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<title>
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Entry
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- #108010 - ARTERIOVENOUS MALFORMATIONS OF THE BRAIN
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- OMIM
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<span class="h4">#108010</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/108010"><strong>Clinical Synopsis</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="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular 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://clinicaltrials.gov/search?cond=(ARTERIOVENOUS MALFORMATIONS OF THE BRAIN) OR (KRAS OR IL6)" 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=10604&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.diseaseinfosearch.org/x/3852" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=108010[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=46724" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0060688" 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/108010" 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://wormbase.org/resources/disease/DOID:0060688" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="small">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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</span>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:108010" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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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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<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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|
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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|
|
<strong>SNOMEDCT:</strong> 234142008<br />
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<strong>ICD10CM:</strong> Q28.2<br />
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<strong>ORPHA:</strong> 46724<br />
|
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|
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<strong>DO:</strong> 0060688<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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108010
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</span>
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</span>
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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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ARTERIOVENOUS MALFORMATIONS OF THE BRAIN
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BAVM<br />
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CEREBRAL ARTERIOVENOUS MALFORMATIONS
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Other entities represented in this entry:
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INTRACRANIAL HEMORRHAGE IN BRAIN ARTERIOVENOUS MALFORMATIONS, SUSCEPTIBILITY TO, INCLUDED
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<tbody>
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<span class="mim-font">
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<a href="/geneMap/7/108?start=-3&limit=10&highlight=108">
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7p15.3
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<span class="mim-font">
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{Intracranial hemorrhage in brain cerebrovascular malformations, susceptibility to}
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</td>
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<span class="mim-font">
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<a href="/entry/108010"> 108010 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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IL6
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<span class="mim-font">
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<a href="/entry/147620"> 147620 </a>
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<span class="mim-font">
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<a href="/geneMap/12/240?start=-3&limit=10&highlight=240">
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12p12.1
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</a>
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<span class="mim-font">
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Arteriovenous malformation of the brain, somatic
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<span class="mim-font">
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<a href="/entry/108010"> 108010 </a>
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<span class="mim-font">
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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KRAS
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<span class="mim-font">
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<a href="/entry/190070"> 190070 </a>
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/108010" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/108010" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<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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<p />
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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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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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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 class="h5 mim-font">
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<strong> CARDIOVASCULAR </strong>
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<div style="margin-left: 2em;">
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<span class="h5 mim-font">
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<em> Vascular </em>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Cerebral arteriovenous malformation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/234142008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">234142008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q28.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q28.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0917804&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0917804</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002408" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002408</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002408" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002408</a>]</span><br />
