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<title>
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Entry
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- #619538 - CEREBRAL CAVERNOUS MALFORMATIONS 4; CCM4
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- OMIM
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<span class="h4">#619538</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/619538"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS116860"> <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="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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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<div style="display: table-cell;">External Links</div>
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<div><a href="https://clinicaltrials.gov/search?cond=(CEREBRAL CAVERNOUS MALFORMATIONS) OR (PIK3CA)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=18935&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=619538[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=221061" 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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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 221061<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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619538
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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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CEREBRAL CAVERNOUS MALFORMATIONS 4; CCM4
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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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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
|
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<span class="mim-font">
|
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<a href="/geneMap/3/876?start=-3&limit=10&highlight=876">
|
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3q26.32
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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Cerebral cavernous malformations 4, somatic
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/619538"> 619538 </a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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PIK3CA
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/171834"> 171834 </a>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/619538" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<span class="sr-only">Toggle Dropdown</span>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS116860" class="btn btn-info" role="button"> Phenotypic Series </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/619538" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/619538" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Somatic mutation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/124975008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">124975008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866227&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866227</a>, <a href="https://bioportal.bioontology.org/search?q=C0544886&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0544886</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> NEUROLOGIC </strong>
|
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</span>
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<em> Central Nervous System </em>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
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|
|
- Cerebral cavernous malformations <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/444869007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">444869007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2919945&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2919945</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033522" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033522</a>]</span><br /> -
|
|
Intracranial vascular lesions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5563462&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5563462</a>]</span><br /> -
|
|
Intracranial bleeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1386000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1386000</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/432.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">432.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151699&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151699</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002170" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002170</a>]</span><br /> -
|
|
Focal neurologic signs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848821&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848821</a>]</span><br />
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</span>
|
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</div>
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Adult onset <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853562&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853562</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003581</a>]</span><br />
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|
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</span>
|
|
</div>
|
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|
