&highlight=515"> 7q22.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617907"> Erythrocytosis, familial, 5 </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">
|
|
<a href="/entry/617907"> 617907 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/133170"> EPO </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/133170"> 133170 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/702?start=-3&limit=10&highlight=702"> 7q33 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/222800"> Erythrocytosis, familial, 8 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</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">
|
|
<a href="/entry/222800"> 222800 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613896"> BPGM </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613896"> 613896 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/9/27?start=-3&limit=10&highlight=27"> 9p24.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/133100"> Erythrocytosis, somatic </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</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">
|
|
<a href="/entry/133100"> 133100 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/147796"> JAK2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/147796"> 147796 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/11/110?start=-3&limit=10&highlight=110"> 11p15.4 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617980"> Erythrocytosis, familial, 6 </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">
|
|
<a href="/entry/617980"> 617980 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/141900"> HBB </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/141900"> 141900 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/12/812?start=-3&limit=10&highlight=812"> 12q24.12 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/133100"> Erythrocytosis, somatic </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</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">
|
|
<a href="/entry/133100"> 133100 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605093"> SH2B3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605093"> 605093 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/16/17?start=-3&limit=10&highlight=17"> 16p13.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617981"> Erythrocytosis, familial, 7 </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">
|
|
<a href="/entry/617981"> 617981 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/141850"> HBA2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/141850"> 141850 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/16/18?start=-3&limit=10&highlight=18"> 16p13.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617981"> Erythrocytosis, familial, 7 </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">
|
|
<a href="/entry/617981"> 617981 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/141800"> HBA1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/141800"> 141800 </a>
|
|
</span>
|
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<p>A number sign (#) is used with this entry because of evidence that familial erythrocytosis-2 (ECYT2) is caused by homozygous or compound heterozygous mutation in the VHL gene (<a href="/entry/608537">608537</a>) on chromosome 3p25.</p><p>Chuvash polycythemia, endemic in the Chuvash Republic of the Russian Federation and in Ischia, Italy, is associated with a specific mutation in the VHL gene (R200W; <a href="/entry/608537#0019">608537.0019</a>).</p><p>Heterozygous mutation in the VHL gene can cause von Hippel-Lindau syndrome (VHLS; <a href="/entry/193300">193300</a>).</p>
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<p>Familial erythrocytosis-2 (ECYT2) is an autosomal recessive disorder characterized by increased red blood cell mass, increased serum levels of erythropoietin (EPO; <a href="/entry/133170">133170</a>), and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events (<a href="#7" class="mim-tip-reference" title="Cario, H. <strong>Childhood polycythemias/erythrocytoses: classification, diagnosis, clinical presentation, and treatment.</strong> Ann. Hemat. 84: 137-145, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15599750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15599750</a>] [<a href="https://doi.org/10.1007/s00277-004-0985-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15599750">Cario, 2005</a>). Familial erythrocytosis-2 has features of both primary and secondary erythrocytosis. In addition to increased circulating levels of EPO, consistent with a secondary, extrinsic process, erythroid progenitors may be hypersensitive to EPO, consistent with a primary, intrinsic process (<a href="#23" class="mim-tip-reference" title="Prchal, J. T. <strong>Polycythemia vera and other primary polycythemias.</strong> Curr. Opin. Hemat. 12: 112-116, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15725900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15725900</a>] [<a href="https://doi.org/10.1097/01.moh.0000154029.05396.d2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15725900">Prchal, 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15599750+15725900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a general phenotypic description and a discussion of genetic heterogeneity of familial erythrocytosis, see ECYT1 (<a href="/entry/133100">133100</a>).</p>
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<p>The term 'polycythemia' (Greek: 'many cells in the blood') is used interchangeably with 'erythrocytosis,' although the latter term more specifically refers to an increase in the number of circulating differentiated red blood cells (<a href="#23" class="mim-tip-reference" title="Prchal, J. T. <strong>Polycythemia vera and other primary polycythemias.</strong> Curr. Opin. Hemat. 12: 112-116, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15725900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15725900</a>] [<a href="https://doi.org/10.1097/01.moh.0000154029.05396.d2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15725900">Prchal, 2005</a>; <a href="#7" class="mim-tip-reference" title="Cario, H. <strong>Childhood polycythemias/erythrocytoses: classification, diagnosis, clinical presentation, and treatment.</strong> Ann. Hemat. 84: 137-145, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15599750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15599750</a>] [<a href="https://doi.org/10.1007/s00277-004-0985-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15599750">Cario, 2005</a>). 'Erythrocytosis' is the preferred term used here in order to distinguish inherited disorders characterized by increased circulating red blood cells from 'polycythemia vera' (PV; <a href="/entry/263300">263300</a>), which is a clonal myeloproliferative disorder associated with somatic mutations in the JAK2 gene (<a href="/entry/147796">147796</a>). Familial erythrocytosis is also distinct from erythroleukemia (<a href="/entry/133180">133180</a>), which is considered to be a subtype of acute myelogenous leukemia (AML; <a href="/entry/601626">601626</a>) characterized by immature erythroid cells in the bone marrow and peripheral blood. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15599750+15725900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#16" class="mim-tip-reference" title="Nadler, S. B., Cohn, I. <strong>Familial polycythemia.</strong> Am. J. Med. Sci. 198: 41-48, 1939."None>Nadler and Cohn (1939)</a> described a family in which 4 of 11 children showed polycythemia. The mother stated that these 4 children had red faces from the time of birth. <a href="#4" class="mim-tip-reference" title="Auerbach, M. L., Wolff, J. A., Mettier, S. R. <strong>Benign familial polycythemia in childhood: report of two cases.</strong> Pediatrics 21: 54-58, 1958.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13494077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13494077</a>]" pmid="13494077">Auerbach et al. (1958)</a> reported 3 families. In 1 family, 2 brothers and a sister were affected, and in a second, the proband and an aunt. The parents were normal. Unlike patients with polycythemia vera, the subjects demonstrated no increase in white count, platelets, or uric acid, and the process was benign. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13494077" 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="Yonemitsu, H., Yamaguchi, K., Shigeta, H., Okuda, K., Takaku, F. <strong>Two cases of familial erythrocytosis with increased erythropoietin activity in plasma and urine.</strong> Blood 42: 793-797, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4746102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4746102</a>]" pmid="4746102">Yonemitsu et al. (1973)</a> described 2 affected sons of parents related as half first cousins. Both had a marked increase in erythropoietin concentration in plasma and urine. <a href="#1" class="mim-tip-reference" title="Adamson, J. W., Stamatoyannopoulos, G., Kontras, S., Lascari, A., Detter, J. C. <strong>Recessive familial erythrocytosis: aspects of marrow regulation in two families.</strong> Blood 41: 641-652, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4694081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4694081</a>]" pmid="4694081">Adamson et al. (1973)</a> studied 2 families with recessive erythrocytosis and found increased erythropoietin production uninfluenced by alterations in the oxygen-carrying capacity of the blood when the hematocrit was lowered by phlebotomy. Hemoglobin and red cell function and renal vasculature were normal. A genetic defect in regulation of erythropoietin production was postulated. <a href="#10" class="mim-tip-reference" title="Greenberg, B. R., Golde, D. W. <strong>Erythropoiesis in familial erythrocytosis.</strong> New Eng. J. Med. 296: 1080-1084, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/850518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">850518</a>] [<a href="https://doi.org/10.1056/NEJM197705122961902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="850518">Greenberg and Golde (1977)</a> studied 2 brothers, aged 26 and 28, whose erythrocytosis had been discovered incidentally. The parents were hematologically normal. Studies showed increased serum erythropoietin resulting in an expansion of the erythroid precursor pool. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4694081+4746102+850518" 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="Whitcomb, W. H., Peschle, C., Moore, M., Nitschke, R., Adamson, J. W. <strong>Congenital erythrocytosis: a new form associated with an erythropoietin-dependent mechanism.</strong> Brit. J. Haemat. 44: 17-24, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7378290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7378290</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1980.tb01179.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7378290">Whitcomb et al. (1980)</a> studied 3 cases of congenital erythrocytosis and found an absolute or relative elevation of erythropoietin. Urinary excretion of erythropoietin was more than doubled by phlebotomy. The authors postulated an inherited defect 'likely residing in the renal sensor responsible for the production of erythropoietin.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7378290" 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>Early-Onset Congenital Erythrocytosis with Confirmed VHL Mutations</em></strong></p><p>
