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Entry
- #187300 - TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 1; HHT1
- OMIM
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<span class="h4">#187300</span>
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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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<li role="presentation">
<a href="/clinicalSynopsis/187300"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS187300"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#clinicalFeatures">Clinical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#heterogeneity">Heterogeneity</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#history">History</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=187300[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>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=774" 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>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/414d9f5d-a2d3-4d4c-adc8-49d6a4198c37/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:1270" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/187300" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:1270" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:187300" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 21877004<br />
<strong>ICD10CM:</strong> I78.0<br />
<strong>ICD9CM:</strong> 448.0<br />
<strong>ORPHA:</strong> 774<br />
<strong>DO:</strong> 1270<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
187300
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 1; HHT1
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
HHT<br />
TELANGIECTASIA, HEREDITARY HEMORRHAGIC, OF RENDU, OSLER, AND WEBER<br />
OSLER-RENDU-WEBER DISEASE<br />
ORW DISEASE
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/525?start=-3&limit=10&highlight=525">
9q34.11
</a>
</span>
</td>
<td>
<span class="mim-font">
Telangiectasia, hereditary hemorrhagic, type 1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/187300"> 187300 </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">
ENG
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/131195"> 131195 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/187300" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS187300" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/187300" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/187300" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Conjunctival telangiectases <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/231870008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">231870008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239105&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239105</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000524" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000524</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000524" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000524</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Nose </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Spontaneous, recurrent epistaxis (onset childhood) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857695&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857695</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/2571000112102" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">2571000112102</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004406" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004406</a>]</span><br /> -
Nasal mucosa telangiectases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857696&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857696</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Mouth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Lip telangiectases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857697&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857697</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000214" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000214</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000214" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000214</a>]</span><br /> -
Tongue telangiectases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857698&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857698</a>]</span><br /> -
Palate telangiectases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857699&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857699</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002707" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002707</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002707" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002707</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Right-to-left shunt <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/79692001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">79692001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0428871&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0428871</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001694" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001694</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001694" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001694</a>]</span><br /> -
High-output congestive heart failure <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0742747&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0742747</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001722" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001722</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001722" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001722</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Arterial aneurysm <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/233981004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">233981004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0340613&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0340613</a>]</span><br /> -
Venous varicosities <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128060009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128060009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399989005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399989005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12856003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12856003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I83.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I83.90</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042345&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042345</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002619" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002619</a>]</span><br /> -
Arteriovenous fistulas of celiac and mesenteric vessels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857693&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857693</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002642" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002642</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002642" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002642</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Dyspnea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267036007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267036007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230145002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230145002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R06.02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R06.02</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R06.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R06.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R06.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R06.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/786.05" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">786.05</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013404&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013404</a>, <a href="https://bioportal.bioontology.org/search?q=C2024878&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2024878</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002094" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002094</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002094" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002094</a>]</span><br />
</span>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Lung </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pulmonary arteriovenous malformation (PAVM), especially lower lobes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857690&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857690</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006548" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006548</a>]</span><br /> -
Cyanosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/3415004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">3415004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/119419001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">119419001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R23.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R23.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/782.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">782.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0010520&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010520</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000961" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000961</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000961" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000961</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Liver </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cirrhosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/19943007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">19943007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K74.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K74.60</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023890&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023890</a>, <a href="https://bioportal.bioontology.org/search?q=C1623038&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1623038</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001394</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001394" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001394</a>]</span><br /> -
Hepatic arteriovenous malformation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/84150000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">84150000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0520557&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0520557</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006574" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006574</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006574" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006574</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- GI hemorrhage (onset usually in 5th -6th decade) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861247&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861247</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74474003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74474003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K92.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K92.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/578" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">578</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/578.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">578.9</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002239" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002239</a>]</span><br /> -
Angiodysplasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1295237006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1295237006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1290553006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1290553006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/90858003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">90858003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K55.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K55.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085411&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085411</a>, <a href="https://bioportal.bioontology.org/search?q=C0267370&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0267370</a>]</span><br /> -
Telangiectases (stomach, duodenum, small bowel, colon) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838166&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838166</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/247479008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">247479008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/112641009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">112641009</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001009</a>]</span><br /> -
Arteriovenous malformation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/24551003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">24551003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11071001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11071001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/234141001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">234141001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/403966009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">403966009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14156004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14156004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/233982006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">233982006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I77.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I77.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003857&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003857</a>, <a href="https://bioportal.bioontology.org/search?q=C0334533&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0334533</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100026" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100026</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100026" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100026</a>]</span><br /> -