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<strong> MOLECULAR BASIS </strong>
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<span class="mim-font">
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- Caused by somatic mutation in the KRAS protooncogene, GTPase, gene (KRAS, <a href="/entry/190070#0025">190070.0025</a>)<br />
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</span>
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of the occurrence of cerebral arteriovenous malformations in several genetic disorders including hereditary hemorrhagic telangiectasia (HHT; <a href="/entry/187300">187300</a>) and hereditary neurocutaneous angioma (<a href="/entry/106070">106070</a>). A promoter polymorphism in the IL6 gene (<a href="/entry/147620">147620</a>) is associated with susceptibility to intracranial hemorrhage in brain arteriovenous malformations. Somatic activating mutations in the KRAS gene (<a href="/entry/190070">190070</a>) have been identified as a cause of arteriovenous malformations of the brain.</p>
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</span>
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<div>
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<br />
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<p>Arteriovenous malformations of the brain are tortuous, morphologically abnormal vascular channels between arteries and veins that lack an intervening capillary network, allowing high-pressure arterial blood from feeding arteries to shunt directly into the venous outflow system. These vascular malformations occur in approximately 15 per 100,000 persons and are a leading cause of hemorrhagic stroke in young adults and children (summary by <a href="#6" class="mim-tip-reference" title="Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others. <strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong> New Eng. J. Med. 378: 250-261, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>] [<a href="https://doi.org/10.1056/NEJMoa1709449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29298116">Nikolaev et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29298116" 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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<br />
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Clinical Features</strong>
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<p>Cerebral arteriovenous malformations are considered to be distinct from cerebral cavernous malformations (<a href="/entry/116860">116860</a>), which are venous and usually arteriographically 'silent' (<a href="#8" class="mim-tip-reference" title="Rigamonti, D. <strong>Personal Communication.</strong> Baltimore, Md. 9/15/1993."None>Rigamonti, 1993</a>).</p><p><a href="#9" class="mim-tip-reference" title="Snead, O. C., III, Acker, J. D., Morawetz, R. <strong>Familial arteriovenous malformation.</strong> Ann. Neurol. 5: 585-587, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/475353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">475353</a>] [<a href="https://doi.org/10.1002/ana.410050617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="475353">Snead et al. (1979)</a> reported cerebral arteriovenous malformations in 3 sibs with the same mother. Two were by one father and the third by another. HHT and von Hippel-Lindau disease were excluded. They found reports of 4 instances of familial aggregation. <a href="#1" class="mim-tip-reference" title="Aberfeld, D. C., Rao, K. R. <strong>Familial arteriovenous malformation of the brain.</strong> Neurology 31: 184-186, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7193302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7193302</a>] [<a href="https://doi.org/10.1212/wnl.31.2.184" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7193302">Aberfeld and Rao (1981)</a> reported affected brother and sister. <a href="#10" class="mim-tip-reference" title="Yokoyama, K., Asano, Y., Murakawa, T., Takada, M., Ando, T., Sakai, N., Yamada, H., Iwata, H. <strong>Familial occurrence of arteriovenous malformation of the brain.</strong> J. Neurosurg. 74: 585-589, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2002372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2002372</a>] [<a href="https://doi.org/10.3171/jns.1991.74.4.0585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2002372">Yokoyama et al. (1991)</a> described 6 cases in 3 families. These included a father-son pair, a mother-son pair, and male and female first cousins. They commented on the report by <a href="#2" class="mim-tip-reference" title="Boyd, M. C., Steinbok, P., Paty, D. W. <strong>Familial arteriovenous malformations: report of four cases in one family.</strong> J. Neurosurg. 62: 597-599, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3973731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3973731</a>] [<a href="https://doi.org/10.3171/jns.1985.62.4.0597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3973731">Boyd et al. (1985)</a> of affected father and 3 sons and another father and daughter combination. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3973731+475353+2002372+7193302" 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="#3" class="mim-tip-reference" title="Chen, Y., Hao, Q., Kim, H., Su, H., Letarte, M., Karumanchi, S. A., Lawton, M. T., Barbaro, N. M., Yang, G.-Y., Young, W. L. <strong>Soluble endoglin modulates aberrant cerebral vascular remodeling.</strong> Ann. Neurol. 66: 19-27, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19670444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19670444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19670444[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/10.1002/ana.21710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19670444">Chen et al. (2009)</a> found increased levels of soluble endoglin (ENG; <a href="/entry/131195">131195</a>) in vascular surgical specimens from 33 patients with arteriovenous malformations of the brain compared to similar specimens from 8 epileptic patients. However, there was no difference in expression of membrane-bound endoglin and no difference in plasma soluble endoglin between BAVM patients and controls. Transduction of soluble endoglin in mouse brain resulted in the formation of abnormal and dysplastic capillary structures, and was associated with increased levels of matrix metalloproteinase activity and oxidative radicals. <a href="#3" class="mim-tip-reference" title="Chen, Y., Hao, Q., Kim, H., Su, H., Letarte, M., Karumanchi, S. A., Lawton, M. T., Barbaro, N. M., Yang, G.