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<a href="#17" class="mim-tip-reference" title="Pastore, Y., Jedlickova, K., Guan, Y., Liu, E., Fahner, J., Hasle, H., Prchal, J. F., Prchal, J. T. <strong>Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia.</strong> Am. J. Hum. Genet. 73: 412-419, 2003. Note: Erratum: Am. J. Hum. Genet. 74: 598 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12844285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12844285</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12844285[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/377108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12844285">Pastore et al. (2003)</a> reported 7 patients from 6 unrelated families with ECYT2. The patients, who ranged in age from 12 to 19 years, presented by age 5 years, except for 1 patient who presented at age 9 years. Features included polycythemia treated with phlebotomy and increased serum EPO; 1 patient had thrombosis. Two sibs of Danish origin and an unrelated Caucasian patient carried a homozygous R200W mutation (<a href="/entry/608537#0019">608537.0019</a>), consistent with the Chuvash type (see below), and 3 additional Caucasian patients were compound heterozygous for R200W and another missense variant. One patient of Croatian descent carried a homozygous H191D mutation (<a href="/entry/608537#0024">608537.0024</a>). The EPO levels in patients with the R200W mutation ranged from normal to high. VHLS-related tumors were not observed in any of the families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12844285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Tomasic, N. L., Piterkova, L., Huff, C., Bilic, E., Yoon, D., Miasnikova, G. Y., Sergueeva, A. I., Niu, X., Nekhai, S., Gordeuk, V., Prchal, J. T. <strong>The phenotype of polycythemia due to Croatian homozygous VHL (571C-G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C-T:R200W)</strong> Haematologica 98: 560-567, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23403324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23403324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23403324[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3324/haematol.2012.070508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23403324">Tomasic et al. (2013)</a> reported a 5-year-old Croatian girl with early-onset ECYT2. She presented at age 2 years with failure to thrive, increased hematocrit and hemoglobin, low ferritin, and extremely high erythropoietin. She also had delayed psychomotor development. A distant relative had previously been reported by <a href="#17" class="mim-tip-reference" title="Pastore, Y., Jedlickova, K., Guan, Y., Liu, E., Fahner, J., Hasle, H., Prchal, J. F., Prchal, J. T. <strong>Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia.</strong> Am. J. Hum. Genet. 73: 412-419, 2003. Note: Erratum: Am. J. Hum. Genet. 74: 598 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12844285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12844285</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12844285[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/377108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12844285">Pastore et al. (2003)</a>; that patient was a 26-year-old man who presented at 1 year of age. Haplotype analysis indicated a common ancestor between the 2 patients, who both carried a homozygous H191D mutation, although there was no evidence for a common origin of both mutant alleles. Patient erythroid precursors showed normal growth and were not hypersensitive to EPO in vitro; these findings differed from those observed in Chuvash polycythemia, in which the erythroid precursors are intrinsically hyperproliferative and also show hypersensitivity to EPO. <a href="#28" class="mim-tip-reference" title="Tomasic, N. L., Piterkova, L., Huff, C., Bilic, E., Yoon, D., Miasnikova, G. Y., Sergueeva, A. I., Niu, X., Nekhai, S., Gordeuk, V., Prchal, J. T. <strong>The phenotype of polycythemia due to Croatian homozygous VHL (571C-G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C-T:R200W)</strong> Haematologica 98: 560-567, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23403324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23403324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23403324[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3324/haematol.2012.070508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23403324">Tomasic et al. (2013)</a> concluded that the erythrocytosis in patients with the H191D mutation is solely driven by increased circulating EPO. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23403324+12844285" 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="Sarangi, S., Lanikova, L., Kapralova, K., Acharya, S., Swierczek, S., Lipton, J. M., Wolfe, L., Prchal, J. T. <strong>The homozygous VHL-D126N missense mutation is associated with dramatically elevated erythropoietin levels, consequent polycythemia, and early onset severe pulmonary hypertension.</strong> Pediat. Blood Cancer 61: 2104-2106, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24729484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24729484</a>] [<a href="https://doi.org/10.1002/pbc.25056" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24729484">Sarangi et al. (2014)</a> reported a 7-month-old infant, born of consanguineous Bangladeshi parents, with congenital ECYT2. He had failure to thrive, developmental delay, and polycythemia with dramatically increased erythropoietin levels. Imaging of the abdomen showed multiple hepatic hemangiomas. He was treated with phlebotomy, but developed pulmonary hypertension and recurrent respiratory infections, resulting in death at age 2. Brain imaging showed extensive cerebral, cerebellar, and brainstem infarctions. Neither parent had polycythemia or evidence of VHL-associated tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24729484" 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="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. <strong>Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.</strong> Blood 132: 469-483, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29891534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29891534</a>] [<a href="https://doi.org/10.1182/blood-2018-03-838235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29891534">Lenglet et al. (2018)</a> reported 10 patients from 9 unrelated families with ECYT2. The patients were diagnosed between 4 months and 21 years of age. In addition to increased hemoglobin, hematocrit, and EPO, 2 patients had splenomegaly and 2 had deep vein thrombosis. <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><a href="#21" class="mim-tip-reference" title="Perrotta, S., Roberti, E., Bencivenga, D., Corsetto, P., O'Brien, K. A., Caiazza, M., Stampone, E., Allison, L., Fleck, R. A., Scianguetta, S., Tartaglione, I., Robbins, P. A., and 10 others. <strong>Effects of germline VHL deficiency on growth, metabolism, and mitochondria.</strong> New Eng. J. Med. 382: 835-844, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32101665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32101665</a>] [<a href="https://doi.org/10.1056/NEJMoa1907362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32101665">Perrotta et al. (2020)</a> reported a 22-year-old man, born of consanguineous Italian parents, with a complex form of ECYT2 with growth failure, persistent hypoglycemia, limited exercise capacity, and mitochondrial dysfunction. He was born by emergency cesarean section due to fetal bradycardia and showed persistent bradycardia and hypoglycemia after birth. He received phototherapy for neonatal jaundice and had phlebotomy for elevated hemoglobin and hematocrit. Later in infancy he showed marked failure to thrive with no signs of growth hormone deficiency, but was treated with growth hormone. At age 12-13 years, he had high levels of erythropoietin, low ferritin, low blood pressure (75/35), abnormal cardiac rhythm, and poor growth (height at -3 SD) treated successfully with IGF1 (<a href="/entry/147440">147440</a>). He continued to have regular phlebotomy with strict control of iron bioavailability. The patient had exercise intolerance with altered ventilatory control mimicking acclimatization to high-altitude hypoxia. Studies of mitochondria from skeletal muscle tissue showed markedly decreased respiratory capacity compared to controls, with oxygen consumption uncoupled from ATP synthesis: oxidative phosphorylation supported by fatty-acid substrates and substrates for electron chain complexes I and II were 28%, 44%, and 34% lower than those in controls. Morphologically, the mitochondria contained abnormal intermitochondrial connecting ducts, possibly suggesting stress conditions. The patient also had metabolic changes in glucose and lipid metabolism indicating a shift from oxidative phosphorylation to glycolysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32101665" 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>Chuvash Polycythemia</em></strong></p><p>
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<a href="#22" class="mim-tip-reference" title="Polyakova, L. A. <strong>[Familial erythrocytosis among the residents of the Chuvash ASSR.]</strong> Probl. Gematol. Pereliv. Krovi. 19: 30-33, 1974. Note: Article in Russian."None>Polyakova (1974)</a> described familial erythrocytosis in the Chuvash population, an ethnic isolate in the mid-Volga river region of Russia of Asian descent (<a href="#23" class="mim-tip-reference" title="Prchal, J. T. <strong>Polycythemia vera and other primary polycythemias.</strong> Curr. Opin. Hemat. 12: 112-116, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15725900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15725900</a>] [<a href="https://doi.org/10.1097/01.moh.0000154029.05396.d2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15725900">Prchal, 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15725900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Sergeyeva, A., Gordeuk, V. R., Tokarev, Y. N., Sokol, L., Prchal, J. F., Prchal, J. T. <strong>Congenital polycythemia in Chuvashia.</strong> Blood 89: 2148-2154, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9058738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9058738</a>]" pmid="9058738">Sergeyeva et al. (1997)</a> studied the autosomal recessive form of congenital erythrocytosis common in the Chuvash population. They stated that hundreds of individuals appeared to be affected in an autosomal recessive pattern. They studied 6 polycythemic Chuvash patients less than 20 years of age from unrelated families and 12 first-degree family members. Hemoglobins were markedly elevated in the index subjects (22.6 +/- 1.4 g/dl) and serum erythropoietin concentrations were elevated. Platelet and white blood cell counts were normal. Southern blot analysis of the Bgl2 erythropoietin gene polymorphism showed that one affected individual was a heterozygote, suggesting absence of linkage of polycythemia with the EPO gene. There was no evidence of linkage to the erythropoietin receptor gene (EPOR; <a href="/entry/133171">133171</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9058738" 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 matched cohort study, <a href="#9" class="mim-tip-reference" title="Gordeuk, V. R., Sergueeva, A. I., Miasnikova, G. Y., Okhotin, D., Voloshin, Y., Choyke, P. L., Butman, J. A., Jedlickova, K., Prchal, J. T., Polyakova, L. A. <strong>Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors.</strong> Blood 103: 3924-3932, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14726398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14726398</a>] [<a href="https://doi.org/10.1182/blood-2003-07-2535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14726398">Gordeuk et al. (2004)</a> found that patients with Chuvash polycythemia had increased frequency of vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum VEGF (<a href="/entry/192240">192240</a>) concentrations (p less than 0.0005), as well as premature mortality related to cerebrovascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classic VHL syndrome were not found, suggesting that overexpression of the alpha subunit of hypoxia-inducible factor-1 (HIF1A; <a href="/entry/603348">603348</a>) and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in patients compared to controls, erythropoietin response to hypoxia was identical. <a href="#9" class="mim-tip-reference" title="Gordeuk, V. R., Sergueeva, A. I., Miasnikova, G. Y., Okhotin, D., Voloshin, Y., Choyke, P. L., Butman, J. A., Jedlickova, K., Prchal, J. T., Polyakova, L. A. <strong>Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors.</strong> Blood 103: 3924-3932, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14726398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14726398</a>] [<a href="https://doi.org/10.1182/blood-2003-07-2535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14726398">Gordeuk et al. (2004)</a> concluded that Chuvash polycythemia is a distinct syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14726398" 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="#8" class="mim-tip-reference" title="Davey, M. G., Lawrence, J. R., Lander, H., Robson, H. N. <strong>Familial erythrocytosis: a report of two cases and a review.</strong> Acta Haemat. 