Melena <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/2901004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">2901004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K92.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K92.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0025222&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025222</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002249</a>]</span><br /> -
Hematochezia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405729008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405729008</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/578.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">578.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1321898&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1321898</a>, <a href="https://bioportal.bioontology.org/search?q=C0018932&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018932</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025085" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025085</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002573" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002573</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002573" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002573</a>]</span><br /> -
Hematemesis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8765009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8765009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K92.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K92.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/578.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">578.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018926&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018926</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002248" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002248</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002248" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002248</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Hands </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Nail bed telangiectases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838167&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838167</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001232" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001232</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001232" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001232</a>]</span><br /> -
Finger pad telangiectases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861248&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861248</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006107</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006107</a>]</span><br /> -
Clubbing <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/367004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">367004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0149651&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0149651</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001217" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001217</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001217" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001217</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=88854f443999653cb252ee449dfb6bc5" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Clubbing-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=88854f443999653cb252ee449dfb6bc5&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Telangiectases (especially on tongue, lips, palate, fingers, face, conjunctiva, trunk, nail beds, and fingertips) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857689&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857689</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/247479008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">247479008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/112641009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">112641009</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001009</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- 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 /> -
Migraine headache <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/37796009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">37796009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G43.909" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G43.909</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G43" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G43</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G43.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G43.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/346" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">346</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/346.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">346.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0149931&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0149931</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002076" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002076</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002076" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002076</a>]</span><br /> -
Transient ischemic attack <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/266257000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">266257000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G45.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G45.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0007787&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007787</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002326" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002326</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002326" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002326</a>]</span><br /> -
Ischemic stroke <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422504002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422504002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0948008&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0948008</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002140" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002140</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002140" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002140</a>]</span><br /> -
Seizure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Subarachnoid hemorrhage <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/21454007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">21454007</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/430" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">430</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038525&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038525</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002138" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002138</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002138" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002138</a>]</span><br /> -
Spinal arteriovenous malformation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/261482004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">261482004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0348023&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0348023</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002390" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002390</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002390" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002390</a>]</span><br /> -
Intracerebral hemorrhage <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/274100004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">274100004</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/431" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">431</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2937358&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2937358</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001342" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001342</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001342" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001342</a>]</span><br /> -
Brain abscess <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/60404007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">60404007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/441806004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">441806004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1510428&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1510428</a>, <a href="https://bioportal.bioontology.org/search?q=C0006105&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0006105</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030049" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030049</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030049" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030049</a>]</span><br /> -
Paradoxical cerebral emboli <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861246&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861246</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Polycythemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/127062003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">127062003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/109992005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">109992005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D75.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D75.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0032461&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0032461</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001901" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001901</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001901" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001901</a>]</span><br /> -
Anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271737000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271737000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D64.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D64.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/285.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">285.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002871&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002871</a>, <a href="https://bioportal.bioontology.org/search?q=C1000483&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1000483</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001903" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001903</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001903" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001903</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Definite diagnosis if 3/4 criteria present (epistaxis, telangiectasia, visceral lesion, or family history)<br /> -
Cutaneous telangiectases often not evident until 20-30 years of age<br /> -
Incidence 1 in 5,000-8,000<br /> -
Genetic heterogeneity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242960&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242960</a>]</span><br /> -
PAVMs occur more frequently in hereditary hemorrhagic telangiectasia 1 (HHT1) than HHT2<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the endoglin gene (ENG, <a href="/entry/131195#0001">131195.0001</a>)<br />
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Telangiectasia, hereditary hemorrhagic (see also primary pulmonary hypertension (<a href="/phenotypicSeries/PS178600">PS178600</a>)
- <a href="/phenotypicSeries/PS187300">PS187300</a>
- 4 Entries
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<strong>Gene/Locus<br />MIM number</strong>
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<a href="/geneMap/7/152?start=-3&limit=10&highlight=152"> 7p14 </a>
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<a href="/entry/610655"> Telangiectasia, hereditary hemorrhagic, type 4 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
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<a href="/entry/610655"> 610655 </a>
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<a href="/entry/610655"> HHT4 </a>
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<a href="/entry/610655"> 610655 </a>
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<a href="/geneMap/9/525?start=-3&limit=10&highlight=525"> 9q34.11 </a>
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<a href="/entry/187300"> Telangiectasia, hereditary hemorrhagic, type 1 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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<a href="/entry/187300"> 187300 </a>
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<a href="/entry/131195"> ENG </a>
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<a href="/entry/131195"> 131195 </a>
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<a href="/geneMap/10/180?start=-3&limit=10&highlight=180"> 10q11.22 </a>
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<a href="/entry/615506"> Telangiectasia, hereditary hemorrhagic, type 5 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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<a href="/entry/615506"> 615506 </a>
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<a href="/entry/605120"> GDF2 </a>
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<a href="/entry/605120"> 605120 </a>
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<a href="/geneMap/12/393?start=-3&limit=10&highlight=393"> 12q13.13 </a>
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<a href="/entry/600376"> Telangiectasia, hereditary hemorrhagic, type 2 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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<a href="/entry/600376"> 600376 </a>
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<a href="/entry/601284"> ACVRL1 </a>