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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> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the phosphatidylinositol 3-kinase, catalytic, alpha gene (PIK3CA, <a href="/entry/171834#0001">171834.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
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|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
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|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Cerebral cavernous malformations
|
|
- <a href="/phenotypicSeries/PS116860">PS116860</a>
|
|
- 7 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/3/842?start=-3&limit=10&highlight=842"> 3q26.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603285"> Cerebral cavernous malformations-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/603285"> 603285 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609118"> PDCD10 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609118"> 609118 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/876?start=-3&limit=10&highlight=876"> 3q26.32 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619538"> Cerebral cavernous malformations 4, 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/619538"> 619538 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/171834"> PIK3CA </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/171834"> 171834 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/243?start=-3&limit=10&highlight=243"> 7p13 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603284"> Cerebral cavernous malformations-2 </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/603284"> 603284 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607929"> CCM2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607929"> 607929 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/406?start=-3&limit=10&highlight=406"> 7q21.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/116860"> Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations </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/116860"> 116860 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604214"> KRIT1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604214"> 604214 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/406?start=-3&limit=10&highlight=406"> 7q21.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/116860"> Cavernous malformations of CNS and retina </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/116860"> 116860 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604214"> KRIT1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604214"> 604214 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/406?start=-3&limit=10&highlight=406"> 7q21.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/116860"> Cerebral cavernous malformations-1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
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<p>A number sign (#) is used with this entry because of evidence that cerebral cavernous malformations-4 (CCM4) is caused by somatic mutation in the PIK3CA gene (<a href="/entry/171834">171834</a>) on chromosome 3q26.</p>
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<p>Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system that are composed of abnormally enlarged capillary cavities without intervening brain parenchyma. CCMs manifest primarily as subclinical bleeding, but can also lead to seizures and hemorrhagic stroke with substantial neurologic complications, especially when localized in the brainstem. More than 80% of CCMs occur sporadically (summary by <a href="#2" class="mim-tip-reference" title="Peyre, M., Miyagishima, D., Bielle, F., Chapon, F., Sierant, M., Venot, Q., Lerond, J., Marijon, P., Abi-Jaoude, S., Le Van, T., Labreche, K., Houlston, R., Faisant, M., Clemenceau, S., Boch, A.-L., Nouet, A., Carpentier, A., Boetto, J., Louvi, A., Kalamarides, M. <strong>Somatic PIK3CA mutations in sporadic cerebral cavernous malformations.</strong> New Eng. J. Med. 385: 996-1004, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34496175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34496175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34496175[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/10.1056/NEJMoa2100440" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34496175">Peyre et al., 2021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34496175" 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 phenotypic description and discussion of genetic heterogeneity of cerebral cavernous malformations, see CCM1 (<a href="/entry/116860">116860</a>).</p>
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<p><a href="#2" class="mim-tip-reference" title="Peyre, M., Miyagishima, D., Bielle, F., Chapon, F., Sierant, M., Venot, Q., Lerond, J., Marijon, P., Abi-Jaoude, S., Le Van, T., Labreche, K., Houlston, R., Faisant, M., Clemenceau, S., Boch, A.-L., Nouet, A., Carpentier, A., Boetto, J., Louvi, A., Kalamarides, M. <strong>Somatic PIK3CA mutations in sporadic cerebral cavernous malformations.</strong> New Eng. J. Med. 385: 996-1004, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34496175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34496175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34496175[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/10.1056/NEJMoa2100440" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34496175">Peyre et al. (2021)</a> reported 34 unrelated adult patients with CCMs who had no family history of the disorder, suggesting sporadic occurrence. Clinical details were limited, but the CCMs occurred in various brain regions, including the cerebellum and brainstem. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34496175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 34 (39%) of 88 sporadic CCM samples, <a href="#2" class="mim-tip-reference" title="Peyre, M., Miyagishima, D., Bielle, F., Chapon, F., Sierant, M., Venot, Q., Lerond, J., Marijon, P., Abi-Jaoude, S., Le Van, T., Labreche, K., Houlston, R., Faisant, M., Clemenceau, S., Boch, A.-L., Nouet, A., Carpentier, A., Boetto, J., Louvi, A., Kalamarides, M. <strong>Somatic PIK3CA mutations in sporadic cerebral cavernous malformations.</strong> New Eng. J. Med. 385: 996-1004, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34496175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34496175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34496175[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/10.1056/NEJMoa2100440" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34496175">Peyre et al. (2021)</a> identified 1 of 3 somatic missense mutations in the PIK3CA gene (H1047R, <a href="/entry/171834#0001">171834.0001</a>; H1047L, <a href="/entry/171834#0002">171834.0002</a>; and E542K, <a href="/entry/171834#0009">171834.0009</a>). The mutations were found by targeted DNA sequencing after studies in mice suggested that Pik3ca mutations can lead to CCM formation (see ANIMAL MODEL). Four of the samples with PIK3CA mutations also had mutations in the CCM-related genes CCM1 (KRIT1; <a href="/entry/604214">604214</a>), CCM2 (<a href="/entry/607929">607929</a>), and AKT1 (<a href="/entry/164730">164730</a>). The authors noted that cooccurrence of mutations is frequently seen in tumors. PIK3CA-mutant CCMs in humans and mice showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with activating mutations. <a href="#2" class="mim-tip-reference" title="Peyre, M., Miyagishima, D., Bielle, F., Chapon, F., Sierant, M., Venot, Q., Lerond, J., Marijon, P., Abi-Jaoude, S., Le Van, T., Labreche, K., Houlston, R., Faisant, M., Clemenceau, S., Boch, A.-L., Nouet, A., Carpentier, A., Boetto, J., Louvi, A., Kalamarides, M. <strong>Somatic PIK3CA mutations in sporadic cerebral cavernous malformations.</strong> New Eng. J. Med. 385: 996-1004, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34496175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34496175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34496175[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/10.1056/NEJMoa2100440" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34496175">Peyre et al. (2021)</a> noted that the incidence of activating mutations in the PIK3CA gene in sporadic CCMs far exceeds that of mutations in CCM1, CCM2, or CCM3, all of which cause familial disease. PIK3CA mutations were not observed in 11 samples of arteriovenous malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34496175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="mim-changed mim-change"><p><a href="#1" class="mim-tip-reference" title="Hong, T., Xiao, X., Ren, J., Cui, B., Zong, Y., Zou, J., Kou, Z., Jiang, N., Meng, G., Zeng, G., Shan, Y., Wu, H., and 12 others. <strong>Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations.</strong> Brain 144: 2648-2658, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33729480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33729480</a>] [<a href="https://doi.org/10.1093/brain/awab117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33729480">Hong et al. (2021)</a> identified a somatic mutation in the MAP3K3 gene (I441M; <a href="/entry/602359#0001">602359.0001</a>) in 41 patients and a somatic mutation (C420R, E542K, E545K or H1047R) in the PIK3CA gene in 45 patients. Fourteen of the patients had somatic mutations in both MAP3K3 and PIK3CA. The mutations were identified by whole-exome sequencing and digital droplet PCR. The PIK3CA mutation frequencies ranged from 0.4% to 24.4% in the CCM tissue. Single cell RNA sequencing was performed in tissue from 2 CCMs with MAP3K3 mutations, 3 CCMs with PIK3CA mutations, and 1 CCM with mutations in both genes. CCMs with only PIK3CA mutations demonstrated downregulated apoptosis and increased expression of SERPINA5 and GDF15 compared to the CCMs with MAP3K3 mutations or both MAP3K3 and PIK3CA mutations. <a href="#1" class="mim-tip-reference" title="Hong, T., Xiao, X., Ren, J., Cui, B., Zong, Y., Zou, J., Kou, Z., Jiang, N., Meng, G., Zeng, G., Shan, Y., Wu, H., and 12 others. <strong>Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations.</strong> Brain 144: 2648-2658, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33729480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33729480</a>] [<a href="https://doi.org/10.1093/brain/awab117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33729480">Hong et al. (2021)</a> hypothesized that PIK3CA mutations in CCM tissue may lead to increased vascular stress, endothelial dysfunction, and hemorrhagic risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33729480" 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></div>