-Y., Young, W. L. <strong>Soluble endoglin modulates aberrant cerebral vascular remodeling.</strong> Ann. Neurol. 66: 19-27, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19670444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19670444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19670444[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/10.1002/ana.21710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19670444">Chen et al. (2009)</a> suggested that soluble endoglin may play a role in the formation of sporadic BAVM by acting as a decoy receptor, resulting in inhibition of TGF-beta (TGFB1; <a href="/entry/190180">190180</a>) signaling and functional haploinsufficiency of ENG, as observed in patients with hereditary hemorrhagic telangiectasia-1 (HHT1; <a href="/entry/187300">187300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19670444" 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><strong><em>Association with IL6 Promoter Polymorphism</em></strong></p><p>
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Among 180 patients with brain arteriovenous malformations (BAVM), <a href="#7" class="mim-tip-reference" title="Pawlikowska, L., Tran, M. N., Achrol, A. S., McCulloch, C. E., Ha, C., Lind, D. L., Hashimoto, T., Zaroff, J., Lawton, M. T., Marchuk, D. A., Kwok, P.-Y., Young, W. L., UCSF BAVM Study Project. <strong>Polymorphisms in genes involved in inflammatory and angiogenic pathways and the risk of hemorrhagic presentation of brain arteriovenous malformations.</strong> Stroke 35: 2294-2299, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15331795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15331795</a>] [<a href="https://doi.org/10.1161/01.STR.0000141932.44613.b1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15331795">Pawlikowska et al. (2004)</a> found an association between a promoter polymorphism in the IL6 gene (-174G/C; <a href="/entry/147620#0001">147620.0001</a>) and intracranial hemorrhage. Patients who were homozygous for the G allele had an increased risk intracranial bleed (odds ratio of 2.62) compared to carriers of the C allele. In brain tissue from patients with BAVM, <a href="#4" class="mim-tip-reference" title="Chen, Y., Pawlikowska, L., Yao, J. S., Shen, F., Zhai, W., Achrol, A. S., Lawton, M. T., Kwok, P.-Y., Yang, G.-Y., Young, W. L. <strong>Interleukin-6 involvement in brain arteriovenous malformations.</strong> Ann. Neurol. 59: 72-80, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278864</a>] [<a href="https://doi.org/10.1002/ana.20697" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16278864">Chen et al. (2006)</a> found that the highest IL6 protein and mRNA levels were associated with the IL6 -174GG genotype compared to the GC and CC genotypes. IL6 protein levels were increased in BAVM tissue from patients with hemorrhagic presentation compared to those without hemorrhage. In vivo studies demonstrated that IL6 enhanced expression and activity of IL1B (<a href="/entry/147720">147720</a>), TNFA (<a href="/entry/191160">191160</a>), IL8 (<a href="/entry/146930">146930</a>), and several matrix metalloproteinases, MMP3 (<a href="/entry/185250">185250</a>), MMP9 (<a href="/entry/120361">120361</a>), and MMP12 (<a href="/entry/601046">601046</a>). IL6 also increased proliferation and migration of cultured human cerebral endothelial cells. <a href="#4" class="mim-tip-reference" title="Chen, Y., Pawlikowska, L., Yao, J. S., Shen, F., Zhai, W., Achrol, A. S., Lawton, M. T., Kwok, P.-Y., Yang, G.-Y., Young, W. L. <strong>Interleukin-6 involvement in brain arteriovenous malformations.</strong> Ann. Neurol. 59: 72-80, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278864</a>] [<a href="https://doi.org/10.1002/ana.20697" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16278864">Chen et al. (2006)</a> suggested that IL6 expression may modulate downstream inflammatory and angiogenic targets that contribute to intracranial hemorrhage in BAVMs. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15331795+16278864" 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>Somatic Mutation in KRAS</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others. <strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong> New Eng. J. Med. 378: 250-261, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>] [<a href="https://doi.org/10.1056/NEJMoa1709449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29298116">Nikolaev et al. (2018)</a> analyzed tissue and blood samples from patients with BAVM to detect somatic mutations. They performed exome DNA sequencing of tissue samples of BAVM from 26 patients in the main study group and of paired blood samples from 17 of these patients, and confirmed their findings using droplet digital PCR analysis of tissue samples from 39 patients in the initial study group (21 of whom had matching blood samples) and from 33 patients in an independent validation group. <a href="#6" class="mim-tip-reference" title="Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others. <strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong> New Eng. J. Med. 378: 250-261, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>] [<a href="https://doi.org/10.1056/NEJMoa1709449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29298116">Nikolaev et al. (2018)</a> detected somatic activating KRAS mutations gly12 to asp (<a href="/entry/190070#0025">190070.0025</a>) and gly12 to val (<a href="/entry/190070#0026">190070.0026</a>) in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from BAVM, <a href="#6" class="mim-tip-reference" title="Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others. <strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong> New Eng. J. Med. 378: 250-261, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>] [<a href="https://doi.org/10.1056/NEJMoa1709449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29298116">Nikolaev et al. (2018)</a> detected KRAS mutations and observed that expression of mutant KRAS (KRAS G12V) in endothelial cells in vitro induced increased ERK activity, increased expression of genes related to angiogenesis and Notch (<a href="/entry/190198">190198</a>) signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK-ERK signaling (see <a href="/entry/176872">176872</a>). <a href="#6" class="mim-tip-reference" title="Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others. <strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong> New Eng. J. Med. 378: 250-261, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>] [<a href="https://doi.org/10.1056/NEJMoa1709449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29298116">Nikolaev et al. (2018)</a> concluded that they identified activating KRAS mutations in the majority of BAVM tissue samples that were analyzed, and proposed that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain epithelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29298116" 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="#5" class="mim-tip-reference" title="Murphy, P. A., Lam, M. T. Y., Wu, X., Kim, T. N., Vartanian, S. M., Bollen, A. W., Carlson, T. R., Wang, R. A. <strong>Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice.</strong> Proc. Nat. Acad. Sci. 105: 10901-10906, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18667694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18667694</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18667694[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/10.1073/pnas.0802743105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18667694">Murphy et al. (2008)</a> found that mice with constitutively active Notch4 (<a href="/entry/164951">164951</a>) expression in endothelial cells from birth developed hallmarks of brain arteriovenous malformations by 3 weeks of age, including cerebral arteriovenous shunting and vessel enlargement. Most died by 5 weeks of age. Approximately 25% of the mutant mice showed signs of neurologic dysfunction, including ataxia and seizures. Imaging studies detected cerebral arteriovenous malformations. Repression of Notch4 resolved ataxia and reversed the disease progression, demonstrating that Notch4 is not only sufficient to induce but also required to sustain the disease. Postmortem examination showed hemorrhage and neuronal cell death within the cerebral cortex and cerebellum, as well as widespread enlargement of the cerebral microvasculature, which coincided with a reduction in capillary density. These findings suggested that vessel enlargement underlies the development of BAVM and linked this pathology to the known function of the NOTCH pathway as an inhibitor of vessel sprouting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18667694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Familial arteriovenous malformation of the brain.</strong>
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Neurology 31: 184-186, 1981.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7193302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7193302</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7193302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Familial arteriovenous malformations: report of four cases in one family.</strong>
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J. Neurosurg. 62: 597-599, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3973731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3973731</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3973731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Chen, Y., Hao, Q., Kim, H., Su, H., Letarte, M., Karumanchi, S. A., Lawton, M. T., Barbaro, N. M., Yang, G.-Y., Young, W. L.
|
|
<strong>Soluble endoglin modulates aberrant cerebral vascular remodeling.</strong>
|
|
Ann. Neurol. 66: 19-27, 2009.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19670444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19670444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19670444[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=19670444" 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/ana.21710" 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="4" class="mim-anchor"></a>
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<a id="Chen2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Chen, Y., Pawlikowska, L., Yao, J. S., Shen, F., Zhai, W., Achrol, A. S., Lawton, M. T., Kwok, P.-Y., Yang, G.-Y., Young, W. L.
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|
<strong>Interleukin-6 involvement in brain arteriovenous malformations.</strong>
|
|
Ann. Neurol. 59: 72-80, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278864</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16278864" 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/ana.20697" 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="5" class="mim-anchor"></a>
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<a id="Murphy2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Murphy, P. A., Lam, M. T. Y., Wu, X., Kim, T. N., Vartanian, S. M., Bollen, A. W., Carlson, T. R., Wang, R. A.
|
|
<strong>Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice.</strong>
|
|
Proc. Nat. Acad. Sci. 105: 10901-10906, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18667694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18667694</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18667694[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=18667694" 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/10.1073/pnas.0802743105" 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="6" class="mim-anchor"></a>
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<a id="Nikolaev2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others.
|
|
<strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong>
|
|
New Eng. J. Med. 378: 250-261, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29298116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29298116</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29298116" 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/NEJMoa1709449" 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="7" class="mim-anchor"></a>
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<a id="Pawlikowska2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Pawlikowska, L., Tran, M. N., Achrol, A. S., McCulloch, C. E., Ha, C., Lind, D. L., Hashimoto, T., Zaroff, J., Lawton, M. T., Marchuk, D. A., Kwok, P.-Y., Young, W. L., UCSF BAVM Study Project.
|
|
<strong>Polymorphisms in genes involved in inflammatory and angiogenic pathways and the risk of hemorrhagic presentation of brain arteriovenous malformations.</strong>
|
|
Stroke 35: 2294-2299, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15331795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15331795</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15331795" 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/10.1161/01.STR.0000141932.44613.b1" 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="8" class="mim-anchor"></a>
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<a id="Rigamonti1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Rigamonti, D.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 9/15/1993.