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<a href="/entry/601284"> 601284 </a>
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because hereditary hemorrhagic telangiectasia type 1 (HHT1) is caused by heterozygous mutation in the gene encoding endoglin (ENG; <a href="/entry/131195">131195</a>) on chromosome 9q34.</p>
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<strong>Description</strong>
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<p>Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia leading to telangiectases and arteriovenous malformations of skin, mucosa, and viscera. Epistaxis and gastrointestinal bleeding are frequent complications of mucosal involvement. Visceral involvement includes that of the lung, liver, and brain. The most frequent form of hereditary hemorrhagic telangiectasia maps to the long arm of chromosome 9.</p><p><strong><em>Genetic Heterogeneity of Hereditary Hemorrhagic Telangiectasia</em></strong></p><p>
See also HHT2 (<a href="/entry/600376">600376</a>), caused by mutation in the ALK1 gene (ACVRL1; <a href="/entry/601284">601284</a>) on chromosome 12q13; HHT4 (<a href="/entry/610655">610655</a>), mapped to chromosome 7p14; and HHT5 (<a href="/entry/615506">615506</a>), caused by mutation in the GDF2 gene (<a href="/entry/605120">605120</a>) on chromosome 10q11.</p><p>A locus formerly designated HHT3 and mapped to chromosome 5 was found to be in error; see HISTORY. Affected members of the family in which the HHT3 locus was mapped were found to have a mutation in ENG (see MOLECULAR GENETICS) and have been included in HHT1.</p><p>See also juvenile polyposis/HHT syndrome (<a href="/entry/175050">175050</a>), caused by mutation in the SMAD4 gene (<a href="/entry/600993">600993</a>).</p>
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<p>HHT is highly penetrant; in a series of 384 patients, <a href="#84" class="mim-tip-reference" title="Plauchu, H., de Chadarevian, J. P., Bideau, A., Robert, J.-M. &lt;strong&gt;Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population.&lt;/strong&gt; Am. J. Med. Genet. 32: 291-297, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2729347/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2729347&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320320302&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2729347">Plauchu et al. (1989)</a> found at least 1 manifestation in 97%, while <a href="#85" class="mim-tip-reference" title="Porteous, M. E. M., Burn, J., Proctor, S. J. &lt;strong&gt;Hereditary haemorrhagic telangiectasia: a clinical analysis.&lt;/strong&gt; J. Med. Genet. 29: 527-530, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1518020/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1518020&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.29.8.527&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1518020">Porteous et al. (1992)</a> found complete penetrance by 40 years of age in a series of 35 British families with 98 affected members. Sixty-two percent of these were clinically affected by age 16, with epistaxes being the presenting feature in 90% of cases. <a href="#1" class="mim-tip-reference" title="Aassar, O. S., Friedman, C. M., White, R. I., Jr. &lt;strong&gt;The natural history of epistaxis in hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Laryngoscope 101: 977-980, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1886446/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1886446&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1288/00005537-199109000-00008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1886446">Aassar et al. (1991)</a> found that the mean age of onset of epistaxis in HHT was 12 years, with more than 90% becoming manifest before 21 years. Blood loss from the nasal mucosa may become severe. Telangiectases also occur on the mucosal surface of the tongue (where bleeding may prove difficult to control), lips, face, conjunctiva, ears and fingers. <a href="#84" class="mim-tip-reference" title="Plauchu, H., de Chadarevian, J. P., Bideau, A., Robert, J.-M. &lt;strong&gt;Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population.&lt;/strong&gt; Am. J. Med. Genet. 32: 291-297, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2729347/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2729347&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320320302&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2729347">Plauchu et al. (1989)</a> noted facial involvement in 33% and lesions on the hands or wrists of 41% of their patients <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1518020+2729347+1886446" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#85" class="mim-tip-reference" title="Porteous, M. E. M., Burn, J., Proctor, S. J. &lt;strong&gt;Hereditary haemorrhagic telangiectasia: a clinical analysis.&lt;/strong&gt; J. Med. Genet. 29: 527-530, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1518020/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1518020&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.29.8.527&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1518020">Porteous et al. (1992)</a> found significant gastrointestinal hemorrhage in 16% of patients, with half of these requiring transfusion. The preponderance of upper GI involvement may have reflected the reliance on upper GI endoscopy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1518020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By angiographic methods, various types of visceral angiodysplasias have been demonstrated (<a href="#44" class="mim-tip-reference" title="Halpern, M., Turner, A. F., Citron, B. P. &lt;strong&gt;Hereditary hemorrhagic telangiectasia. A visceral angiodysplasia associated with gastrointestinal hemorrhage.&lt;/strong&gt; Radiology 90: 1143-1149, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5656734/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5656734&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1148/90.6.1143&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5656734">Halpern et al., 1968</a>). These include arterial aneurysm, arteriovenous communication including discrete arteriovenous fistula, conglomerate masses of angiectasia, phlebectasia, and angioma. Pulmonary arteriovenous malformations (PAVMs) are a significant cause of morbidity. Some are sufficiently large to cause heart failure leading to polycythaemia and clubbing. Paradoxical emboli may cause infarction or abscess formation in the brain and elsewhere. <a href="#113" class="mim-tip-reference" title="Vase, P., Holm, M., Arendrup, H. &lt;strong&gt;Pulmonary arteriovenous fistules in hereditary haemorrhagic telangiectasia.&lt;/strong&gt; Acta Med. Scand. 218: 105-109, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4050544/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4050544&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.0954-6820.1985.tb08832.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4050544">Vase et al. (1985)</a> reported PAVMs in 20% of their series. <a href="#84" class="mim-tip-reference" title="Plauchu, H., de Chadarevian, J. P., Bideau, A., Robert, J.-M. &lt;strong&gt;Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population.&lt;/strong&gt; Am. J. Med. Genet. 32: 291-297, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2729347/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2729347&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320320302&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2729347">Plauchu et al. (1989)</a> found PAVMs in 4.6% with an age range of 1 to 78 years. In the study of <a href="#85" class="mim-tip-reference" title="Porteous, M. E. M., Burn, J., Proctor, S. J. &lt;strong&gt;Hereditary haemorrhagic telangiectasia: a clinical analysis.&lt;/strong&gt; J. Med. Genet. 29: 527-530, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1518020/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1518020&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.29.8.527&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1518020">Porteous et al. (1992)</a> 13 (23%) of those who had undergone chest radiography had a visible PAVM; 4 suffered embolic complications, 3 cerebral abscesses, and one a stroke. In one 17-year-old, 50% of the circulating volume was passing through a single PAVM. <a href="#90" class="mim-tip-reference" title="Reyes-Mujica, M., Lopez-Corella, E., Perez-Fernandez, L., Cuevas-Schacht, F., Carrillo-Farga, J. &lt;strong&gt;Osler-Weber-Rendu disease in an infant.&lt;/strong&gt; Hum. Path. 19: 1243-1246, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3169731/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3169731&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0046-8177(88)80160-6&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3169731">Reyes-Mujica et al. (1988)</a> described HHT in a 23-month-old girl who died of massive pulmonary hemorrhage. There were no skin lesions but vascular anomalies of varying severity were found in the tongue, esophagus, liver, kidney, central nervous system, ovaries, spleen, and lymph nodes. Before death, the child had 15 episodes of hemoptysis and 2 of epistaxis. The parents, by contrast, had no evidence of the disease but 1 grandfather had died after bleeding from the mouth following physical exertion. <a href="#30" class="mim-tip-reference" title="Dines, D. E., Arms, R. A., Bernatz, P. E., Gomes, M. R. &lt;strong&gt;Pulmonary arteriovenous fistulas.&lt;/strong&gt; Mayo Clin. Proc. 49: 460-465, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4834927/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4834927&lt;/a&gt;]" pmid="4834927">Dines et al. (1974)</a> reviewed 63 cases of pulmonary arteriovenous fistula seen at the Mayo Clinic; HHT was recognized in 38 (60%). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2729347+3169731+1518020+4834927+5656734+4050544" 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>Cirrhosis of the liver may occur; <a href="#84" class="mim-tip-reference" title="Plauchu, H., de Chadarevian, J. P., Bideau, A., Robert, J.-M. &lt;strong&gt;Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population.&lt;/strong&gt; Am. J. Med. Genet. 32: 291-297, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2729347/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2729347&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320320302&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2729347">Plauchu et al. (1989)</a> found liver involvement in 27 patients (8%); 17 of these had cirrhosis, which was the cause of death in 5. <a href="#76" class="mim-tip-reference" title="Michaeli, D., Ben-Bassat, I., Miller, H. I., Deutsch, V. &lt;strong&gt;Hepatic telangiectases and portosystemic encephalopathy in Osler-Weber-Rendu disease.&lt;/strong&gt; Gastroenterology 54: 929-932, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5652528/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5652528&lt;/a&gt;]" pmid="5652528">Michaeli et al. (1968)</a> described a 47-year-old woman with HHT disease and hepatic portacaval shunts of sufficient magnitude to cause repeated episodes of encephalopathy. The liver was not scarred. <a href="#79" class="mim-tip-reference" title="Nikolopoulos, N., Xynos, E., Vassilakis, J. S. &lt;strong&gt;Familial occurrence of hyperdynamic circulation status due to intrahepatic fistulae in hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Hepatogastroenterology 35: 167-168, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3181861/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3181861&lt;/a&gt;]" pmid="3181861">Nikolopoulos et al. (1988)</a> raised the question of familial tendency to hepatic involvement in HHT. They described 2 brothers with intrahepatic arteriovenous shunts of sufficient size to cause hyperdynamic circulation, leading to cirrhosis; the mother and 3 maternal uncles died of cirrhosis with rupture of esophageal varices. Members of the previous generation also had a history of hyperdynamic circulation. <a href="#99" class="mim-tip-reference" title="Selmaier, M., Cidlinsky, K., Ell, C., Hahn, E. G. &lt;strong&gt;Haemangiomatose der Leber bei Morbus Osler.&lt;/strong&gt; Dtsch. Med. Wschr. 118: 1015-1019, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8334948/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8334948&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1055/s-2008-1059420&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8334948">Selmaier et al. (1993)</a> described the case of a 50-year-old woman with heart failure resulting from calcified hemangiomatosis of the liver with a high shunt volume. <a href="#97" class="mim-tip-reference" title="Saxena, R., Hytiroglou, P., Atillasoy, E. O., Cakaloglu, Y., Emre, S., Thung, S. N. &lt;strong&gt;Coexistence of hereditary hemorrhagic telangiectasia and fibropolycystic liver disease.&lt;/strong&gt; Am. J. Surg. Path. 22: 368-372, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9500780/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9500780&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/00000478-199803000-00013&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9500780">Saxena et al. (1998)</a> reported the case of a 43-year-old woman who received a transplant for end-stage liver disease due to HHT and fibropolycystic liver disease. The liver showed extensive vascular malformations of arteries and veins, as well as telangiectasia and fibrosis. In addition, there were cystically dilated ducts containing inspissated bile and extensive von Meyenburg complexes. The case raised the question of a possible relationship between polycystic liver disease (<a href="/entry/174050">174050</a>) and HHT. (A von Meyenburg complex consists of clusters of small bile ducts occurring in polycystic livers, separate from the portal areas.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2729347+8334948+3181861+5652528+9500780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the liver, the vascular abnormalities of HHT are associated with marked fibrosis and/or cirrhosis. <a href="#118" class="mim-tip-reference" title="Weik, C., Greiner, L. &lt;strong&gt;The liver in hereditary hemorrhagic telangiectasia (Weber-Rendu-Osler disease).&lt;/strong&gt; Scand. J. Gastroent. 