39: 65-74, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4968783/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4968783</a>] [<a href="https://doi.org/10.1159/000208945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4968783">Davey et al. (1968)</a> and <a href="#27" class="mim-tip-reference" title="Stamatoyannopoulos, G. <strong>Familial erythrocytosis.</strong> Birth Defects Orig. Art. Ser. 8(3): 39-45, 1972."None>Stamatoyannopoulos (1972)</a> noted autosomal recessive inheritance of erythrocytosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4968783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The transmission pattern of ECYT2 in the families reported by <a href="#17" class="mim-tip-reference" title="Pastore, Y., Jedlickova, K., Guan, Y., Liu, E., Fahner, J., Hasle, H., Prchal, J. F., Prchal, J. T. <strong>Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia.</strong> Am. J. Hum. Genet. 73: 412-419, 2003. Note: Erratum: Am. J. Hum. Genet. 74: 598 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12844285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12844285</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12844285[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/377108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12844285">Pastore et al. (2003)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12844285" 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="#29" class="mim-tip-reference" title="Vasserman, N. N., Karzakova, L. M., Tverskaya, S. M., Saperov, V. N., Muchukova, O. M., Pavlova, G. P., Efimova, N. K., Vankina, N. N., Evgrafov, O. V. <strong>Localization of the gene responsible for familial benign polycythemia to chromosome 11q23.</strong> Hum. Hered. 49: 129-132, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364675</a>] [<a href="https://doi.org/10.1159/000022859" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10364675">Vasserman et al. (1999)</a> studied the autosomal recessive benign erythrocytosis that has a high incidence in Chuvashia in the Russian Federation. They studied 12 unrelated families and excluded the erythropoietin gene and the erythropoietin receptor gene as candidates by linkage analysis. Using genomewide searching, they demonstrated linkage of the disorder between markers D11S4142 and D11S1356 on 11q23 (maximum lod = 6.61). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Ang, S. O., Chen, H., Gordeuk, V. R., Sergueeva, A. I., Polyakova, L. A., Miasnikova, G. Y., Kralovics, R., Stockton, D. W., Prchal, J. T. <strong>Endemic polycythemia in Russia: mutation in the VHL gene.</strong> Blood Cells Molec. Dis. 28: 57-62, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11987242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11987242</a>] [<a href="https://doi.org/10.1006/bcmd.2002.0488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11987242">Ang et al. (2002)</a> found that in a genomewide screen, the Chuvash polycythemia locus mapped not to 11q23 but to 3p, in a region containing the VHL gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11987242" 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="#17" class="mim-tip-reference" title="Pastore, Y., Jedlickova, K., Guan, Y., Liu, E., Fahner, J., Hasle, H., Prchal, J. F., Prchal, J. T. <strong>Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia.</strong> Am. J. Hum. Genet. 73: 412-419, 2003. Note: Erratum: Am. J. Hum. Genet. 74: 598 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12844285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12844285</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12844285[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/377108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12844285">Pastore et al. (2003)</a> identified homozygous or compound heterozygous mutations in the VHL gene in 7 of 13 patients with congenital erythrocytosis and suggested that such mutations are the most frequent cause of the disorder. Three patients of European descent were homozygous for the Chuvash mutation (R200W; <a href="/entry/608537#0019">608537.0019</a>), 3 were compound heterozygous for R200W and another missense variant (L188V, <a href="/entry/608537#0014">608537.0014</a> or P192S, <a href="/entry/608537#0023">608537.0023</a>), and a patient of Croatian descent was homozygous for H191D (<a href="/entry/608537#0024">608537.0024</a>). Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12844285" 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 an 8-year-old boy with ECYT2, <a href="#5" class="mim-tip-reference" title="Bond, J., Gale, D. P., Connor, T., Adams, S., de Boer, J., Gascoyne, D. M., Williams, O., Maxwell, P. H., Ancliff, P. J. <strong>Dysregulation of the HIF pathway due to VHL mutation causing severe erythrocytosis and pulmonary arterial hypertension. (Letter)</strong> Blood 117: 3699-3701, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21454469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21454469</a>] [<a href="https://doi.org/10.1182/blood-2010-12-327569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21454469">Bond et al. (2011)</a> identified compound heterozygous missense mutations in the VHL gene (D126N, <a href="/entry/608537#0028">608537.0028</a> and S183L, <a href="/entry/608537#0029">608537.0029</a>). The mutations were found by direct gene sequencing. Transfection of the mutations into renal carcinoma cells showed decreased protein levels consistent with instability of the mutant proteins, suggesting a loss-of-function effect. Transfected cells also showed decreased pH, decreased glucose, and increased lactate, consistent with upregulation of glycolysis. These changes were associated with increased expression of HIF1A (<a href="/entry/603348">603348</a>), PHD3 (<a href="/entry/606426">606426</a>), and GLUT1 (<a href="/entry/138140">138140</a>), suggesting impaired ability of mutant VHL to regulate HIF. The patient presented at 2 months of age with right ventricular dysfunction and hypertrophy, pulmonary hypertension, increased hematocrit and hemoglobin, and significantly increased EPO. He was managed successfully by phlebotomy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21454469" 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="Sarangi, S., Lanikova, L., Kapralova, K., Acharya, S., Swierczek, S., Lipton, J. M., Wolfe, L., Prchal, J. T. <strong>The homozygous VHL-D126N missense mutation is associated with dramatically elevated erythropoietin levels, consequent polycythemia, and early onset severe pulmonary hypertension.</strong> Pediat. Blood Cancer 61: 2104-2106, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24729484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24729484</a>] [<a href="https://doi.org/10.1002/pbc.25056" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24729484">Sarangi et al. (2014)</a> identified a homozygous D126N mutation in the VHL gene in a 2-year-old boy, born of consanguineous Bangladeshi parents, with fatal ECYT2. In vitro studies showed that patient erythroid progenitors were not hypersensitive to EPO and did not overexpress NFE2 (<a href="/entry/601490">601490</a>) or RUNX1 (<a href="/entry/151385">151385</a>) transcripts, which are associated with EPO hypersensitivity. This demonstrated a different pathogenic mechanism from patients with Chuvash polycythemia due to the R200W mutation (<a href="/entry/608537#0019">608537.0019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24729484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Tomasic, N. L., Piterkova, L., Huff, C., Bilic, E., Yoon, D., Miasnikova, G. Y., Sergueeva, A. I., Niu, X., Nekhai, S., Gordeuk, V., Prchal, J. T. <strong>The phenotype of polycythemia due to Croatian homozygous VHL (571C-G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C-T:R200W)</strong> Haematologica 98: 560-567, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23403324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23403324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23403324[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3324/haematol.2012.070508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23403324">Tomasic et al. (2013)</a> reported a 5-year-old Croatian girl with early-onset ECYT2 due to a homozygous H191D mutation (<a href="/entry/608537#0024">608537.0024</a>). Family history revealed that she was related to the Croatian patient reported by <a href="#17" class="mim-tip-reference" title="Pastore, Y., Jedlickova, K., Guan, Y., Liu, E., Fahner, J., Hasle, H., Prchal, J. F., Prchal, J. T. <strong>Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia.</strong> Am. J. Hum. Genet. 73: 412-419, 2003. Note: Erratum: Am. J. Hum. Genet. 74: 598 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12844285/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12844285</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12844285[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/377108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12844285">Pastore et al. (2003)</a>. Patient erythroid precursors showed normal growth and were not hypersensitive to EPO in vitro; these findings differed from those observed in Chuvash polycythemia in which the erythroid precursors are intrinsically hyperproliferative and also show hypersensitivity to EPO. <a href="#28" class="mim-tip-reference" title="Tomasic, N. L., Piterkova, L., Huff, C., Bilic, E., Yoon, D., Miasnikova, G. Y., Sergueeva, A. I., Niu, X., Nekhai, S., Gordeuk, V., Prchal, J. T. <strong>The phenotype of polycythemia due to Croatian homozygous VHL (571C-G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C-T:R200W)</strong> Haematologica 98: 560-567, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23403324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23403324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23403324[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3324/haematol.2012.070508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23403324">Tomasic et al. (2013)</a> concluded that the polycythemia in patients with the H191D mutation is solely driven by increased circulating EPO. Patient cells showed changes in gene expression, including increased expression of several HIF1A-related genes (TFRC, <a href="/entry/190010">190010</a>; VEGF, <a href="/entry/192240">192240</a>; and HK1, <a href="/entry/142600">142600</a>), and decreased expression of other genes (BNIP3L, <a href="/entry/605368">605368</a> and ADM, <a href="/entry/103275">103275</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23403324+12844285" 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 15-year-old girl of Asian Indian descent with ECYT2, <a href="#12" class="mim-tip-reference" title="Lanikova, L., Lorenzo, F., Yang, C., Vankayalapati, H., Drachtman, R., Divorky, V., Prchal, J. T. <strong>Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer.</strong> Blood 121: 3918-3924, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23538339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23538339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23538339[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood-2012-11-469296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23538339">Lanikova et al. (2013)</a> identified a homozygous missense mutation in the VHL gene (P138L; <a href="/entry/608537#0035">608537.0035</a>). The mutation, which was found by direct sequencing of the VHL gene, segregated with the disorder in the family. Cellular transfection studies showed that the mutant protein had decreased stability compared to controls. Patient erythrocytes were hypersensitive to EPO in vitro, and there was overexpression of the NFE2 and RUNX1 genes, as well as an increase in expression of HIF1A target genes. Immunoprecipitation studies showed that the mutation decreased the affinity of VHL to HIF1A, resulting in decreased ubiquitination under nonhypoxic conditions compared to controls. <a href="#12" class="mim-tip-reference" title="Lanikova, L., Lorenzo, F., Yang, C., Vankayalapati, H., Drachtman, R., Divorky, V., Prchal, J. T. <strong>Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer.</strong> Blood 121: 3918-3924, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23538339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23538339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23538339[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1182/blood-2012-11-469296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23538339">Lanikova et al. (2013)</a> noted that a germline mutation in the VHL gene affecting this residue (P138T) had been identified in patients with von Hippel-Lindau syndrome (see <a href="#14" class="mim-tip-reference" title="Leonardi, E., Martella, M., Tosatto, S. C. E., Murgia, A. <strong>Identification and in silico analysis of novel von Hippel-Lindau (VHL) gene variants from a large population.