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<div class="mim-changed mim-change"><p><a href="#1" class="mim-tip-reference" title="Hong, T., Xiao, X., Ren, J., Cui, B., Zong, Y., Zou, J., Kou, Z., Jiang, N., Meng, G., Zeng, G., Shan, Y., Wu, H., and 12 others. <strong>Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations.</strong> Brain 144: 2648-2658, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33729480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33729480</a>] [<a href="https://doi.org/10.1093/brain/awab117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33729480">Hong et al. (2021)</a> compared clinical characteristics between CCMs with somatic mutations in the MAP3K3 gene, PIK3CA gene, or in both genes. CCMs with mutations in only the PIK3CA gene were more likely to be overtly hemorrhagic and were significantly larger compared to the CCMs with mutations in the MAP3K3 gene or in both genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33729480" 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></div>
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<p><a href="#2" class="mim-tip-reference" title="Peyre, M., Miyagishima, D., Bielle, F., Chapon, F., Sierant, M., Venot, Q., Lerond, J., Marijon, P., Abi-Jaoude, S., Le Van, T., Labreche, K., Houlston, R., Faisant, M., Clemenceau, S., Boch, A.-L., Nouet, A., Carpentier, A., Boetto, J., Louvi, A., Kalamarides, M. <strong>Somatic PIK3CA mutations in sporadic cerebral cavernous malformations.</strong> New Eng. J. Med. 385: 996-1004, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34496175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34496175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34496175[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/10.1056/NEJMoa2100440" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34496175">Peyre et al. (2021)</a> found that mutant mice selectively expressing the Pik3ca H1047R mutation in PGDS (<a href="/entry/602598">602598</a>)-expressing cells developed intraparenchymal CCM lesions, most of which were localized to the brainstem. Histologically, the lesions ranged from intraparenchymal vessel dilatations to capillary telangiectasia and the formation of young cavernous lesions. A subset of mice developed meningothelial proliferations. <a href="#2" class="mim-tip-reference" title="Peyre, M., Miyagishima, D., Bielle, F., Chapon, F., Sierant, M., Venot, Q., Lerond, J., Marijon, P., Abi-Jaoude, S., Le Van, T., Labreche, K., Houlston, R., Faisant, M., Clemenceau, S., Boch, A.-L., Nouet, A., Carpentier, A., Boetto, J., Louvi, A., Kalamarides, M. <strong>Somatic PIK3CA mutations in sporadic cerebral cavernous malformations.</strong> New Eng. J. Med. 385: 996-1004, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34496175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34496175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34496175[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/10.1056/NEJMoa2100440" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34496175">Peyre et al. (2021)</a> noted that PGDS is expressed in pericytes surrounding intraparenchymal vessels, which is consistent with it being the most likely cell of origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34496175" 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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Hong, T., Xiao, X., Ren, J., Cui, B., Zong, Y., Zou, J., Kou, Z., Jiang, N., Meng, G., Zeng, G., Shan, Y., Wu, H., and 12 others.
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<strong>Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations.</strong>
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Brain 144: 2648-2658, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33729480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33729480</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33729480" 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/10.1093/brain/awab117" target="_blank">Full Text</a>]
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Peyre, M., Miyagishima, D., Bielle, F., Chapon, F., Sierant, M., Venot, Q., Lerond, J., Marijon, P., Abi-Jaoude, S., Le Van, T., Labreche, K., Houlston, R., Faisant, M., Clemenceau, S., Boch, A.-L., Nouet, A., Carpentier, A., Boetto, J., Louvi, A., Kalamarides, M.
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<strong>Somatic PIK3CA mutations in sporadic cerebral cavernous malformations.</strong>
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New Eng. J. Med. 385: 996-1004, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34496175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34496175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34496175[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=34496175" 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/10.1056/NEJMoa2100440" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 12/20/2024
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Cassandra L. Kniffin : 09/23/2021
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carol : 12/20/2024
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alopez : 10/05/2021<br>ckniffin : 09/27/2021
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<strong>ORPHA:</strong> 221061;
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3q26.32
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Cerebral cavernous malformations 4, somatic
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PIK3CA
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171834
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<p>A number sign (#) is used with this entry because of evidence that cerebral cavernous malformations-4 (CCM4) is caused by somatic mutation in the PIK3CA gene (171834) on chromosome 3q26.</p>