34: 1241-1246, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10636073/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10636073&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1080/003655299750024779&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10636073">Weik and Greiner (1999)</a> found hepatic manifestations of HHT in 4 women and 1 man (51 to 63 years of age) presenting initially with slight disturbances of liver function. In 3 patients, progressive liver insufficiency developed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10636073" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Garcia-Tsao, G., Korzenik, J. R., Young, L., Henderson, K. J., Jain, D., Byrd, B., Pollak, J. S., White, R. I., Jr. &lt;strong&gt;Liver disease in patients with hereditary hemorrhagic telangiectasia.&lt;/strong&gt; New Eng. J. Med. 343: 931-936, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11006369/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11006369&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM200009283431305&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11006369">Garcia-Tsao et al. (2000)</a> described the clinical findings and results of hemodynamic, angiographic, and imaging studies in 19 patients with HHT and symptomatic liver involvement. Ages ranged from 34 to 74 years in the 14 women and 5 men. All but 1 had a hyperdynamic circulation (cardiac index, 4.2 to 7.3 liters per minute per square meter of body-surface area). In 8 patients, the clinical findings were consistent with the presence of high-output heart failure. Manifestations of portal hypertension such as ascites or variceal bleeding were present in 6 patients. Manifestations of biliary disease, such as an elevated alkaline phosphatase level and abnormalities on bile duct imaging, were present in 5 patients. One of these patients died after an unsuccessful attempt at liver transplantation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11006369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Cooke, D. A. P. &lt;strong&gt;Renal arteriovenous malformation demonstrated angiographically in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease).&lt;/strong&gt; J. Roy. Soc. Med. 79: 744-746, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3806547/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3806547&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1177/014107688607901220&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3806547">Cooke (1986)</a> described renal arteriovenous malformations in a patient with episodic hematuria and renal colic due to clots. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3806547" 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>Telangiectases may occur in the bladder, although <a href="#84" class="mim-tip-reference" title="Plauchu, H., de Chadarevian, J. P., Bideau, A., Robert, J.-M. &lt;strong&gt;Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population.&lt;/strong&gt; Am. J. Med. Genet. 32: 291-297, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2729347/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2729347&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320320302&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2729347">Plauchu et al. (1989)</a> found only 2 symptomatic patients among their 324 cases. <a href="#58" class="mim-tip-reference" title="Kurnik, P. B., Heymann, W. R. &lt;strong&gt;Coronary artery ectasia associated with hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Arch. Intern. Med. 149: 2357-2359, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2802901/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2802901&lt;/a&gt;]" pmid="2802901">Kurnik and Heymann (1989)</a> described 3-vessel coronary artery ectasia without evidence of atherosclerosis in a 51-year-old man with classic HHT disease. This manifestation had not previously been described although ectasia of other vessels such as intraabdominal ones is well known. In a study of 20 patients with HHT, <a href="#14" class="mim-tip-reference" title="Brant, A. M., Schachat, A. P., White, R. I. &lt;strong&gt;Ocular manifestations in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease).&lt;/strong&gt; Am. J. Ophthal. 107: 642-646, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2658618/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2658618&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9394(89)90261-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2658618">Brant et al. (1989)</a> found conjunctival telangiectases in 7 and retinal vascular malformations in 2. Visual loss from the intraocular lesions is a rare complication. Bloody tears sometimes occur in patients with conjunctival telangiectases and bleeding from the eyes may also result from the backing up of blood in the lacrimal duct during epistaxis with packing of the nostrils. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2729347+2802901+2658618" 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>Most of the neurologic morbidity is related to emboli but vascular malformations may occur; <a href="#40" class="mim-tip-reference" title="Guillen, B., Guizar, J., de la Cruz, J., Salamanca, F. &lt;strong&gt;Hereditary hemorrhagic telangiectasia: report of 15 affected cases in a Mexican family.&lt;/strong&gt; Clin. Genet. 39: 214-218, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2036743/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2036743&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1991.tb03014.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2036743">Guillen et al. (1991)</a> found 1 individual, in a Mexican family with 15 affected members, who needed surgical treatment for a cerebral lesion, while 3 of the patients seen by <a href="#85" class="mim-tip-reference" title="Porteous, M. E. M., Burn, J., Proctor, S. J. &lt;strong&gt;Hereditary haemorrhagic telangiectasia: a clinical analysis.&lt;/strong&gt; J. Med. Genet. 29: 527-530, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1518020/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1518020&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.29.8.527&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1518020">Porteous et al. (1992)</a> had symptomatic cerebral lesions. In the latter report, 46.3% of patients with no known CNS pathology described visual symptoms suggestive of migrainous aura in the absence of headache and nausea compared to 5.7% of controls. <a href="#106" class="mim-tip-reference" title="Steele, J. S., Nath, P. U., Burn, J., Porteous, M. E. M. &lt;strong&gt;An association between migrainous aura and hereditary haemorrhagic telangiectasia.&lt;/strong&gt; Headache 33: 145-148, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8486513/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8486513&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1526-4610.1993.hed3303145.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8486513">Steele et al. (1993)</a> investigated migraine prevalence in 58 British adult HHT gene carriers without known neurologic deficits; 40 carriers of the gene for familial adenomatous polyposis (FAP; <a href="/entry/175100">175100</a>) were used as controls. They found that 50% of the HHT carriers fulfill diagnostic criteria for migraine with aura, 4 times the disease control group and 10 times the estimated population prevalence. White had observed this symptom separately and noted that headaches improved in patients who had undergone balloon occlusion of PAVMs (<a href="#121" class="mim-tip-reference" title="White, R. I., Jr., Lynch-Nyhan, A., Terry, P., Buescher, P. C., Farmlett, E. J., Charnas, L., Shuman, K., Kim, W., Kinnison, M., Mitchell, S. E. &lt;strong&gt;Pulmonary arteriovenous malformations: techniques and long-term outcome of embolotherapy.&lt;/strong&gt; Radiology 169: 663-669, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3186989/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3186989&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1148/radiology.169.3.3186989&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3186989">White et al., 1988</a>). This raises the possibility of vasoactive substances which would normally be removed in the pulmonary vascular bed reaching the central nervous system, though if this is the explanation it would suggest that almost half of gene carriers have pulmonary involvement. Another factor may be occult intracranial AVMs; 6 to 8% of HHT patients with PAVMs also have intracranial lesions (<a href="#91" class="mim-tip-reference" title="Roman, G., Fisher, M., Perl, D. P., Poser, C. M. &lt;strong&gt;Manifestations of hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber Disease): report of 2 cases and review of the literature.&lt;/strong&gt; Ann. Neurol. 4: 130-144, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/707984/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;707984&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410040207&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="707984">Roman et al., 1978</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1518020+2036743+707984+8486513+3186989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Fulbright, R. K., Chaloupka, J. C., Putman, C. M., Sze, G. K., Merriam, M. M., Lee, G. K., Fayad, P. B., Awad, I. A., White, R. I., Jr. &lt;strong&gt;MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations.&lt;/strong&gt; Am. J. Neuroradiol. 19: 477-484, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9541302/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9541302&lt;/a&gt;]" pmid="9541302">Fulbright et al. (1998)</a> reviewed brain magnetic resonance imaging (MRI) of 184 consecutive patients with HHT. Catheter angiography was performed in 17 patients in whom cerebrovascular malformations (CVMs) were detected on MRIs. They found 63 CVMs in 42 patients. Classic arteriovenous malformations (n = 10) had a conspicuous network of vessels with flow voids and enlarged adjacent pial vessels. Apparent venous malformations (n = 5) were best seen after administration of contrast material as a prominent vessel coursing through normal brain parenchyma. Indeterminate vascular malformations (n = 48) had a spectrum of appearances characterized by variable combinations of heterogeneous signal intensity, enhancement, or hemosiderin. Angiography in 17 patients revealed 47 CVMs. Forty-six were arteriovenous malformations (AVMs), including 25 CVMs not seen with MRI and 21 CVMs that by MR criteria included 8 AVMs and 13 indeterminate vascular malformations. Angiography confirmed 1 venous malformation seen with MRI but failed to detect 3 indeterminate lesions revealed by MRI. Thus, MRI revealed a CVM prevalence of 23% (42 of 184). Most CVMs (48 of 63) had an atypical appearance for vascular malformations on MR images. Angiographic correlation suggests that MRI underestimates the prevalence of CVMs and that the majority of indeterminate CVMs, despite their variable MRI appearance, are AVMs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9541302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Kopel, L., Lage, S. G. &lt;strong&gt;Cardiac tamponade in hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Am. J. Med. 105: 252-253, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9753031/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9753031&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0002-9343(98)00238-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9753031">Kopel and Lage (1998)</a> described a 37-year-old woman with HHT who developed a large pericardial effusion with cardiac tamponade. Pericardiocentesis yielded a large amount of hemorrhagic pericardial fluid. Because of recurrent cardiac tamponade, the patient underwent partial surgical pericardial excision. Histologic examination of the pericardium showed vascular dysplasia with signs of hemorrhage and inflammation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Canzonieri, C., Centenara, L., Ornati, F., Pagella, F., Matti, E., Alvisi, C., Danesino, C., Perego, M., Olivieri, C. &lt;strong&gt;Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes.&lt;/strong&gt; Genet. Med. 16: 3-10, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23722869/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23722869&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2013.62&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23722869">Canzonieri et al. (2014)</a> examined the gastrointestinal tract of consecutive HHT patients to assess distribution, number, size, and type of telangiectases in relation to genotype. Twenty-two patients (13 men; mean age 59 +/- 9 years) were analyzed, 7 with HHT1, 13 with HHT2 (<a href="/entry/600376">600376</a>), and 2 undefined. Gastrointestinal telangiectases were identified in 86% of HHT1 patients and in 77% of HHT2 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23722869" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#93" class="mim-tip-reference" title="Ruiz-Llorente, L., McDonald, J., Wooderchak-Donahue, W., Briggs, E., Chesnutt, M., Bayrak-Toydemir, P., Bernabeu, C. &lt;strong&gt;Characterization of a family mutation in the 5-prime untranslated region of the endoglin gene causative of hereditary hemorrhagic telangiectasia.&lt;/strong&gt; J. Hum. Genet. 64: 333-339, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30728427/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30728427&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=30728427[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s10038-019-0564-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30728427">Ruiz-Llorente et al. (2019)</a> reported a 3-generation Spanish family with HHT and mutation in the ENG gene. All 6 affected individuals exhibited telangiectasias, and all but the youngest (a 9-year-old girl) also experienced epistaxis. In addition, 4 of the 5 affected adults had PAVM, and 1 also had CVM. One patient, a 66-year-old woman, had no solid organ involvement detected by pulmonary or brain imaging, but her 2 affected sons had PAVM and CVM at ages 25 and 34 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30728427" 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>Reviews</em></strong></p><p>