</strong> Ann. Hum. Genet. 75: 483-496, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21463266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21463266</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2011.00647.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21463266">Leonardi et al., 2011</a>), but the parents, who were heterozygous carriers of the P138L mutation, had no signs of VHLS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21463266+23538339" 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 10 patients from 9 unrelated families with familial ECYT2, <a href="#13" 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. <strong>Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.</strong> Blood 132: 469-483, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29891534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29891534</a>] [<a href="https://doi.org/10.1182/blood-2018-03-838235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29891534">Lenglet et al. (2018)</a> identified compound heterozygous mutations in the VHL gene. All patients carried heterozygous mutations in the newly identified cryptic exon 1 in the VHL gene, designated exon 1-prime (E1-prime) (see, e.g., <a href="/entry/608537#0030">608537.0030</a> and <a href="/entry/608537#0031">608537.0031</a>), resulting in a splicing alteration. The E1-prime exon is located deep in intron 1 and is normally expressed in many tissues. Prior to the study of <a href="#13" 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. <strong>Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.</strong> Blood 132: 469-483, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29891534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29891534</a>] [<a href="https://doi.org/10.1182/blood-2018-03-838235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29891534">Lenglet et al. (2018)</a>, several of these patients were thought to carry only 1 VHL mutation (e.g., R200W, consistent with Chuvash polycythemia; the patient from F2 had previously been reported by <a href="#6" class="mim-tip-reference" title="Cario, H., Schwarz, K., Jorch, N., Kyank, U., Petrides, P. E., Schneider, D. T., Uhle, R., Debatin, K.-M., Kohne, E. <strong>Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis.</strong> Haematologica 90: 19-24, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15642664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15642664</a>]" pmid="15642664">Cario et al., 2005</a>). The mutations, which were found by a combination of whole-genome and Sanger sequencing, segregated with the disorder in the families. RT-PCR analysis from lymphocytes derived from these patients showed decreased mRNA levels, increased amounts of E1/E3 transcripts suggesting that the mutations resulted in the skipping of exon 2, and severe decreases in the wildtype VHL mRNA and protein isoforms compared to controls. The findings by <a href="#13" 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. <strong>Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.</strong> Blood 132: 469-483, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29891534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29891534</a>] [<a href="https://doi.org/10.1182/blood-2018-03-838235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29891534">Lenglet et al. (2018)</a> confirmed that ECYT2 is an autosomal recessive disorder, and the authors postulated that the splice site mutations in these patients caused a global defect in VHL protein expression with downregulation of VHL, rather than reduced HIF1A binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29891534+15642664" 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 22-year-old man, born of consanguineous Italian parents, with ECYT2, <a href="#21" class="mim-tip-reference" title="Perrotta, S., Roberti, E., Bencivenga, D., Corsetto, P., O'Brien, K. A., Caiazza, M., Stampone, E., Allison, L., Fleck, R. A., Scianguetta, S., Tartaglione, I., Robbins, P. A., and 10 others. <strong>Effects of germline VHL deficiency on growth, metabolism, and mitochondria.</strong> New Eng. J. Med. 382: 835-844, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32101665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32101665</a>] [<a href="https://doi.org/10.1056/NEJMoa1907362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32101665">Perrotta et al. (2020)</a> identified a homozygous c.222C-A transversion in exon 1 of the VHL gene, predicted to result in a synonymous val75-to-val (V75V; <a href="/entry/608537#0034">608537.0034</a>) substitution. The mutation, which was found by direct sequencing, segregated with the disorder in the family. Analysis of patient cells showed that it created an alternate splice donor site, resulting in a frameshift and premature termination. Patient and paternal cells showed 80% and 40% lower levels of wildtype mRNA, respectively, compared to controls. Patient cells showed decreased amounts of the 3 main VHL protein isoforms (213, 160, and 172) as well as increased HIF1A, suggesting a loss of VHL function. Patient cells also showed increased levels of BNIP3L (<a href="/entry/605368">605368</a>) and MXI1 (<a href="/entry/600020">600020</a>) compared to controls, suggesting possible mitochondrial dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32101665" 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>Chuvash Polycythemia</em></strong></p><p>
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In patients with Chuvash polycythemia, <a href="#2" class="mim-tip-reference" title="Ang, S. O., Chen, H., Gordeuk, V. R., Sergueeva, A. I., Polyakova, L. A., Miasnikova, G. Y., Kralovics, R., Stockton, D. W., Prchal, J. T. <strong>Endemic polycythemia in Russia: mutation in the VHL gene.</strong> Blood Cells Molec. Dis. 28: 57-62, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11987242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11987242</a>] [<a href="https://doi.org/10.1006/bcmd.2002.0488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11987242">Ang et al. (2002)</a> identified a homozygous mutation in the VHL gene (R200W; <a href="/entry/608537#0019">608537.0019</a>). The VHL protein downregulates HIF1A, the main regulator of adaptation to hypoxia, by targeting the protein for degradation. Ang et al. (<a href="#2" class="mim-tip-reference" title="Ang, S. O., Chen, H., Gordeuk, V. R., Sergueeva, A. I., Polyakova, L. A., Miasnikova, G. Y., Kralovics, R., Stockton, D. W., Prchal, J. T. <strong>Endemic polycythemia in Russia: mutation in the VHL gene.</strong> Blood Cells Molec. Dis. 28: 57-62, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11987242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11987242</a>] [<a href="https://doi.org/10.1006/bcmd.2002.0488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11987242">2002</a>, <a href="#3" class="mim-tip-reference" title="Ang, S. O., Chen, H., Hirota, K., Gordeuk, V. R., Jelinek, J., Guan, Y., Liu, E., Sergueeva, A. I., Miasnikova, G. Y., Mole, D., Maxwell, P. H., Stockton, D. W., Semenza, G. L., Prchal, J. T. <strong>Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia.</strong> Nature Genet. 32: 614-621, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12415268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12415268</a>] [<a href="https://doi.org/10.1038/ng1019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12415268">2002</a>) suggested that in this scenario, disruption of function of the VHL protein causes a failure to degrade HIF1-alpha resulting in its accumulation, upregulation of downstream target genes such as EPO, and the clinical manifestations of polycythemia. Chuvash polycythemia is thus a congenital disorder of oxygen homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11987242+12415268" 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="#24" class="mim-tip-reference" title="Russell, R. C., Sufan, R. I., Zhou, B., Heir, P., Bunda, S., Sybingco, S. S., Greer, S. N., Roche, O., Heathcote, S. A., Chow, V. W. K., Boba, L. M., Richmond, T. D., Hickey, M. M., Barber, D. L., Cheresh, D. A., Simon, M. C., Irwin, M. S., Kim, W. Y., Ohh, M. <strong>Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia.</strong> Nature Med. 17: 845-853, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21685897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21685897</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21685897[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21685897">Russell et al. (2011)</a> presented evidence suggesting 2 main molecular mechanisms by which the R200W and H191D (<a href="/entry/608537#0024">608537.0024</a>) VHL mutations result in polycythemia. In vitro studies showed that the R200W mutation attenuated formation of the E3 ubiquitin ligase and attenuated binding of HIF1 (<a href="/entry/603348">603348</a>). In patients, this would lead to overproduction of the HIF-target erythropoietin (EPO; <a href="/entry/133170">133170</a>) and thus secondary polycythemia. In addition, VHL mutations cause conformational changes causing increased binding to SOCS1 (<a href="/entry/603597">603597</a>), which inhibits binding and degradation of phosphorylated JAK2 (<a href="/entry/147796">147796</a>). The resulting pJAK2 stabilization promotes hyperactivation of the JAK2-STAT5 (<a href="/entry/601511">601511</a>) pathway in erythroid progenitors, causing hypersensitivity to erythropoietin and thereby to primary polycythemia. Treatment of R200W-homozygous transgenic mice with a JAK2 inhibitor resulted in decreased hematocrit, smaller spleen, and decreased sensitivity to EPO compared to untreated transgenic mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21685897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Tomasic, N. L., Piterkova, L., Huff, C., Bilic, E., Yoon, D., Miasnikova, G. Y., Sergueeva, A. I., Niu, X., Nekhai, S., Gordeuk, V., Prchal, J. T. <strong>The phenotype of polycythemia due to Croatian homozygous VHL (571C-G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C-T:R200W)</strong> Haematologica 98: 560-567, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23403324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23403324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23403324[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3324/haematol.2012.070508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23403324">Tomasic et al. (2013)</a> stated that <a href="#24" class="mim-tip-reference" title="Russell, R. C., Sufan, R. I., Zhou, B., Heir, P., Bunda, S., Sybingco, S. S., Greer, S. N., Roche, O., Heathcote, S. A., Chow, V. W. K., Boba, L. M., Richmond, T. D., Hickey, M. M., Barber, D. L., Cheresh, D. A., Simon, M. C., Irwin, M. S., Kim, W. Y., Ohh, M. <strong>Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia.</strong> Nature Med. 17: 845-853, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21685897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21685897</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21685897[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2370" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21685897">Russell et al. (2011)</a> erroneously quoted the H191D mutation as a Chuvash polycythemia variant. The data presented by <a href="#28" class="mim-tip-reference" title="Tomasic, N. L., Piterkova, L., Huff, C., Bilic, E., Yoon, D., Miasnikova, G. Y., Sergueeva, A. I., Niu, X., Nekhai, S., Gordeuk, V., Prchal, J. T. <strong>The phenotype of polycythemia due to Croatian homozygous VHL (571C-G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C-T:R200W)</strong> Haematologica 98: 560-567, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23403324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23403324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23403324[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3324/haematol.2012.070508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23403324">Tomasic et al. (2013)</a> showed that erythrocyte precursors from homozygous H191D patients did not exhibit intrinsic hyperproliferation or a hyperproliferative response to EPO, as observed in R200W homozygotes. Their study indicated different functional effects of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23403324+21685897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By haplotype analysis of 101 ethnically diverse individuals with the common R200W mutation in the VHL gene, including 72 Chuvash individuals, <a href="#15" class="mim-tip-reference" title="Liu, E., Percy, M. J., Amos, C. I., Guan, Y., Shete, S., Stockton, D. W., McMullin, M. F., Polyakova, L. A., Ang, S. O., Pastore, Y. D., Jedlickova, K., Lappin, T. R. J., Gordeuk, V., Prchal, J. T. <strong>The worldwide distribution of the VHL 598C-T mutation indicates a single founder effect.