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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="9" class="mim-anchor"></a>
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<a id="Snead1979" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Snead, O. C., III, Acker, J. D., Morawetz, R.
|
|
<strong>Familial arteriovenous malformation.</strong>
|
|
Ann. Neurol. 5: 585-587, 1979.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/475353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">475353</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=475353" 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/ana.410050617" 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="10" class="mim-anchor"></a>
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<a id="Yokoyama1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yokoyama, K., Asano, Y., Murakawa, T., Takada, M., Ando, T., Sakai, N., Yamada, H., Iwata, H.
|
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<strong>Familial occurrence of arteriovenous malformation of the brain.</strong>
|
|
J. Neurosurg. 74: 585-589, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2002372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2002372</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2002372" 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/10.3171/jns.1991.74.4.0585" target="_blank">Full Text</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">
|
|
Ada Hamosh - updated : 03/06/2018
|
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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 : 1/25/2011<br>Cassandra L. Kniffin - updated : 5/28/2009<br>Cassandra L. Kniffin - updated : 4/13/2006<br>Victor A. McKusick - updated : 2/7/2000
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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 : 8/5/1991
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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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alopez : 02/04/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="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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alopez : 03/06/2018<br>wwang : 02/17/2011<br>ckniffin : 1/25/2011<br>wwang : 6/5/2009<br>ckniffin : 5/28/2009<br>mgross : 7/25/2008<br>terry : 11/3/2006<br>wwang : 4/19/2006<br>ckniffin : 4/13/2006<br>carol : 2/7/2000<br>terry : 4/30/1999<br>mimadm : 4/9/1994<br>supermim : 3/16/1992<br>carol : 8/5/1991
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</span>
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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 class="row">
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<div class="col-md-8 col-md-offset-1">
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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> 108010
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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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ARTERIOVENOUS MALFORMATIONS OF THE BRAIN
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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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<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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BAVM<br />
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CEREBRAL ARTERIOVENOUS MALFORMATIONS
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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">
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|
INTRACRANIAL HEMORRHAGE IN BRAIN ARTERIOVENOUS MALFORMATIONS, SUSCEPTIBILITY TO, 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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 234142008;
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<strong>ICD10CM:</strong> Q28.2;
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<strong>ORPHA:</strong> 46724;
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<strong>DO:</strong> 0060688;
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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">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
|
<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>
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|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
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>
|
|
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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7p15.3
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
{Intracranial hemorrhage in brain cerebrovascular malformations, susceptibility to}
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
108010
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Somatic mutation
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
IL6
|
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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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147620
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</span>
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</td>
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</tr>
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<tr>
|
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<td>
|
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<span class="mim-font">
|
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12p12.1
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Arteriovenous malformation of the brain, somatic
|
|
</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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108010
|
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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">
|
|
3
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
KRAS
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
190070
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<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>TEXT</strong>
|
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</span>
|
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of the occurrence of cerebral arteriovenous malformations in several genetic disorders including hereditary hemorrhagic telangiectasia (HHT; 187300) and hereditary neurocutaneous angioma (106070). A promoter polymorphism in the IL6 gene (147620) is associated with susceptibility to intracranial hemorrhage in brain arteriovenous malformations. Somatic activating mutations in the KRAS gene (190070) have been identified as a cause of arteriovenous malformations of the brain.</p>