<a href="#41" class="mim-tip-reference" title="Guttmacher, A. E., Marchuk, D. A., White, R. I., Jr. &lt;strong&gt;Hereditary hemorrhagic telangiectasia.&lt;/strong&gt; New Eng. J. Med. 333: 918-924, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7666879/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7666879&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199510053331407&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7666879">Guttmacher et al. (1995)</a> reviewed all aspects of HHT. They emphasized that it is important for those affected to be aware of their diagnosis and its implications and to inform health care providers of their condition. <a href="#41" class="mim-tip-reference" title="Guttmacher, A. E., Marchuk, D. A., White, R. I., Jr. &lt;strong&gt;Hereditary hemorrhagic telangiectasia.&lt;/strong&gt; New Eng. J. Med. 333: 918-924, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7666879/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7666879&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199510053331407&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7666879">Guttmacher et al. (1995)</a> announced that educational materials for patients and providers are available from the HHT Foundation International, Inc. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7666879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Haitjema, T., Westermann, C. J. J., Overtoom, T. T. C., Timmer, R., Disch, F., Mauser, H., Lammers, J.-W. J. &lt;strong&gt;Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease): New insights in pathogenesis, complications, and treatment.&lt;/strong&gt; Arch. Intern Med. 156: 714-719, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8615703/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8615703&lt;/a&gt;]" pmid="8615703">Haitjema et al. (1996)</a> provided a review. <a href="#67" class="mim-tip-reference" title="Marchuk, D. A., Guttmacher, A. E., Penner, J. A., Ganguly, P. &lt;strong&gt;Report on the workshop on hereditary hemorrhagic telangiectasia, July 10-11, 1997.&lt;/strong&gt; Am. J. Med. Genet. 76: 269-273, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9508248/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9508248&lt;/a&gt;]" pmid="9508248">Marchuk et al. (1998)</a> reported on a 1997 workshop on hereditary hemorrhagic telangiectasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9508248+8615703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Govani, F. S., Shovlin, C. L. &lt;strong&gt;Hereditary haemorrhagic telangiectasia: a clinical and scientific review.&lt;/strong&gt; Europ. J. Hum. Genet. 17: 860-871, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19337313/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19337313&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19337313[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ejhg.2009.35&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19337313">Govani and Shovlin (2009)</a> reviewed the molecular and genetic basis of hereditary hemorrhagic telangiectasia and discussed approaches for diagnosis and clinical management. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19337313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<p>HHT disease is inherited as an autosomal dominant trait. <a href="#104" class="mim-tip-reference" title="Snyder, L. H., Doan, C. A. &lt;strong&gt;Clinical and experimental studies in human inheritance: is the homozygous form of multiple telangiectasia lethal?&lt;/strong&gt; J. Lab. Clin. Med. 29: 1211-1216, 1944."None>Snyder and Doan (1944)</a> reported a possible instance of homozygosity, 2 affected parents had a stillborn offspring who had extensive angiomatous malformation of the viscera.</p><p>In a large Arab family in the Sahara, <a href="#78" class="mim-tip-reference" title="Muller, J.-Y., Michailov, T., Izrael, V., Bernard, J. &lt;strong&gt;Maladie de Rendu-Osler dans une grande famille saharienne.&lt;/strong&gt; Nouv. Presse Med. 7: 1723-1725, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/673716/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;673716&lt;/a&gt;]" pmid="673716">Muller et al. (1978)</a> found 87 cases in 6 generations. Because of the extensive consanguinity in the kindred, a person considered to be homozygous was identified. In the case of 4 couples indicated in the pedigree, both partners were affected. The son of one such couple had a total of 13 children by 4 different wives. All the wives were unaffected; all the children were affected. According to the Bayes theory, the probability of homozygosity was estimated to be 0.99975. The father, who was the presumed homozygote and also the proband, had severe but no exceptionally unusual manifestations of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=673716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="mapping" class="mim-anchor"></a>
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<p>Using microsatellite markers in a study of 2 extensively affected families, <a href="#72" class="mim-tip-reference" title="McDonald, M., Papenberg, K., Ghosh, S., Glatfelter, A., Biesecker, B., Helmbold, E., Zolotor, A., Jackson, C. E., McKinnon, W., Collins, F. S., Porteous, M. E., Guttmacher, A. E., Boehnke, M., Marchuk, D. A. &lt;strong&gt;Genetic linkage of hereditary hemorrhagic telangiectasia to markers on 9q. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 53 (suppl.): A140, 1993."None>McDonald et al. (1993)</a> showed that the HHT gene maps to 9q. D9S164 showed a combined maximum lod score of 4.39 at a recombination fraction of 0.14, and D9S103 showed a combined maximum lod score of 3.53 at a recombination fraction of 0.11. The probable location of the HHT gene, otherwise symbolized ORW, is 9q33-q34.1. <a href="#73" class="mim-tip-reference" title="McDonald, M. T., Papenberg, K. A., Ghosh, S., Glatfelter, A. A., Biesecker, B. B., Helmbold, E. A., Markel, D. S., Zolotor, A., McKinnon, W. C., Vanderstoep, J. L., Jackson, C. E., Iannuzzi, M., Collins, F. S., Boehnke, M., Porteous, M. E., Guttmacher, A. E., Marchuk, D. A. &lt;strong&gt;A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33-34.&lt;/strong&gt; Nature Genet. 6: 197-204, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8162075/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8162075&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0294-197&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8162075">McDonald et al. (1994)</a> estimated that the closest marker, D9S65, is within 1 cM of the gene; it showed a combined lod score of 11.41 with HHT. <a href="#103" class="mim-tip-reference" title="Shovlin, C. L., Hughes, J. M. B., Tuddenham, E. G. D., Temperley, I., Perembelon, Y. F. N., Scott, J., Seidman, C. E., Seidman, J. G. &lt;strong&gt;A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3.&lt;/strong&gt; Nature Genet. 6: 205-209, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8162076/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8162076&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0294-205&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8162076">Shovlin et al. (1994)</a> independently assigned HHT to 9q. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8162075+8162076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<p><a href="#68" class="mim-tip-reference" title="McAllister, K. A., Grogg, K. M., Johnson, D. W., Gallione, C. J., Baldwin, M. A., Jackson, C. E., Helmbold, E. A., Markel, D. S., McKinnon, W. C., Murrell, J., McCormick, M. K., Pericak-Vance, M. A., Heutink, P., Oostra, B. A., Haitjema, T., Westerman, C. J. J., Porteous, M. E., Guttmacher, A. E., Letarte, M., Marchuk, D. A. &lt;strong&gt;Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1.&lt;/strong&gt; Nature Genet. 8: 345-351, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7894484/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7894484&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1294-345&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7894484">McAllister et al. (1994)</a> examined endoglin (ENG; <a href="/entry/131195">131195</a>), a transforming growth factor-beta (TGF-beta) binding protein, as a candidate gene for HHT because of its chromosomal location, expression pattern, and function. They identified heterozygous mutations in the ENG gene (<a href="/entry/131195#0001">131195.0001</a>-<a href="/entry/131195#0003">131195.0003</a>) in 3 affected individuals from different families. This was the first human disease defined as due to a mutation in a member of the TGF-beta receptor complex. Primary pulmonary hypertension (PPH1; <a href="/entry/178600">178600</a>) is another autosomal dominant inherited vascular disorder that is caused by a defect in BMPR2 (<a href="/entry/600799">600799</a>), which is a member of the TGF-beta signaling pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 160 unrelated cases of HHT, <a href="#62" class="mim-tip-reference" title="Lesca, G., Plauchu, H., Coulet, F., Lefebvre, S., Plessis, G., Odent, S., Riviere, S., Leheup, B., Goizet, C., Carette, M.-F., Cordier, J.-F., Pinson, S., Soubrier, F., Calender, A., Giraud, S. &lt;strong&gt;Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.&lt;/strong&gt; Hum. Mutat. 23: 289-299, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15024723/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15024723&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20017&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15024723">Lesca et al. (2004)</a> screened the coding sequences of the ENG and ALK1 genes. Germline mutations were identified in 100 patients (62.5%); 36 of the mutations were in ENG and 64 were in ALK1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15024723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#117" class="mim-tip-reference" title="Wehner, L.-E., Folz, B. J., Argyriou, L., Twelkemeyer, S., Teske, U., Geisthoff, U. W., Werner, J. A., Engel, W., Nayernia, K. &lt;strong&gt;Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations.&lt;/strong&gt; Clin. Genet. 69: 239-245, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16542389/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16542389&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2006.00574.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16542389">Wehner et al. (2006)</a> identified mutations in 32 (62.7%) of 51 unrelated German patients with HHT. Thirteen mutations were in the ENG gene, consistent with HHT1, and 17 mutations were in the ACVRL1 gene, consistent with HHT2. Analysis of genotype/phenotype correlations was consistent with a more common frequency of PAVMs in patients with HHT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16542389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Bossler, A. D., Richards, J., George, C., Godmilow, L., Ganguly, A. &lt;strong&gt;Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype.&lt;/strong&gt; Hum. Mutat. 27: 667-675, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16752392/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16752392&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20342&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16752392">Bossler et al. (2006)</a> described the results of mutation analysis on a consecutive series of 200 individuals undergoing clinical genetic testing for HHT. A total of 127 probands were found, with sequence changes consisting of 103 unique alterations, 68 of which were novel. In addition 8 intragenic rearrangements in the ENG gene (<a href="/entry/131195">131195</a>), and 2 in ACVRL1 gene (<a href="/entry/601284">601284</a>) were identified. Surprisingly, almost 50% of the individuals with a single symptom were found to have a significant sequence alteration; 3 of these reported only nosebleeds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16752392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a German woman with clinical features of HHT and negative direct sequencing results, <a href="#100" class="mim-tip-reference" title="Shoukier, M., Teske, U., Weise, A., Engel, W., Argyriou, L. &lt;strong&gt;Characterization of five novel large deletions causing hereditary haemorrhagic telangiectasia.&lt;/strong&gt; Clin. Genet. 73: 320-330, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18312453/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18312453&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2008.00968.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18312453">Shoukier et al. (2008)</a> identified a deletion of exon 4 of the ENG gene using quantitative real-time polymerase chain reaction (qRT-PCR) and confirmed by multiplex ligation-dependent probe amplification (MLPA). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18312453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 3-generation Spanish family with HHT that was negative for mutation after screening with an HHT gene panel, <a href="#93" class="mim-tip-reference" title="Ruiz-Llorente, L., McDonald, J., Wooderchak-Donahue, W., Briggs, E., Chesnutt, M., Bayrak-Toydemir, P., Bernabeu, C. &lt;strong&gt;Characterization of a family mutation in the 5-prime untranslated region of the endoglin gene causative of hereditary hemorrhagic telangiectasia.&lt;/strong&gt; J. Hum. Genet. 64: 333-339, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30728427/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;30728427&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=30728427[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s10038-019-0564-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="30728427">Ruiz-Llorente et al. (2019)</a> sequenced the 5-prime UTR of the ENG gene and identified a variant (c.-142A-T; <a href="/entry/131195#0010">131195.0010</a>) that creates a putative AUG initiation codon at -141 bases from the constitutive translation initiation codon. The mutation segregated with disease in the family, and was not found in the dbSNP or gnomAD databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30728427" 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>From a cohort of 274 sequenced patients with genetically unresolved HHT, <a href="#105" class="mim-tip-reference" title="Soukarieh, O., Tillet, E., Proust, C., Dupont, C., Jaspard-Vinassa, B., Soubrier, F., Goyenvalle, A., Eyries, M., Tregouet, D. A. &lt;strong&gt;uAUG creating variants in the 5-prime-UTR of ENG causing hereditary hemorrhagic telangiectasia.&lt;/strong&gt; NPJ Genomic Med. 8: 32, 2023.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/37848456/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;37848456&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=37848456[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41525-023-00378-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="37848456">Soukarieh et al. (2023)</a> identified 2 patients with mutations in the 5-prime UTR of the ENG gene, c.