</strong> Blood 103: 1937-1940, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14604959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14604959</a>] [<a href="https://doi.org/10.1182/blood-2003-07-2550" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14604959">Liu et al. (2004)</a> determined that the R200W mutation is due to a founder effect that originated from 14,000 to 62,000 years ago. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14604959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Cario, H., Schwarz, K., Jorch, N., Kyank, U., Petrides, P. E., Schneider, D. T., Uhle, R., Debatin, K.-M., Kohne, E. <strong>Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis.</strong> Haematologica 90: 19-24, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15642664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15642664</a>]" pmid="15642664">Cario et al. (2005)</a> reported a Turkish patient who was homozygous for the R200W mutation. Haplotype analysis showed a different haplotype than that associated with the Chuvash population, indicating that the mutation arose independently and is not geographically restricted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15642664" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Perrotta, S., Nobili, B., Ferraro, M., Migliaccio, C., Borriello, A., Cucciolla, V., Martinelli, V., Rossi, F., Punzo, F., Cirillo, P., Parisi, G., Zappia, V., Rotoli, B., Ragione, F. D. <strong>Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster.</strong> Blood 107: 514-519, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16210343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16210343</a>] [<a href="https://doi.org/10.1182/blood-2005-06-2422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16210343">Perrotta et al. (2006)</a> found that the R200W mutation is more frequent on the island of Ischia in the Bay of Naples (0.070) than it is in Chuvashia (0.057). The haplotype of all patients in Ischia matched that identified in the Chuvash cluster, thus supporting the single-founder hypothesis. <a href="#20" class="mim-tip-reference" title="Perrotta, S., Nobili, B., Ferraro, M., Migliaccio, C., Borriello, A., Cucciolla, V., Martinelli, V., Rossi, F., Punzo, F., Cirillo, P., Parisi, G., Zappia, V., Rotoli, B., Ragione, F. D. <strong>Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster.</strong> Blood 107: 514-519, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16210343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16210343</a>] [<a href="https://doi.org/10.1182/blood-2005-06-2422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16210343">Perrotta et al. (2006)</a> also found that unaffected heterozygotes had increased HIF1-alpha activity, which might confer a biochemical advantage for mutation maintenance. They suggested that this form of familial polycythemia may be endemic in other regions of the world, a hypothesis supported by the reports of Percy et al. (<a href="#19" class="mim-tip-reference" title="Percy, M. J., McMullin, M. F., Treacy, M., Potter, M., Watson, W. H., Jowitt, S. N., Lappin, T. R. J. <strong>Identification of the Chuvash-type congenital polycythemia in patients of Asian and Western European ancestry.</strong> Blood 100: 660 only, 2002."None>2002</a>, <a href="#18" class="mim-tip-reference" title="Percy, M. J., McMullin, M. F., Jowitt, S. N., Potter, M., Treacy, M., Watson, W. H., Lappin, T. R. <strong>Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry.</strong> Blood 102: 1097-1099, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12702509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12702509</a>] [<a href="https://doi.org/10.1182/blood-2002-10-3246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12702509">2003</a>). Because this disorder is not strictly confined to Chuvashia and not solely a result of the 598C-T mutation, <a href="#20" class="mim-tip-reference" title="Perrotta, S., Nobili, B., Ferraro, M., Migliaccio, C., Borriello, A., Cucciolla, V., Martinelli, V., Rossi, F., Punzo, F., Cirillo, P., Parisi, G., Zappia, V., Rotoli, B., Ragione, F. D. <strong>Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster.</strong> Blood 107: 514-519, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16210343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16210343</a>] [<a href="https://doi.org/10.1182/blood-2005-06-2422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16210343">Perrotta et al. (2006)</a> suggested that a more accurate designation would be 'VHL-dependent polycythemia.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16210343+12702509" 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="#11" class="mim-tip-reference" title="Hickey, M. M., Lam, J. C., Bezman, N. A., Rathmell, W. K., Simon, M. C. <strong>von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2-alpha signaling and splenic erythropoiesis.</strong> J. Clin. Invest. 117: 3879-3889, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17992257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17992257</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17992257[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI32614" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17992257">Hickey et al. (2007)</a> found that mice homozygous for the R200W mutation developed polycythemia similar to the human disease. Although bone marrow cellularity and morphology was similar to controls, spleens from the mutant mice showed increased numbers of erythroid progenitors and megakaryocytes, as well as erythroid differentiation of splenic cells in vitro. Further analysis showed upregulation of HIF2A (<a href="/entry/603349">603349</a>) and of key target genes, including EPO (<a href="/entry/133170">133170</a>), VEGF (<a href="/entry/192240">192240</a>), GLUT1 (<a href="/entry/138140">138140</a>), and PAI1 (<a href="/entry/173360">173360</a>), that contribute to polycythemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17992257" 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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Adamson, J. W., Stamatoyannopoulos, G., Kontras, S., Lascari, A., Detter, J. C.
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<strong>Recessive familial erythrocytosis: aspects of marrow regulation in two families.</strong>
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Blood 41: 641-652, 1973.
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Ang, S. O., Chen, H., Gordeuk, V. R., Sergueeva, A. I., Polyakova, L. A., Miasnikova, G. Y., Kralovics, R., Stockton, D. W., Prchal, J. T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11987242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11987242</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11987242" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/bcmd.2002.0488" target="_blank">Full Text</a>]
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Ang, S. O., Chen, H., Hirota, K., Gordeuk, V. R., Jelinek, J., Guan, Y., Liu, E., Sergueeva, A. I., Miasnikova, G. Y., Mole, D., Maxwell, P. H., Stockton, D. W., Semenza, G. L., Prchal, J. T.
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<strong>Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia.</strong>
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Nature Genet. 32: 614-621, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12415268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12415268</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12415268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1019" target="_blank">Full Text</a>]
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Auerbach, M. L., Wolff, J. A., Mettier, S. R.
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<strong>Benign familial polycythemia in childhood: report of two cases.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13494077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13494077</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13494077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bond, J., Gale, D. P., Connor, T., Adams, S., de Boer, J., Gascoyne, D. M., Williams, O., Maxwell, P. H., Ancliff, P. J.
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<strong>Dysregulation of the HIF pathway due to VHL mutation causing severe erythrocytosis and pulmonary arterial hypertension. (Letter)</strong>
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Blood 117: 3699-3701, 2011.
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[<a href="https://doi.org/10.1182/blood-2010-12-327569" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000208945" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood-2003-07-2535" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197705122961902" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI32614" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood-2012-11-469296" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood-2018-03-838235" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.2011.00647.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/377108" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood-2002-10-3246" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1182/blood-2005-06-2422" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1907362" target="_blank">Full Text</a>]
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<p class="mim-text-font">
|
|
Prchal, J. T.
|
|
<strong>Polycythemia vera and other primary polycythemias.</strong>
|
|
Curr. Opin. Hemat. 12: 112-116, 2005.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15725900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15725900</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15725900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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[<a href="https://doi.org/10.1097/01.moh.0000154029.05396.d2" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Russell2011" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
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|
Russell, R. C., Sufan, R. I., Zhou, B., Heir, P., Bunda, S., Sybingco, S. S., Greer, S. N., Roche, O., Heathcote, S. A., Chow, V. W. K., Boba, L. M., Richmond, T. D., Hickey, M. M., Barber, D. L., Cheresh, D. A., Simon, M. C., Irwin, M. S., Kim, W. Y., Ohh, M.
|
|
<strong>Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia.</strong>
|
|
Nature Med. 17: 845-853, 2011.
|
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21685897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21685897</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21685897[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=21685897" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nm.2370" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Sarangi2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sarangi, S., Lanikova, L., Kapralova, K., Acharya, S., Swierczek, S., Lipton, J. M., Wolfe, L., Prchal, J. T.
|
|
<strong>The homozygous VHL-D126N missense mutation is associated with dramatically elevated erythropoietin levels, consequent polycythemia, and early onset severe pulmonary hypertension.</strong>
|
|
Pediat. Blood Cancer 61: 2104-2106, 2014.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24729484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24729484</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24729484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/pbc.25056" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Sergeyeva1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Sergeyeva, A., Gordeuk, V. R., Tokarev, Y. N., Sokol, L., Prchal, J. F., Prchal, J. T.
|
|
<strong>Congenital polycythemia in Chuvashia.</strong>
|
|
Blood 89: 2148-2154, 1997.