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<p>Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system that are composed of abnormally enlarged capillary cavities without intervening brain parenchyma. CCMs manifest primarily as subclinical bleeding, but can also lead to seizures and hemorrhagic stroke with substantial neurologic complications, especially when localized in the brainstem. More than 80% of CCMs occur sporadically (summary by Peyre et al., 2021). </p><p>For a phenotypic description and discussion of genetic heterogeneity of cerebral cavernous malformations, see CCM1 (116860).</p>
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<p>Peyre et al. (2021) reported 34 unrelated adult patients with CCMs who had no family history of the disorder, suggesting sporadic occurrence. Clinical details were limited, but the CCMs occurred in various brain regions, including the cerebellum and brainstem. </p>
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<p>In 34 (39%) of 88 sporadic CCM samples, Peyre et al. (2021) identified 1 of 3 somatic missense mutations in the PIK3CA gene (H1047R, 171834.0001; H1047L, 171834.0002; and E542K, 171834.0009). The mutations were found by targeted DNA sequencing after studies in mice suggested that Pik3ca mutations can lead to CCM formation (see ANIMAL MODEL). Four of the samples with PIK3CA mutations also had mutations in the CCM-related genes CCM1 (KRIT1; 604214), CCM2 (607929), and AKT1 (164730). The authors noted that cooccurrence of mutations is frequently seen in tumors. PIK3CA-mutant CCMs in humans and mice showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with activating mutations. Peyre et al. (2021) noted that the incidence of activating mutations in the PIK3CA gene in sporadic CCMs far exceeds that of mutations in CCM1, CCM2, or CCM3, all of which cause familial disease. PIK3CA mutations were not observed in 11 samples of arteriovenous malformations. </p><p>Hong et al. (2021) identified a somatic mutation in the MAP3K3 gene (I441M; 602359.0001) in 41 patients and a somatic mutation (C420R, E542K, E545K or H1047R) in the PIK3CA gene in 45 patients. Fourteen of the patients had somatic mutations in both MAP3K3 and PIK3CA. The mutations were identified by whole-exome sequencing and digital droplet PCR. The PIK3CA mutation frequencies ranged from 0.4% to 24.4% in the CCM tissue. Single cell RNA sequencing was performed in tissue from 2 CCMs with MAP3K3 mutations, 3 CCMs with PIK3CA mutations, and 1 CCM with mutations in both genes. CCMs with only PIK3CA mutations demonstrated downregulated apoptosis and increased expression of SERPINA5 and GDF15 compared to the CCMs with MAP3K3 mutations or both MAP3K3 and PIK3CA mutations. Hong et al. (2021) hypothesized that PIK3CA mutations in CCM tissue may lead to increased vascular stress, endothelial dysfunction, and hemorrhagic risk. </p>
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<p>Hong et al. (2021) compared clinical characteristics between CCMs with somatic mutations in the MAP3K3 gene, PIK3CA gene, or in both genes. CCMs with mutations in only the PIK3CA gene were more likely to be overtly hemorrhagic and were significantly larger compared to the CCMs with mutations in the MAP3K3 gene or in both genes. </p>
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<p>Peyre et al. (2021) found that mutant mice selectively expressing the Pik3ca H1047R mutation in PGDS (602598)-expressing cells developed intraparenchymal CCM lesions, most of which were localized to the brainstem. Histologically, the lesions ranged from intraparenchymal vessel dilatations to capillary telangiectasia and the formation of young cavernous lesions. A subset of mice developed meningothelial proliferations. Peyre et al. (2021) noted that PGDS is expressed in pericytes surrounding intraparenchymal vessels, which is consistent with it being the most likely cell of origin. </p>
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<strong>REFERENCES</strong>
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Hong, T., Xiao, X., Ren, J., Cui, B., Zong, Y., Zou, J., Kou, Z., Jiang, N., Meng, G., Zeng, G., Shan, Y., Wu, H., and 12 others.
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<strong>Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations.</strong>
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Brain 144: 2648-2658, 2021.
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[PubMed: 33729480]
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[Full Text: https://doi.org/10.1093/brain/awab117]
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Peyre, M., Miyagishima, D., Bielle, F., Chapon, F., Sierant, M., Venot, Q., Lerond, J., Marijon, P., Abi-Jaoude, S., Le Van, T., Labreche, K., Houlston, R., Faisant, M., Clemenceau, S., Boch, A.-L., Nouet, A., Carpentier, A., Boetto, J., Louvi, A., Kalamarides, M.
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<strong>Somatic PIK3CA mutations in sporadic cerebral cavernous malformations.</strong>
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New Eng. J. Med. 385: 996-1004, 2021.
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[PubMed: 34496175]
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[Full Text: https://doi.org/10.1056/NEJMoa2100440]
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Hilary J. Vernon - updated : 12/20/2024
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carol : 12/20/2024<br>alopez : 10/05/2021<br>ckniffin : 09/27/2021
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