-79C-T and c.-68G-A, which were confirmed by Sanger sequencing. Functional analysis of these 2 variants as well as 3 additional previously published 5-prime UTR ENG variants identified in HHT patients, including the c.-142A-T mutation, revealed that all 5 variants created upstream AUGs at the origin of upstream overlapping open reading frames (uoORFs) ending at the same stop codon (c.125), and all showed altered protein levels and function. Experiments using constructs in which the canonical start site had been deleted revealed that the identified upstream AUGs could initiate translation, suggesting that the associated effects were translation-dependent. The authors noted that all of the uoORF-creating variants studied showed ENG protein levels and BMP response element (BRE) activity that were less than 40% and 50%, respectively, compared to wildtype ENG, and were associated with severe HHT symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37848456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a whole-genome sequencing study performed prospectively for HHT gene-negative patients as part of the British National Health Service 100,000 Genomes Project, <a href="#101" class="mim-tip-reference" title="Shovlin, C. L., Almaghlouth, F. I., Alsafi, A., Coote, N., Rennie, C., Wallace, G. M., Govani, F. S., Genomics England Research Consortium. &lt;strong&gt;Updates on diagnostic criteria for hereditary haemorrhagic telangiectasia in the light of whole genome sequencing of &#x27;gene-negative&#x27; individuals recruited to the 100 000 Genomes Project.&lt;/strong&gt; J. Med. Genet. 61: 182-185, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/37586837/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;37586837&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=37586837[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg-2023-109195&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="37586837">Shovlin et al. (2024)</a> restudied a 4-generation pedigree with HHT that was originally reported by <a href="#115" class="mim-tip-reference" title="Wallace, G. M. F., Shovlin, C. L. &lt;strong&gt;A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1.&lt;/strong&gt; Thorax 55: 685-690, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10899246/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10899246&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/thorax.55.8.685&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10899246">Wallace and Shovlin (2000)</a> and mapped to chromosome 5q31-q32 by <a href="#23" class="mim-tip-reference" title="Cole, S. G., Begbie, M. E., Wallace, G. M. F., Shovlin, C. L. &lt;strong&gt;A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5.&lt;/strong&gt; J. Med. Genet. 42: 577-582, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15994879/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15994879&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2004.028712&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15994879">Cole et al. (2005)</a>, a locus that was designated HHT3. However, <a href="#101" class="mim-tip-reference" title="Shovlin, C. L., Almaghlouth, F. I., Alsafi, A., Coote, N., Rennie, C., Wallace, G. M., Govani, F. S., Genomics England Research Consortium. &lt;strong&gt;Updates on diagnostic criteria for hereditary haemorrhagic telangiectasia in the light of whole genome sequencing of &#x27;gene-negative&#x27; individuals recruited to the 100 000 Genomes Project.&lt;/strong&gt; J. Med. Genet. 61: 182-185, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/37586837/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;37586837&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=37586837[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg-2023-109195&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="37586837">Shovlin et al. (2024)</a> identified a pathogenic frameshift variant in the ENG gene in an affected member of that family. The ENG mutation was not present in all family members who were previously designated as affected in the earlier linkage analyses: the authors noted that at least 1 of the individuals in the family who met 3 of the consensus clinical criteria for diagnosis of HHT was, in fact, unaffected. Thus, in addition to awareness that there may be a paucity of clinical signs in individuals with genetically confirmed HHT, the authors emphasized the importance of being cognizant of the potential for overdiagnosis in relatives of patients with HHT who also have recurrent nosebleeds and telangiectasia at characteristic sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15994879+37586837+10899246" 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>Exclusion Studies</em></strong></p><p>
<a href="#39" class="mim-tip-reference" title="Greenspan, D. S., Northrup, H., Au, K.-S., McAllister, K. A., Francomano, C. A., Wenstrup, R. J., Marchuk, D. A., Kwiatkowski, D. J. &lt;strong&gt;COL5A1: fine genetic mapping and exclusion as a candidate gene in families with nail-patella syndrome, tuberous sclerosis 1, hereditary hemorrhagic telangiectasia, and Ehlers-Danlos syndrome type II.&lt;/strong&gt; Genomics 25: 737-739, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7759113/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7759113&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0888-7543(95)80021-d&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7759113">Greenspan et al. (1995)</a> excluded the COL5A1 gene as a candidate for HHT mapping to chromosome 9q. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7759113" 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="#7" class="mim-tip-reference" title="Berg, J., Porteous, M., Reinhardt, D., Gallione, C., Holloway, S., Umasunthar, T., Lux, A., McKinnon, W., Marchuk, D., Guttmacher, A. &lt;strong&gt;Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations.&lt;/strong&gt; J. Med. Genet. 40: 585-590, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12920067/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12920067&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.40.8.585&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12920067">Berg et al. (2003)</a> performed a questionnaire-based study to delineate phenotypic differences between HHT1 and HHT2, which are caused by mutation in the ENG gene and ALK1 (<a href="/entry/601284">601284</a>) gene, respectively. The questionnaires were completed by 83 patients with known mutations (49 had HHT1 and 34 had HHT2). Patients with HHT1 reported an earlier onset of epistaxis and telangiectasis than those with HHT2. Pulmonary arteriovenous malformations were reported only in the group of HHT1 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920067" 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>Among 14 kindreds with HHT1 and 12 with HHT2 confirmed by genetic analysis, <a href="#6" class="mim-tip-reference" title="Bayrak-Toydemir, P., McDonald, J., Markewitz, B., Lewin, S., Miller, F., Chou, L.-S., Gedge, F., Tang, W., Coon, H., Mao, R. &lt;strong&gt;Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.&lt;/strong&gt; Am. J. Med. Genet. 140A: 463-470, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16470787/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16470787&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16470787">Bayrak-Toydemir et al. (2006)</a> found that HHT2 was associated with later onset and more hepatic involvement than HHT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16470787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#64" class="mim-tip-reference" title="Letteboer, T. G. W., Mager, J. J., Snijder, R. J., Koeleman, B. P. C., Lindhout, D., Ploos van Amstel, J. K., Westermann, C. J. J. &lt;strong&gt;Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia.&lt;/strong&gt; J. Med. Genet. 43: 371-377, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16155196/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16155196&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2005.035451&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16155196">Letteboer et al. (2006)</a> analyzed phenotype in relation to sex in 584 Dutch probands and affected family members with HHT1 and HHT2 confirmed by genetic analysis. For the HHT1 group, they found a significantly higher prevalence of PAVM and hepatic AVM in women than in men. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16155196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 268 Dutch patients with HHT1 and 130 Dutch patients with HHT2, <a href="#63" class="mim-tip-reference" title="Letteboer, T. G. W., Mager, H.-J., Snijder, R. J., Lindhout, D., van Amstel, H.-K. P., Zanen, P., Westermann, K. J. J. &lt;strong&gt;Genotype-phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Am. J. Med. Genet. 146A: 2733-2739, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18831062/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18831062&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32243&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18831062">Letteboer et al. (2008)</a> found that oral and nasal mucosal telangiectases were present earlier in life in patients with HHT1 compared to patients with HHT2, whereas dermal lesions were more frequent and appeared earlier in life in patients with HHT2. In both groups, telangiectases of the nasal mucosa were present at a higher prevalence and started to appear earlier in life than those of the oral mucosa or dermal sites. The number of sites affected increased with age in both groups. In patients with HHT1, more women than men had skin telangiectases, particularly on the face. These results confirmed that the frequency of AVMs differ between patients with HHT1 and HHT2, and that these differences can be detected on physical examination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18831062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="heterogeneity" class="mim-anchor"></a>
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<strong>Heterogeneity</strong>
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<p>Genetic heterogeneity was indicated by the results of linkage studies by several groups. <a href="#103" class="mim-tip-reference" title="Shovlin, C. L., Hughes, J. M. B., Tuddenham, E. G. D., Temperley, I., Perembelon, Y. F. N., Scott, J., Seidman, C. E., Seidman, J. G. &lt;strong&gt;A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3.&lt;/strong&gt; Nature Genet. 6: 205-209, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8162076/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8162076&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0294-205&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8162076">Shovlin et al. (1994)</a> found one family that did not map to 9q3. <a href="#86" class="mim-tip-reference" title="Porteous, M. E. M., Curtis, A., Williams, O., Marchuk, D., Bhattacharya, S. S., Burn, J. &lt;strong&gt;Genetic heterogeneity in hereditary haemorrhagic telangiectasia.&lt;/strong&gt; J. Med. Genet. 31: 925-926, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7891373/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7891373&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.31.12.925&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7891373">Porteous et al. (1994)</a> pointed out that all of the previously reported 9q34-linked families contained at least 1 affected member with a symptomatic PAVM. <a href="#86" class="mim-tip-reference" title="Porteous, M. E. M., Curtis, A., Williams, O., Marchuk, D., Bhattacharya, S. S., Burn, J. &lt;strong&gt;Genetic heterogeneity in hereditary haemorrhagic telangiectasia.&lt;/strong&gt; J. Med. Genet. 31: 925-926, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7891373/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7891373&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.31.12.925&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7891373">Porteous et al. (1994)</a> reported 4 families apparently unlinked to 9q34 and with no evidence of PAVMs. In a study by <a href="#68" class="mim-tip-reference" title="McAllister, K. A., Grogg, K. M., Johnson, D. W., Gallione, C. J., Baldwin, M. A., Jackson, C. E., Helmbold, E. A., Markel, D. S., McKinnon, W. C., Murrell, J., McCormick, M. K., Pericak-Vance, M. A., Heutink, P., Oostra, B. A., Haitjema, T., Westerman, C. J. J., Porteous, M. E., Guttmacher, A. E., Letarte, M., Marchuk, D. A. &lt;strong&gt;Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1.&lt;/strong&gt; Nature Genet. 8: 345-351, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7894484/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7894484&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1294-345&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7894484">McAllister et al. (1994)</a>, 4 of 7 families gave a posterior probability of more than 99% being of the linked type and 3 families appeared unlinked to 9q34. They were impressed also by the absence of PAVMs in the 3 9q3-unlinked families. In 3 unrelated families of Dutch origin, <a href="#51" class="mim-tip-reference" title="Heutink, P., Haitjema, T., Breedveld, G. J., Janssen, B., Sandkuijl, L. A., Bontekoe, C. J. M., Westerman, C. J. J., Oostra, B. A. &lt;strong&gt;Linkage of hereditary haemorrhagic telangiectasia to chromosome 9q34 and evidence for locus heterogeneity.&lt;/strong&gt; J. Med. Genet. 31: 933-936, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7891375/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7891375&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.31.12.933&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7891375">Heutink et al. (1994)</a> confirmed the linkage to 9q, and in a fourth unrelated family in which 'considerably fewer pulmonary arteriovenous malformations' were present, there was evidence for nonlinkage to this region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7891375+7891373+7894484+8162076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Cronstedt, J., Brechter, C., Carling, L. &lt;strong&gt;Coexistent hereditary haemorrhagic telangiectasia and primary thrombocythaemia--coincidence or syndrome?&lt;/strong&gt; Acta Med. Scand. 212: 261-265, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6890752/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6890752&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.0954-6820.1982.tb03210.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6890752">Cronstedt et al. (1982)</a> observed the coexistence of HHT disease and primary thrombocythemia (<a href="/entry/187950">187950</a>) in 2 patients, both men in their 70s. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6890752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The observation of a family with both type IIA von Willebrand disease (VWF2A; see <a href="/entry/613554">613554</a>) and HHT prompted <a href="#53" class="mim-tip-reference" title="Iannuzzi, M. C., Hidaka, N., Boehnke, M., Bruck, M. E., Hanna, W. T., Collins, F. S., Ginsburg, D. &lt;strong&gt;Analysis of the relationship of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia and identification of a potential type IIA vWD mutation (ile865-to-thr).&lt;/strong&gt; Am. J. Hum. Genet. 48: 757-763, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1673047/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1673047&lt;/a&gt;]" pmid="1673047">Iannuzzi et al. (1991)</a> to study genetic linkage of the 2 conditions. No linkage was detected and the VWF gene (<a href="/entry/613160">613160</a>) was ruled out as a candidate gene for HHT because of the finding of segregation in linkage studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1673047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#116" class="mim-tip-reference" title="Ward, K. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Salt Lake City, Utah 2/24/1996."None>Ward (1996)</a> suggested that there may be a form of hereditary hemorrhagic telangiectasia, unlinked to either chromosome 9 (HHT1) or chromosome 12 (HHT2; <a href="/entry/600376">600376</a>), in which the frequency of pulmonary arteriovenous fistulas is intermediate between the high frequency in HHT1 and the low frequency in HHT2.</p>