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|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9058738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9058738</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9058738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Stamatoyannopoulos1972" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Stamatoyannopoulos, G.
|
|
<strong>Familial erythrocytosis.</strong>
|
|
Birth Defects Orig. Art. Ser. 8(3): 39-45, 1972.
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</p>
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</div>
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</li>
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Tomasic2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tomasic, N. L., Piterkova, L., Huff, C., Bilic, E., Yoon, D., Miasnikova, G. Y., Sergueeva, A. I., Niu, X., Nekhai, S., Gordeuk, V., Prchal, J. T.
|
|
<strong>The phenotype of polycythemia due to Croatian homozygous VHL (571C-G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C-T:R200W)</strong>
|
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Haematologica 98: 560-567, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23403324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23403324</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23403324[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=23403324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.3324/haematol.2012.070508" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="29" class="mim-anchor"></a>
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<a id="Vasserman1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vasserman, N. N., Karzakova, L. M., Tverskaya, S. M., Saperov, V. N., Muchukova, O. M., Pavlova, G. P., Efimova, N. K., Vankina, N. N., Evgrafov, O. V.
|
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<strong>Localization of the gene responsible for familial benign polycythemia to chromosome 11q23.</strong>
|
|
Hum. Hered. 49: 129-132, 1999.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10364675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10364675</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10364675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1159/000022859" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="30" class="mim-anchor"></a>
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<a id="Whitcomb1980" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Whitcomb, W. H., Peschle, C., Moore, M., Nitschke, R., Adamson, J. W.
|
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<strong>Congenital erythrocytosis: a new form associated with an erythropoietin-dependent mechanism.</strong>
|
|
Brit. J. Haemat. 44: 17-24, 1980.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7378290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7378290</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7378290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.1980.tb01179.x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Yonemitsu1973" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
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Yonemitsu, H., Yamaguchi, K., Shigeta, H., Okuda, K., Takaku, F.
|
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<strong>Two cases of familial erythrocytosis with increased erythropoietin activity in plasma and urine.</strong>
|
|
Blood 42: 793-797, 1973.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4746102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4746102</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4746102" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 02/28/2020
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</span>
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</div>
|
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</div>
|
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<div class="row collapse" id="mimCollapseContributors">
|
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
|
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Cassandra L. Kniffin - updated : 8/3/2011<br>Cassandra L. Kniffin - updated : 3/13/2008<br>Cassandra L. Kniffin - reorganized : 5/24/2006<br>Cassandra L. Kniffin - updated : 5/23/2006<br>Victor A. McKusick - updated : 3/28/2006<br>Victor A. McKusick - updated : 8/8/2003<br>Victor A. McKusick - updated : 11/4/2002<br>Victor A. McKusick - updated : 8/4/1999<br>Victor A. McKusick - updated : 7/13/1998
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</span>
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</div>
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</div>
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</div>
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<div>
|
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/22/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/02/2021<br>carol : 02/09/2021<br>carol : 03/06/2020<br>carol : 03/05/2020<br>ckniffin : 02/28/2020<br>alopez : 09/19/2016<br>carol : 08/05/2011<br>wwang : 8/5/2011<br>ckniffin : 8/3/2011<br>terry : 7/20/2011<br>carol : 7/12/2011<br>terry : 9/10/2008<br>wwang : 5/16/2008<br>ckniffin : 3/13/2008<br>carol : 9/11/2007<br>terry : 8/9/2007<br>carol : 5/24/2006<br>ckniffin : 5/23/2006<br>alopez : 3/29/2006<br>terry : 3/28/2006<br>ckniffin : 3/23/2004<br>ckniffin : 3/23/2004<br>tkritzer : 8/14/2003<br>tkritzer : 8/13/2003<br>terry : 8/8/2003<br>alopez : 1/17/2003<br>alopez : 12/3/2002<br>alopez : 11/5/2002<br>alopez : 11/5/2002<br>terry : 11/4/2002<br>jlewis : 8/17/1999<br>terry : 8/4/1999<br>terry : 7/13/1998<br>terry : 7/13/1998<br>pfoster : 4/5/1994<br>mimadm : 3/12/1994<br>supermim : 3/17/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 263400
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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ERYTHROCYTOSIS, FAMILIAL, 2; ECYT2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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POLYCYTHEMIA, VHL-DEPENDENT
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
|
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<span class="h3 mim-font">
|
|
POLYCYTHEMIA, CHUVASH TYPE, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>ORPHA:</strong> 238557;
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|
<strong>DO:</strong> 0060474;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
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|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
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</thead>
|
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<tbody>
|
|
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<tr>
|
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<td>
|
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<span class="mim-font">
|
|
3p25.3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Erythrocytosis, familial, 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
263400
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
VHL
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
608537
|
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</span>
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that familial erythrocytosis-2 (ECYT2) is caused by homozygous or compound heterozygous mutation in the VHL gene (608537) on chromosome 3p25.</p><p>Chuvash polycythemia, endemic in the Chuvash Republic of the Russian Federation and in Ischia, Italy, is associated with a specific mutation in the VHL gene (R200W; 608537.0019).</p><p>Heterozygous mutation in the VHL gene can cause von Hippel-Lindau syndrome (VHLS; 193300).</p>
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<strong>Description</strong>
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<p>Familial erythrocytosis-2 (ECYT2) is an autosomal recessive disorder characterized by increased red blood cell mass, increased serum levels of erythropoietin (EPO; 133170), and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events (Cario, 2005). Familial erythrocytosis-2 has features of both primary and secondary erythrocytosis. In addition to increased circulating levels of EPO, consistent with a secondary, extrinsic process, erythroid progenitors may be hypersensitive to EPO, consistent with a primary, intrinsic process (Prchal, 2005). </p><p>For a general phenotypic description and a discussion of genetic heterogeneity of familial erythrocytosis, see ECYT1 (133100).</p>
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<strong>Nomenclature</strong>
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<p>The term 'polycythemia' (Greek: 'many cells in the blood') is used interchangeably with 'erythrocytosis,' although the latter term more specifically refers to an increase in the number of circulating differentiated red blood cells (Prchal, 2005; Cario, 2005). 'Erythrocytosis' is the preferred term used here in order to distinguish inherited disorders characterized by increased circulating red blood cells from 'polycythemia vera' (PV; 263300), which is a clonal myeloproliferative disorder associated with somatic mutations in the JAK2 gene (147796). Familial erythrocytosis is also distinct from erythroleukemia (133180), which is considered to be a subtype of acute myelogenous leukemia (AML; 601626) characterized by immature erythroid cells in the bone marrow and peripheral blood. </p>
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<strong>Clinical Features</strong>
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<p><strong><em>Early Reports</em></strong></p><p>
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Nadler and Cohn (1939) described a family in which 4 of 11 children showed polycythemia. The mother stated that these 4 children had red faces from the time of birth. Auerbach et al. (1958) reported 3 families. In 1 family, 2 brothers and a sister were affected, and in a second, the proband and an aunt. The parents were normal. Unlike patients with polycythemia vera, the subjects demonstrated no increase in white count, platelets, or uric acid, and the process was benign. </p><p>Yonemitsu et al. (1973) described 2 affected sons of parents related as half first cousins. Both had a marked increase in erythropoietin concentration in plasma and urine. Adamson et al. (1973) studied 2 families with recessive erythrocytosis and found increased erythropoietin production uninfluenced by alterations in the oxygen-carrying capacity of the blood when the hematocrit was lowered by phlebotomy. Hemoglobin and red cell function and renal vasculature were normal. A genetic defect in regulation of erythropoietin production was postulated. Greenberg and Golde (1977) studied 2 brothers, aged 26 and 28, whose erythrocytosis had been discovered incidentally. The parents were hematologically normal. Studies showed increased serum erythropoietin resulting in an expansion of the erythroid precursor pool. </p><p>Whitcomb et al. (1980) studied 3 cases of congenital erythrocytosis and found an absolute or relative elevation of erythropoietin. Urinary excretion of erythropoietin was more than doubled by phlebotomy. The authors postulated an inherited defect 'likely residing in the renal sensor responsible for the production of erythropoietin.' </p><p><strong><em>Early-Onset Congenital Erythrocytosis with Confirmed VHL Mutations</em></strong></p><p>