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<p>Arteriovenous malformations of the brain are tortuous, morphologically abnormal vascular channels between arteries and veins that lack an intervening capillary network, allowing high-pressure arterial blood from feeding arteries to shunt directly into the venous outflow system. These vascular malformations occur in approximately 15 per 100,000 persons and are a leading cause of hemorrhagic stroke in young adults and children (summary by Nikolaev et al., 2018). </p>
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<strong>Clinical Features</strong>
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<p>Cerebral arteriovenous malformations are considered to be distinct from cerebral cavernous malformations (116860), which are venous and usually arteriographically 'silent' (Rigamonti, 1993).</p><p>Snead et al. (1979) reported cerebral arteriovenous malformations in 3 sibs with the same mother. Two were by one father and the third by another. HHT and von Hippel-Lindau disease were excluded. They found reports of 4 instances of familial aggregation. Aberfeld and Rao (1981) reported affected brother and sister. Yokoyama et al. (1991) described 6 cases in 3 families. These included a father-son pair, a mother-son pair, and male and female first cousins. They commented on the report by Boyd et al. (1985) of affected father and 3 sons and another father and daughter combination. </p>
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<strong>Biochemical Features</strong>
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<p>Chen et al. (2009) found increased levels of soluble endoglin (ENG; 131195) in vascular surgical specimens from 33 patients with arteriovenous malformations of the brain compared to similar specimens from 8 epileptic patients. However, there was no difference in expression of membrane-bound endoglin and no difference in plasma soluble endoglin between BAVM patients and controls. Transduction of soluble endoglin in mouse brain resulted in the formation of abnormal and dysplastic capillary structures, and was associated with increased levels of matrix metalloproteinase activity and oxidative radicals. Chen et al. (2009) suggested that soluble endoglin may play a role in the formation of sporadic BAVM by acting as a decoy receptor, resulting in inhibition of TGF-beta (TGFB1; 190180) signaling and functional haploinsufficiency of ENG, as observed in patients with hereditary hemorrhagic telangiectasia-1 (HHT1; 187300). </p>
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<p><strong><em>Association with IL6 Promoter Polymorphism</em></strong></p><p>
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Among 180 patients with brain arteriovenous malformations (BAVM), Pawlikowska et al. (2004) found an association between a promoter polymorphism in the IL6 gene (-174G/C; 147620.0001) and intracranial hemorrhage. Patients who were homozygous for the G allele had an increased risk intracranial bleed (odds ratio of 2.62) compared to carriers of the C allele. In brain tissue from patients with BAVM, Chen et al. (2006) found that the highest IL6 protein and mRNA levels were associated with the IL6 -174GG genotype compared to the GC and CC genotypes. IL6 protein levels were increased in BAVM tissue from patients with hemorrhagic presentation compared to those without hemorrhage. In vivo studies demonstrated that IL6 enhanced expression and activity of IL1B (147720), TNFA (191160), IL8 (146930), and several matrix metalloproteinases, MMP3 (185250), MMP9 (120361), and MMP12 (601046). IL6 also increased proliferation and migration of cultured human cerebral endothelial cells. Chen et al. (2006) suggested that IL6 expression may modulate downstream inflammatory and angiogenic targets that contribute to intracranial hemorrhage in BAVMs. </p><p><strong><em>Somatic Mutation in KRAS</em></strong></p><p>
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Nikolaev et al. (2018) analyzed tissue and blood samples from patients with BAVM to detect somatic mutations. They performed exome DNA sequencing of tissue samples of BAVM from 26 patients in the main study group and of paired blood samples from 17 of these patients, and confirmed their findings using droplet digital PCR analysis of tissue samples from 39 patients in the initial study group (21 of whom had matching blood samples) and from 33 patients in an independent validation group. Nikolaev et al. (2018) detected somatic activating KRAS mutations gly12 to asp (190070.0025) and gly12 to val (190070.0026) in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from BAVM, Nikolaev et al. (2018) detected KRAS mutations and observed that expression of mutant KRAS (KRAS G12V) in endothelial cells in vitro induced increased ERK activity, increased expression of genes related to angiogenesis and Notch (190198) signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK-ERK signaling (see 176872). Nikolaev et al. (2018) concluded that they identified activating KRAS mutations in the majority of BAVM tissue samples that were analyzed, and proposed that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain epithelial cells. </p>
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<p>Murphy et al. (2008) found that mice with constitutively active Notch4 (164951) expression in endothelial cells from birth developed hallmarks of brain arteriovenous malformations by 3 weeks of age, including cerebral arteriovenous shunting and vessel enlargement. Most died by 5 weeks of age. Approximately 25% of the mutant mice showed signs of neurologic dysfunction, including ataxia and seizures. Imaging studies detected cerebral arteriovenous malformations. Repression of Notch4 resolved ataxia and reversed the disease progression, demonstrating that Notch4 is not only sufficient to induce but also required to sustain the disease. Postmortem examination showed hemorrhage and neuronal cell death within the cerebral cortex and cerebellum, as well as widespread enlargement of the cerebral microvasculature, which coincided with a reduction in capillary density. These findings suggested that vessel enlargement underlies the development of BAVM and linked this pathology to the known function of the NOTCH pathway as an inhibitor of vessel sprouting. </p>
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<strong>REFERENCES</strong>
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Aberfeld, D. C., Rao, K. R.