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Pastore et al. (2003) reported 7 patients from 6 unrelated families with ECYT2. The patients, who ranged in age from 12 to 19 years, presented by age 5 years, except for 1 patient who presented at age 9 years. Features included polycythemia treated with phlebotomy and increased serum EPO; 1 patient had thrombosis. Two sibs of Danish origin and an unrelated Caucasian patient carried a homozygous R200W mutation (608537.0019), consistent with the Chuvash type (see below), and 3 additional Caucasian patients were compound heterozygous for R200W and another missense variant. One patient of Croatian descent carried a homozygous H191D mutation (608537.0024). The EPO levels in patients with the R200W mutation ranged from normal to high. VHLS-related tumors were not observed in any of the families. </p><p>Tomasic et al. (2013) reported a 5-year-old Croatian girl with early-onset ECYT2. She presented at age 2 years with failure to thrive, increased hematocrit and hemoglobin, low ferritin, and extremely high erythropoietin. She also had delayed psychomotor development. A distant relative had previously been reported by Pastore et al. (2003); that patient was a 26-year-old man who presented at 1 year of age. Haplotype analysis indicated a common ancestor between the 2 patients, who both carried a homozygous H191D mutation, although there was no evidence for a common origin of both mutant alleles. Patient erythroid precursors showed normal growth and were not hypersensitive to EPO in vitro; these findings differed from those observed in Chuvash polycythemia, in which the erythroid precursors are intrinsically hyperproliferative and also show hypersensitivity to EPO. Tomasic et al. (2013) concluded that the erythrocytosis in patients with the H191D mutation is solely driven by increased circulating EPO. </p><p>Sarangi et al. (2014) reported a 7-month-old infant, born of consanguineous Bangladeshi parents, with congenital ECYT2. He had failure to thrive, developmental delay, and polycythemia with dramatically increased erythropoietin levels. Imaging of the abdomen showed multiple hepatic hemangiomas. He was treated with phlebotomy, but developed pulmonary hypertension and recurrent respiratory infections, resulting in death at age 2. Brain imaging showed extensive cerebral, cerebellar, and brainstem infarctions. Neither parent had polycythemia or evidence of VHL-associated tumors. </p><p>Lenglet et al. (2018) reported 10 patients from 9 unrelated families with ECYT2. The patients were diagnosed between 4 months and 21 years of age. In addition to increased hemoglobin, hematocrit, and EPO, 2 patients had splenomegaly and 2 had deep vein thrombosis. </p><p>Perrotta et al. (2020) reported a 22-year-old man, born of consanguineous Italian parents, with a complex form of ECYT2 with growth failure, persistent hypoglycemia, limited exercise capacity, and mitochondrial dysfunction. He was born by emergency cesarean section due to fetal bradycardia and showed persistent bradycardia and hypoglycemia after birth. He received phototherapy for neonatal jaundice and had phlebotomy for elevated hemoglobin and hematocrit. Later in infancy he showed marked failure to thrive with no signs of growth hormone deficiency, but was treated with growth hormone. At age 12-13 years, he had high levels of erythropoietin, low ferritin, low blood pressure (75/35), abnormal cardiac rhythm, and poor growth (height at -3 SD) treated successfully with IGF1 (147440). He continued to have regular phlebotomy with strict control of iron bioavailability. The patient had exercise intolerance with altered ventilatory control mimicking acclimatization to high-altitude hypoxia. Studies of mitochondria from skeletal muscle tissue showed markedly decreased respiratory capacity compared to controls, with oxygen consumption uncoupled from ATP synthesis: oxidative phosphorylation supported by fatty-acid substrates and substrates for electron chain complexes I and II were 28%, 44%, and 34% lower than those in controls. Morphologically, the mitochondria contained abnormal intermitochondrial connecting ducts, possibly suggesting stress conditions. The patient also had metabolic changes in glucose and lipid metabolism indicating a shift from oxidative phosphorylation to glycolysis. </p><p><strong><em>Chuvash Polycythemia</em></strong></p><p>
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Polyakova (1974) described familial erythrocytosis in the Chuvash population, an ethnic isolate in the mid-Volga river region of Russia of Asian descent (Prchal, 2005). </p><p>Sergeyeva et al. (1997) studied the autosomal recessive form of congenital erythrocytosis common in the Chuvash population. They stated that hundreds of individuals appeared to be affected in an autosomal recessive pattern. They studied 6 polycythemic Chuvash patients less than 20 years of age from unrelated families and 12 first-degree family members. Hemoglobins were markedly elevated in the index subjects (22.6 +/- 1.4 g/dl) and serum erythropoietin concentrations were elevated. Platelet and white blood cell counts were normal. Southern blot analysis of the Bgl2 erythropoietin gene polymorphism showed that one affected individual was a heterozygote, suggesting absence of linkage of polycythemia with the EPO gene. There was no evidence of linkage to the erythropoietin receptor gene (EPOR; 133171). </p><p>In a matched cohort study, Gordeuk et al. (2004) found that patients with Chuvash polycythemia had increased frequency of vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum VEGF (192240) concentrations (p less than 0.0005), as well as premature mortality related to cerebrovascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classic VHL syndrome were not found, suggesting that overexpression of the alpha subunit of hypoxia-inducible factor-1 (HIF1A; 603348) and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in patients compared to controls, erythropoietin response to hypoxia was identical. Gordeuk et al. (2004) concluded that Chuvash polycythemia is a distinct syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes. </p>
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<h4>
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<strong>Inheritance</strong>
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<p>Davey et al. (1968) and Stamatoyannopoulos (1972) noted autosomal recessive inheritance of erythrocytosis. </p><p>The transmission pattern of ECYT2 in the families reported by Pastore et al. (2003) was consistent with autosomal recessive inheritance. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Vasserman et al. (1999) studied the autosomal recessive benign erythrocytosis that has a high incidence in Chuvashia in the Russian Federation. They studied 12 unrelated families and excluded the erythropoietin gene and the erythropoietin receptor gene as candidates by linkage analysis. Using genomewide searching, they demonstrated linkage of the disorder between markers D11S4142 and D11S1356 on 11q23 (maximum lod = 6.61). </p><p>Ang et al. (2002) found that in a genomewide screen, the Chuvash polycythemia locus mapped not to 11q23 but to 3p, in a region containing the VHL gene. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</h4>
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<span class="mim-text-font">
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<p>Pastore et al. (2003) identified homozygous or compound heterozygous mutations in the VHL gene in 7 of 13 patients with congenital erythrocytosis and suggested that such mutations are the most frequent cause of the disorder. Three patients of European descent were homozygous for the Chuvash mutation (R200W; 608537.0019), 3 were compound heterozygous for R200W and another missense variant (L188V, 608537.0014 or P192S, 608537.0023), and a patient of Croatian descent was homozygous for H191D (608537.0024). Functional studies of the variants were not performed. </p><p>In an 8-year-old boy with ECYT2, Bond et al. (2011) identified compound heterozygous missense mutations in the VHL gene (D126N, 608537.0028 and S183L, 608537.0029). The mutations were found by direct gene sequencing. Transfection of the mutations into renal carcinoma cells showed decreased protein levels consistent with instability of the mutant proteins, suggesting a loss-of-function effect. Transfected cells also showed decreased pH, decreased glucose, and increased lactate, consistent with upregulation of glycolysis. These changes were associated with increased expression of HIF1A (603348), PHD3 (606426), and GLUT1 (138140), suggesting impaired ability of mutant VHL to regulate HIF. The patient presented at 2 months of age with right ventricular dysfunction and hypertrophy, pulmonary hypertension, increased hematocrit and hemoglobin, and significantly increased EPO. He was managed successfully by phlebotomy. </p><p>Sarangi et al. (2014) identified a homozygous D126N mutation in the VHL gene in a 2-year-old boy, born of consanguineous Bangladeshi parents, with fatal ECYT2. In vitro studies showed that patient erythroid progenitors were not hypersensitive to EPO and did not overexpress NFE2 (601490) or RUNX1 (151385) transcripts, which are associated with EPO hypersensitivity. This demonstrated a different pathogenic mechanism from patients with Chuvash polycythemia due to the R200W mutation (608537.0019). </p><p>Tomasic et al. (2013) reported a 5-year-old Croatian girl with early-onset ECYT2 due to a homozygous H191D mutation (608537.0024). Family history revealed that she was related to the Croatian patient reported by Pastore et al. (2003). Patient erythroid precursors showed normal growth and were not hypersensitive to EPO in vitro; these findings differed from those observed in Chuvash polycythemia in which the erythroid precursors are intrinsically hyperproliferative and also show hypersensitivity to EPO. Tomasic et al. (2013) concluded that the polycythemia in patients with the H191D mutation is solely driven by increased circulating EPO. Patient cells showed changes in gene expression, including increased expression of several HIF1A-related genes (TFRC, 190010; VEGF, 192240; and HK1, 142600), and decreased expression of other genes (BNIP3L, 605368 and ADM, 103275). </p><p>In a 15-year-old girl of Asian Indian descent with ECYT2, Lanikova et al. (2013) identified a homozygous missense mutation in the VHL gene (P138L; 608537.0035). The mutation, which was found by direct sequencing of the VHL gene, segregated with the disorder in the family. Cellular transfection studies showed that the mutant protein had decreased stability compared to controls. Patient erythrocytes were hypersensitive to EPO in vitro, and there was overexpression of the NFE2 and RUNX1 genes, as well as an increase in expression of HIF1A target genes. Immunoprecipitation studies showed that the mutation decreased the affinity of VHL to HIF1A, resulting in decreased