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<strong>Familial arteriovenous malformation of the brain.</strong>
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Neurology 31: 184-186, 1981.
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[PubMed: 7193302]
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[Full Text: https://doi.org/10.1212/wnl.31.2.184]
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Boyd, M. C., Steinbok, P., Paty, D. W.
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<strong>Familial arteriovenous malformations: report of four cases in one family.</strong>
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J. Neurosurg. 62: 597-599, 1985.
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[PubMed: 3973731]
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[Full Text: https://doi.org/10.3171/jns.1985.62.4.0597]
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Chen, Y., Hao, Q., Kim, H., Su, H., Letarte, M., Karumanchi, S. A., Lawton, M. T., Barbaro, N. M., Yang, G.-Y., Young, W. L.
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<strong>Soluble endoglin modulates aberrant cerebral vascular remodeling.</strong>
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Ann. Neurol. 66: 19-27, 2009.
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[PubMed: 19670444]
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[Full Text: https://doi.org/10.1002/ana.21710]
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Chen, Y., Pawlikowska, L., Yao, J. S., Shen, F., Zhai, W., Achrol, A. S., Lawton, M. T., Kwok, P.-Y., Yang, G.-Y., Young, W. L.
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<strong>Interleukin-6 involvement in brain arteriovenous malformations.</strong>
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Ann. Neurol. 59: 72-80, 2006.
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[PubMed: 16278864]
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[Full Text: https://doi.org/10.1002/ana.20697]
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Murphy, P. A., Lam, M. T. Y., Wu, X., Kim, T. N., Vartanian, S. M., Bollen, A. W., Carlson, T. R., Wang, R. A.
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<strong>Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice.</strong>
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Proc. Nat. Acad. Sci. 105: 10901-10906, 2008.
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[PubMed: 18667694]
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[Full Text: https://doi.org/10.1073/pnas.0802743105]
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Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Rezai Jahromi, B., Khyzha, N., DiStefano, P. V., Suutarinen, S., Kiehl, T.-R., Mendes Pereira, V., Herman, A. M., and 13 others.
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<strong>Somatic activating KRAS mutations in arteriovenous malformations of the brain.</strong>
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New Eng. J. Med. 378: 250-261, 2018.
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[PubMed: 29298116]
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[Full Text: https://doi.org/10.1056/NEJMoa1709449]
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Pawlikowska, L., Tran, M. N., Achrol, A. S., McCulloch, C. E., Ha, C., Lind, D. L., Hashimoto, T., Zaroff, J., Lawton, M. T., Marchuk, D. A., Kwok, P.-Y., Young, W. L., UCSF BAVM Study Project.
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<strong>Polymorphisms in genes involved in inflammatory and angiogenic pathways and the risk of hemorrhagic presentation of brain arteriovenous malformations.</strong>
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Stroke 35: 2294-2299, 2004.
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[PubMed: 15331795]
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[Full Text: https://doi.org/10.1161/01.STR.0000141932.44613.b1]
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Rigamonti, D.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 9/15/1993.
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Snead, O. C., III, Acker, J. D., Morawetz, R.
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<strong>Familial arteriovenous malformation.</strong>
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Ann. Neurol. 5: 585-587, 1979.
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[PubMed: 475353]
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[Full Text: https://doi.org/10.1002/ana.410050617]
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Yokoyama, K., Asano, Y., Murakawa, T., Takada, M., Ando, T., Sakai, N., Yamada, H., Iwata, H.
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<strong>Familial occurrence of arteriovenous malformation of the brain.</strong>
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J. Neurosurg. 74: 585-589, 1991.
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[PubMed: 2002372]
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[Full Text: https://doi.org/10.3171/jns.1991.74.4.0585]
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Ada Hamosh - updated : 03/06/2018<br>Cassandra L. Kniffin - updated : 1/25/2011<br>Cassandra L. Kniffin - updated : 5/28/2009<br>Cassandra L. Kniffin - updated : 4/13/2006<br>Victor A. McKusick - updated : 2/7/2000
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</body>
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</html>
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