ubiquitination under nonhypoxic conditions compared to controls. Lanikova et al. (2013) noted that a germline mutation in the VHL gene affecting this residue (P138T) had been identified in patients with von Hippel-Lindau syndrome (see Leonardi et al., 2011), but the parents, who were heterozygous carriers of the P138L mutation, had no signs of VHLS. </p><p>In 10 patients from 9 unrelated families with familial ECYT2, Lenglet et al. (2018) identified compound heterozygous mutations in the VHL gene. All patients carried heterozygous mutations in the newly identified cryptic exon 1 in the VHL gene, designated exon 1-prime (E1-prime) (see, e.g., 608537.0030 and 608537.0031), resulting in a splicing alteration. The E1-prime exon is located deep in intron 1 and is normally expressed in many tissues. Prior to the study of Lenglet et al. (2018), several of these patients were thought to carry only 1 VHL mutation (e.g., R200W, consistent with Chuvash polycythemia; the patient from F2 had previously been reported by Cario et al., 2005). The mutations, which were found by a combination of whole-genome and Sanger sequencing, segregated with the disorder in the families. RT-PCR analysis from lymphocytes derived from these patients showed decreased mRNA levels, increased amounts of E1/E3 transcripts suggesting that the mutations resulted in the skipping of exon 2, and severe decreases in the wildtype VHL mRNA and protein isoforms compared to controls. The findings by Lenglet et al. (2018) confirmed that ECYT2 is an autosomal recessive disorder, and the authors postulated that the splice site mutations in these patients caused a global defect in VHL protein expression with downregulation of VHL, rather than reduced HIF1A binding. </p><p>In a 22-year-old man, born of consanguineous Italian parents, with ECYT2, Perrotta et al. (2020) identified a homozygous c.222C-A transversion in exon 1 of the VHL gene, predicted to result in a synonymous val75-to-val (V75V; 608537.0034) substitution. The mutation, which was found by direct sequencing, segregated with the disorder in the family. Analysis of patient cells showed that it created an alternate splice donor site, resulting in a frameshift and premature termination. Patient and paternal cells showed 80% and 40% lower levels of wildtype mRNA, respectively, compared to controls. Patient cells showed decreased amounts of the 3 main VHL protein isoforms (213, 160, and 172) as well as increased HIF1A, suggesting a loss of VHL function. Patient cells also showed increased levels of BNIP3L (605368) and MXI1 (600020) compared to controls, suggesting possible mitochondrial dysfunction. </p><p><strong><em>Chuvash Polycythemia</em></strong></p><p>
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In patients with Chuvash polycythemia, Ang et al. (2002) identified a homozygous mutation in the VHL gene (R200W; 608537.0019). The VHL protein downregulates HIF1A, the main regulator of adaptation to hypoxia, by targeting the protein for degradation. Ang et al. (2002, 2002) suggested that in this scenario, disruption of function of the VHL protein causes a failure to degrade HIF1-alpha resulting in its accumulation, upregulation of downstream target genes such as EPO, and the clinical manifestations of polycythemia. Chuvash polycythemia is thus a congenital disorder of oxygen homeostasis. </p>
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<strong>Pathogenesis</strong>
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<span class="mim-text-font">
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<p>Russell et al. (2011) presented evidence suggesting 2 main molecular mechanisms by which the R200W and H191D (608537.0024) VHL mutations result in polycythemia. In vitro studies showed that the R200W mutation attenuated formation of the E3 ubiquitin ligase and attenuated binding of HIF1 (603348). In patients, this would lead to overproduction of the HIF-target erythropoietin (EPO; 133170) and thus secondary polycythemia. In addition, VHL mutations cause conformational changes causing increased binding to SOCS1 (603597), which inhibits binding and degradation of phosphorylated JAK2 (147796). The resulting pJAK2 stabilization promotes hyperactivation of the JAK2-STAT5 (601511) pathway in erythroid progenitors, causing hypersensitivity to erythropoietin and thereby to primary polycythemia. Treatment of R200W-homozygous transgenic mice with a JAK2 inhibitor resulted in decreased hematocrit, smaller spleen, and decreased sensitivity to EPO compared to untreated transgenic mice. </p><p>Tomasic et al. (2013) stated that Russell et al. (2011) erroneously quoted the H191D mutation as a Chuvash polycythemia variant. The data presented by Tomasic et al. (2013) showed that erythrocyte precursors from homozygous H191D patients did not exhibit intrinsic hyperproliferation or a hyperproliferative response to EPO, as observed in R200W homozygotes. Their study indicated different functional effects of the mutations. </p>
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<h4>
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<strong>Population Genetics</strong>
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<p>By haplotype analysis of 101 ethnically diverse individuals with the common R200W mutation in the VHL gene, including 72 Chuvash individuals, Liu et al. (2004) determined that the R200W mutation is due to a founder effect that originated from 14,000 to 62,000 years ago. </p><p>Cario et al. (2005) reported a Turkish patient who was homozygous for the R200W mutation. Haplotype analysis showed a different haplotype than that associated with the Chuvash population, indicating that the mutation arose independently and is not geographically restricted. </p><p>Perrotta et al. (2006) found that the R200W mutation is more frequent on the island of Ischia in the Bay of Naples (0.070) than it is in Chuvashia (0.057). The haplotype of all patients in Ischia matched that identified in the Chuvash cluster, thus supporting the single-founder hypothesis. Perrotta et al. (2006) also found that unaffected heterozygotes had increased HIF1-alpha activity, which might confer a biochemical advantage for mutation maintenance. They suggested that this form of familial polycythemia may be endemic in other regions of the world, a hypothesis supported by the reports of Percy et al. (2002, 2003). Because this disorder is not strictly confined to Chuvashia and not solely a result of the 598C-T mutation, Perrotta et al. (2006) suggested that a more accurate designation would be 'VHL-dependent polycythemia.' </p>
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<strong>Animal Model</strong>
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<p>Hickey et al. (2007) found that mice homozygous for the R200W mutation developed polycythemia similar to the human disease. Although bone marrow cellularity and morphology was similar to controls, spleens from the mutant mice showed increased numbers of erythroid progenitors and megakaryocytes, as well as erythroid differentiation of splenic cells in vitro. Further analysis showed upregulation of HIF2A (603349) and of key target genes, including EPO (133170), VEGF (192240), GLUT1 (138140), and PAI1 (173360), that contribute to polycythemia. </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<ol>
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<p class="mim-text-font">
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Adamson, J. W., Stamatoyannopoulos, G., Kontras, S., Lascari, A., Detter, J. C.
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<strong>Recessive familial erythrocytosis: aspects of marrow regulation in two families.</strong>
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Blood 41: 641-652, 1973.
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[PubMed: 4694081]
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</p>
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<li>
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<p class="mim-text-font">
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Ang, S. O., Chen, H., Gordeuk, V. R., Sergueeva, A. I., Polyakova, L. A., Miasnikova, G. Y., Kralovics, R., Stockton, D. W., Prchal, J. T.
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<strong>Endemic polycythemia in Russia: mutation in the VHL gene.</strong>
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Blood Cells Molec. Dis. 28: 57-62, 2002.
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[PubMed: 11987242]
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[Full Text: https://doi.org/10.1006/bcmd.2002.0488]
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<li>
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<p class="mim-text-font">
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Ang, S. O., Chen, H., Hirota, K., Gordeuk, V. R., Jelinek, J., Guan, Y., Liu, E., Sergueeva, A. I., Miasnikova, G. Y., Mole, D., Maxwell, P. H., Stockton, D. W., Semenza, G. L., Prchal, J. T.
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<strong>Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia.</strong>
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Nature Genet. 32: 614-621, 2002.
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[PubMed: 12415268]
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[Full Text: https://doi.org/10.1038/ng1019]
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<li>
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<p class="mim-text-font">
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Auerbach, M. L., Wolff, J. A., Mettier, S. R.
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 02/28/2020<br>Cassandra L. Kniffin - updated : 8/3/2011<br>Cassandra L. Kniffin - updated : 3/13/2008<br>Cassandra L. Kniffin - reorganized : 5/24/2006<br>Cassandra L. Kniffin - updated : 5/23/2006<br>Victor A. McKusick - updated : 3/28/2006<br>Victor A. McKusick - updated : 8/8/2003<br>Victor A. McKusick - updated : 11/4/2002<br>Victor A. McKusick - updated : 8/4/1999<br>Victor A. McKusick - updated : 7/13/1998
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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Edit History:
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carol : 02/22/2022<br>carol : 04/02/2021<br>carol : 02/09/2021<br>carol : 03/06/2020<br>carol : 03/05/2020<br>ckniffin : 02/28/2020<br>alopez : 09/19/2016<br>carol : 08/05/2011<br>wwang : 8/5/2011<br>ckniffin : 8/3/2011<br>terry : 7/20/2011<br>carol : 7/12/2011<br>terry : 9/10/2008<br>wwang : 5/16/2008<br>ckniffin : 3/13/2008<br>carol : 9/11/2007<br>terry : 8/9/2007<br>carol : 5/24/2006<br>ckniffin : 5/23/2006<br>alopez : 3/29/2006<br>terry : 3/28/2006<br>ckniffin : 3/23/2004<br>ckniffin : 3/23/2004<br>tkritzer : 8/14/2003<br>tkritzer : 8/13/2003<br>terry : 8/8/2003<br>alopez : 1/17/2003<br>alopez : 12/3/2002<br>alopez : 11/5/2002<br>alopez : 11/5/2002<br>terry : 11/4/2002<br>jlewis : 8/17/1999<br>terry : 8/4/1999<br>terry : 7/13/1998<br>terry : 7/13/1998<br>pfoster : 4/5/1994<br>mimadm : 3/12/1994<br>supermim : 3/17/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988
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