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<a id="pathogenesis" class="mim-anchor"></a>
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<strong>Pathogenesis</strong>
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<p><a href="#15" class="mim-tip-reference" title="Braverman, I. M., Keh, A., Jacobson, B. S. &lt;strong&gt;Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia.&lt;/strong&gt; J. Invest. Derm. 95: 422-427, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2212727/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2212727&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/1523-1747.ep12555569&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2212727">Braverman et al. (1990)</a> reconstructed representative cutaneous telangiectases by computer from serial 1- or 2-mm plastic embedded sections. The earliest clinically detectable lesion was a focal dilatation of postcapillary venules, which continued to enlarge and eventually connect with dilated arterioles through capillaries. As the vascular lesion increased in size, the capillary segments disappeared and a direct arteriovenous communication was formed. This sequence of events was associated with a perivascular mononuclear cell infiltrate in which most of the cells were lymphocytes and a minority are monocytes/macrophages by ultrastructural characteristics. The telangiectatic lesions of scleroderma are also composed of dilated postcapillary venules and also associated with perivascular infiltrates. Cherry angiomas, however, which are produced by capillary loop aneurysms, are not associated with infiltrates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2212727" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="diagnosis" class="mim-anchor"></a>
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<strong>Diagnosis</strong>
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<p>An important phenocopy is the CRST syndrome (calcinosis, Raynaud syndrome, sclerodactyly, telangiectasia; <a href="/entry/181750">181750</a>), a probable 'collagen vascular disease.' The mucosal and cutaneous telangiectases are indistinguishable from those of the hereditary disorder (<a href="#122" class="mim-tip-reference" title="Winterbauer, R. H. &lt;strong&gt;Multiple telangiectasia, Raynaud&#x27;s phenomenon, sclerodactyly and subcutaneous calcinosis: a syndrome mimicking hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Bull. Johns Hopkins Hosp. 114: 361-383, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14171636/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14171636&lt;/a&gt;]" pmid="14171636">Winterbauer, 1964</a>). <a href="#24" class="mim-tip-reference" title="Conlon, C. L., Weinger, R. S., Cimo, P. L., Moake, J. L., Olson, J. D. &lt;strong&gt;Telangiectasia and von Willebrand&#x27;s disease in two families.&lt;/strong&gt; Ann. Intern. Med. 89: 921-924, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/309746/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;309746&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.7326/0003-4819-89-6-921&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="309746">Conlon et al. (1978)</a> described 2 families in which telangiectasia like that of HHT disease occurred with von Willebrand disease. Other families with combined von Willebrand disease and HHT disease were described by <a href="#87" class="mim-tip-reference" title="Ramsay, D. M., Buist, T. A. S., Macleod, D. A. D., Heading, R. C. &lt;strong&gt;Persistent gastrointestinal bleeding due to angiodysplasia of the gut in von Willebrand&#x27;s disease.&lt;/strong&gt; Lancet 308: 275-278, 1976. Note: Originally Volume 2.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/59851/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;59851&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(76)90729-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="59851">Ramsay et al. (1976)</a>, <a href="#2" class="mim-tip-reference" title="Ahr, D. J., Rickles, F. R., Hoyer, L. W., O&#x27;Leary, D. S., Conrad, M. E. &lt;strong&gt;Von Willebrand&#x27;s disease and hemorrhagic telangiectasia: association of two complex disorders of hemostasis resulting in life-threatening hemorrhage.&lt;/strong&gt; Am. J. Med. 62: 452-458, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/300225/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;300225&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(77)90846-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="300225">Ahr et al. (1977)</a>, <a href="#46" class="mim-tip-reference" title="Hanna, W., McCarroll, D., Lin, D., Chua, W., McDonald, T. P., Chen, J., Congdon, C., Lange, R. D. &lt;strong&gt;A study of a Caucasian family with variant von Willebrand&#x27;s disease in association with vascular telangiectasia and haemoglobinopathy.&lt;/strong&gt; Thromb. Haemost. 51: 275-278, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6429886/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6429886&lt;/a&gt;]" pmid="6429886">Hanna et al. (1984)</a>, and <a href="#53" class="mim-tip-reference" title="Iannuzzi, M. C., Hidaka, N., Boehnke, M., Bruck, M. E., Hanna, W. T., Collins, F. S., Ginsburg, D. &lt;strong&gt;Analysis of the relationship of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia and identification of a potential type IIA vWD mutation (ile865-to-thr).&lt;/strong&gt; Am. J. Hum. Genet. 48: 757-763, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1673047/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1673047&lt;/a&gt;]" pmid="1673047">Iannuzzi et al. (1991)</a>. Since the CRST syndrome is occasionally familial (<a href="#34" class="mim-tip-reference" title="Frayha, R. A., Tabbara, K. F., Geha, R. S. &lt;strong&gt;Familial CRST syndrome with sicca complex.&lt;/strong&gt; J. Rheum. 4: 53-58, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/886553/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;886553&lt;/a&gt;]" pmid="886553">Frayha et al., 1977</a>), a positive family history is not a conclusive differentiating feature of HHT disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6429886+59851+300225+886553+1673047+309746+14171636" 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>On behalf of the Scientific Advisory Board of the HHT Foundation International, Inc., <a href="#102" class="mim-tip-reference" title="Shovlin, C. L., Guttmacher, A. E., Buscarini, E., Faughnan, M. E., Hyland, R. H., Westermann, C. J. J., Kjeldsen, A. D., Plauchu, H. &lt;strong&gt;Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).&lt;/strong&gt; Am. J. Med. Genet. 91: 66-67, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10751092/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10751092&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(20000306)91:1&lt;66::aid-ajmg12&gt;3.0.co;2-p&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10751092">Shovlin et al. (2000)</a> presented consensus clinical diagnostic criteria. The 4 criteria (epistaxes, telangiectasia, visceral lesions, and an appropriate family history) were carefully delineated. They considered the HHT diagnosis to be definite if 3 criteria were present. They suggested that a diagnosis of HHT cannot be established in patients with only 2 criteria, but should be recorded as possible or suspected in order to maintain a high index of clinical suspicion. If fewer than 2 criteria are present, HHT is unlikely, although children of affected individuals should be considered at risk in view of age-related penetrance in this disorder. They pointed out that these criteria may be refined as molecular diagnostic tests become available in the future. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10751092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#66" class="mim-tip-reference" title="Mager, J. J., Westermann, C. J. J. &lt;strong&gt;Value of capillary microscopy in the diagnosis of hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Arch. Derm. 136: 732-734, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10871934/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10871934&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archderm.136.6.732&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10871934">Mager and Westermann (2000)</a> used capillary microscopy to compare the capillary pattern of the fingernail folds in 54 patients with confirmed diagnoses of HHT and 40 healthy controls. Forty-five (83%) of the 54 patients with HHT had giant loops between the normal capillaries in the nail fold and 2 patients had enlargement of the draining limb of the capillary only. Seven patients (13%) had no vascular abnormalities in the nail fold. Seven of 9 patients with HHT but without cutaneous telangiectases had microvascular abnormalities. None of the volunteers had vascular abnormalities. The difference between both groups was significant (chi square, P less than 0.001). <a href="#66" class="mim-tip-reference" title="Mager, J. J., Westermann, C. J. J. &lt;strong&gt;Value of capillary microscopy in the diagnosis of hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Arch. Derm. 136: 732-734, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10871934/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10871934&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archderm.136.6.732&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10871934">Mager and Westermann (2000)</a> concluded that capillary microscopy can be useful in diagnosing HHT, especially in children with an affected parent and cases where there are few or atypical telangiectases present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10871934" 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="#32" class="mim-tip-reference" title="Flessa, H. C., Glueck, H. I. &lt;strong&gt;Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease): management of epistaxis in nine patients using systemic hormone therapy.&lt;/strong&gt; Arch. Otolaryng. 103: 148-151, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/836242/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;836242&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archotol.1977.00780200074007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="836242">Flessa and Glueck (1977)</a> recommended Enovid (a combination of a progestogen and an estrogen) for control of severe nosebleeds. They described experience with 9 patients of whom 1 was male. <a href="#114" class="mim-tip-reference" title="Vase, P. &lt;strong&gt;Estrogen treatment of hereditary hemorrhagic telangiectasia: a double-blind controlled clinical trial.&lt;/strong&gt; Acta Med. Scand. 209: 393-396, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7018182/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7018182&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.0954-6820.1981.tb11614.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7018182">Vase (1981)</a> could demonstrate no benefit of estrogen therapy. Oral estrogen has been found useful in controlling the frequency and severity of epistaxis (<a href="#50" class="mim-tip-reference" title="Harrison, D. F. &lt;strong&gt;Use of estrogen in treatment of familial hemorrhagic telangiectasia.&lt;/strong&gt; Laryngoscope 92: 314-320, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7040867/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7040867&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1288/00005537-198203000-00017&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7040867">Harrison, 1982</a>). It improves the continuity of telangiectatic endothelium and induces metaplasia of overlying epithelium (<a href="#75" class="mim-tip-reference" title="Menefee, M. G., Flessa, H. C., Glueck, H. I., Hogg, S. P. &lt;strong&gt;Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease): an electron microscopic study of the vascular lesions before and after therapy with hormones.&lt;/strong&gt; Arch. Otolaryng. 101: 246-251, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1120015/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1120015&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archotol.1975.00780330042011&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1120015">Menefee et al., 1975</a>). <a href="#47" class="mim-tip-reference" title="Haq, A. U., Glass, J., Netchvolodoff, C. V., Bowen, L. M. &lt;strong&gt;Hereditary hemorrhagic telangiectasia and danazol. (Letter)&lt;/strong&gt; Ann. Intern. Med. 109: 171 only, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3382114/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3382114&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.7326/0003-4819-109-2-171_1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3382114">Haq et al. (1988)</a> used danazol, a synthetic weak androgen, with highly satisfactory results in a single patient, a 41-year-old man. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7018182+1120015+3382114+836242+7040867" 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>Aminocoporic acid, an antifibrinolytic drug, can reduce epistaxis in HHT (<a href="#94" class="mim-tip-reference" title="Saba, H. I., Morelli, G. A., Logrono, L. A. &lt;strong&gt;Treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid.&lt;/strong&gt; New Eng. J. Med. 330: 1789-1790, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8190155/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8190155&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199406233302504&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8190155">Saba et al., 1994</a>), but its effect is inconsistent (<a href="#57" class="mim-tip-reference" title="Korzenik, J. R., Topazian, M. D., White, R. &lt;strong&gt;Treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid. (Letter)&lt;/strong&gt; New Eng. J. Med. 331: 1236 only, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7935675/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7935675&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199411033311818&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7935675">Korzenik et al., 1994</a>). <a href="#95" class="mim-tip-reference" title="Sabba, C., Gallitelli, M., Palasciano, G. &lt;strong&gt;Efficacy of unusually high doses of tranexamic acid for the treatment of epistaxis in hereditary hemorrhagic telangiectasia. (Letter)&lt;/strong&gt; New Eng. J. Med. 345: 926 only, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11565536/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11565536&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM200109203451216&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11565536">Sabba et al. (2001)</a> successfully treated 3 HHT patients with tranexamic acid, another antifibrinolytic drug which is 10 times as potent as aminocaproic acid and has a longer half-life. <a href="#55" class="mim-tip-reference" title="Klepfish, A., Berrebi, A., Schattner, A. &lt;strong&gt;Intranasal tranexamic acid treatment for severe epistaxis in hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Arch. Intern. Med. 161: 767 only, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11231712/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11231712&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archinte.161.5.767&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11231712">Klepfish et al. (2001)</a> reported successful use of topical tranexamic acid for severe epistaxis in HHT. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7935675+11231712+11565536+8190155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#121" class="mim-tip-reference" title="White, R. I., Jr., Lynch-Nyhan, A., Terry, P., Buescher, P. C., Farmlett, E. J., Charnas, L., Shuman, K., Kim, W., Kinnison, M., Mitchell, S. E. &lt;strong&gt;Pulmonary arteriovenous malformations: techniques and long-term outcome of embolotherapy.&lt;/strong&gt; Radiology 169: 663-669, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3186989/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3186989&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1148/radiology.169.3.3186989&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3186989">White et al. (1988)</a> reported embolotherapy of pulmonary arteriovenous malformations in 67 patients with HHT. Eleven of the patients had been discovered by means of family screening with measurements of arterial blood gases and chest radiography. Hypoxemia in the upright position is a clue to the presence of PAVMs. The AV fistulae are most often found in the lower lobes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3186989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#61" class="mim-tip-reference" title="Lee, D. W., White, R. I., Jr., Egglin, T. K., Pollak, J. S., Fayad, P. B., Wirth, J. A., Rosenblatt, M. M., Dickey, K. W., Burdge, C. M. &lt;strong&gt;Embolotherapy of large pulmonary arteriovenous malformations: long-term results.&lt;/strong&gt; Ann. Thorac. Surg. 64: 930-940, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9354504/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9354504&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0003-4975(97)00815-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9354504">Lee et al. (1997)</a> reported the long-term results of transcatheter embolotherapy of large pulmonary arteriovenous malformations in 221 consecutive patients, many of them with HHT, treated over a period of 18 years by a single physician, Robert I. White, Jr. The follow-up focused particularly on 45 patients with 52 PAVMs supplied by feeding arteries 8 mm in diameter or larger. Of these 45 patients, 38 (84%) with 44 PAVMs (85%) were cured by the first embolotherapy (mean follow-up, 4.7 years). Acute periprocedural complications included self-limited pleurisy (31%), angina secondary to air embolus (2%), and paradoxical embolization of a device during deployment (4%). None of these events led to short- or long-term sequelae. Seven patients (16%) had persistence of the PAVM, attributable to recanalization in 4 patients and to interim accessory artery growth in 3. Two of these patients presented with ischemic stroke several years after the initial treatment. Eight persistent PAVMs were re-treated successfully, 7 by a second procedure and 1 with a third procedure (mean follow-up, 5.9 and 5.3 years, respectively). Thus, embolotherapy was successful in a great majority of cases. Continued patency due to recanalization or accessory artery growth was easily detected and treated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9354504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Bose, P., Holter, J. L., Selby, G. B. &lt;strong&gt;Bevacizumab in hereditary hemorrhagic telangiectasia. (Letter)&lt;/strong&gt; New Eng. J. Med. 360: 2143-2144, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19439755/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19439755&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMc0901421&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19439755">Bose et al. (2009)</a> reported a 42-year-old man with a 3-generation family history of HHT who presented with longstanding epistaxis, hemoptysis, and a hemoglobin level half that of normal. After unsuccessful treatment with oral and intravenous iron, he received 4 cycles over 8 weeks of an anti-VEGF (see <a href="/entry/192240">192240</a>) antibody, bevacizumab. After treatment, the patient's episodes of epistaxis were fewer in number and of shorter duration, and his hemoglobin level remained stable without transfusion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19439755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#81" class="mim-tip-reference" title="Oosting, S., Nagengast, W., de Vries, E. &lt;strong&gt;More on bevacizumab in hereditary hemorrhagic telangiectasia. (Letter)&lt;/strong&gt; New Eng. J. Med. 361: 931 only, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19710496/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19710496&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMc091271&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19710496">Oosting et al. (2009)</a> reported treatment with bevacizumab in a 55-year-old man with HHT who had intractable pain and frequent episodes of pancreatitis related to pancreatic AVMs. The treatment immediately stopped the patient's epistaxis, skin vascular signs became less pronounced, and the frequency and severity of pancreatitis diminished to the point where morphine and tube feeding could be discontinued. No change in the volume of AVMs was observed on CT scan. <a href="#88" class="mim-tip-reference" title="Retornaz, F., Rinaldi, Y., Duvoux, C. &lt;strong&gt;More on bevacizumab in hereditary hemorrhagic telangiectasia. (Letter)&lt;/strong&gt; New Eng. J. Med. 361: 931 only, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19714790/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19714790&lt;/a&gt;]" pmid="19714790">Retornaz et al. (2009)</a> administered bevacizumab to a 65-year-old woman with HHT and life-threatening, recurrent hemorrhage, for which she had received 27 blood transfusions over a 6-month period. After treatment, blood transfusions were not required for 2 months; subsequently, hemorrhage recurred but with a reduced need for blood transfusion. <a href="#12" class="mim-tip-reference" title="Bose, P., Holter J. L., Selby, G. B. &lt;strong&gt;Reply to Oosting et al. and Restornaz et al. (Letter)&lt;/strong&gt; New Eng. J. Med. 361: 931-932, 2009."None>Bose et al. (2009)</a> noted that these cases provided further evidence of the efficacy of bevacizumab in patients with HHT, with improvement in symptoms and transfusion requirements without appreciable change in AVMs; they stated that although there was no difference in the size of their patient's pulmonary AVMs on CT scan before and after bevacizumab, he continued to report symptomatic benefit more than a year after completing therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19710496+19714790" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#60" class="mim-tip-reference" title="Lebrin, F., Srun, S., Raymond, K., Martin, S., van den Brink, S., Freitas, C., Breant, C., Mathivet, T., Larrivee, B., Thomas, J.-L., Arthur, H. M., Westermann, C. J. J., Disch, F., Mager, J. J., Snijder, R. J., Eichmann, A., Mummery, C. L. &lt;strong&gt;Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Nature Med. 16: 420-428, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20364125/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20364125&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nm.2131&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20364125">Lebrin et al. (2010)</a> found that treatment with thalidomide, which has antiangiogenic activity, reduced nosebleed frequency in 6 of 7 individuals with HHT, and reduced the duration of nosebleeds in 3 of 4 for whom data were available. There were some side effects, including constipation and drowsiness. In vitro studies of mouse tissue showed that thalidomide stimulated the recruitment of mural cells to the vessel branches, resulting in a stabilization of blood vessels. Studies in Eng +/- mice also showed that thalidomide normalized inappropriate vessel formation and promoted pericyte and mural cell activation and vessel maturation via increased expression of Pdgfb (<a href="/entry/190040">190040</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20364125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Brinkerhoff, B. T., Poetker, D. M., Choong, N. W. &lt;strong&gt;Long-term therapy with bevacizumab in hereditary hemorrhagic telangiectasia. (Letter)&lt;/strong&gt; New Eng. J. Med. 364: 688-689, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21323562/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21323562&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMc1012774&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21323562">Brinkerhoff et al. (2011)</a> described the long-term outcome of a patient who received multiple repeat courses of intravenous bevacizumab, a potent VEGF antagonist, for treatment of severe HHT. The patient was a 62-year-old male with severe HHT-related epistaxis who required blood transfusions and intravenous iron therapy to maintain a baseline hemoglobin level ranging from 5 to 7 grams per deciliter. Treatment with 4 intravenous infusions every 2 weeks resolved the epistaxis and improved his hemoglobin level to 13 grams per deciliter. After 1 year without treatment, he had a progressive relapse. Retreatment again resulted in cessation of epistaxis and a concomitant rise in hemoglobin. Subsequently a third course was required. In each case, there was a favorable response and no adverse events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21323562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Al-Samkari, H., Kasthuri, R. S., Iyer, V. N., Pishko, A. M., Decker, J. E., Weiss, C. R., Whitehead, K. J., Conrad, M. B., Zumberg, M. S., Zhou, J. Y., Parambil, J., Marsh, D., Clancy, M., Bradley, L., Wisniewski, L., Carper, B. A., Thomas, S. M., McCrae, K. R. &lt;strong&gt;Pomalidomide for epistaxis in hereditary hemorrhagic telangiectasia.&lt;/strong&gt; New Eng. J. Med. 391: 1015-1027, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/39292928/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;39292928&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=39292928[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa2312749&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="39292928">Al-Samkari et al. (2024)</a> conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide, a safer thalidomide derivative, for the treatment of HHT. Patients were randomly assigned, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more was considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations). The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (+/- SD) Epistaxis Severity Score was 5.0+/-1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; p = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash. Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39292928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="populationGenetics" class="mim-anchor"></a>
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<strong>Population Genetics</strong>
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<p>In a study of 18 families, <a href="#112" class="mim-tip-reference" title="Tuente, W. &lt;strong&gt;Klinik und Genetik der Oslerschen Krankheit.&lt;/strong&gt; Z. Mensch. Vererb. Konstitutionsl. 37: 221-250, 1964."None>Tuente (1964)</a> estimated the frequency of the condition to be 1 or 2 in 100,000. The mutation rate was estimated to be 2 x 10(-6) to 3 x 10(-6).</p><p><a href="#85" class="mim-tip-reference" title="Porteous, M. E. M., Burn, J., Proctor, S. J. &lt;strong&gt;Hereditary haemorrhagic telangiectasia: a clinical analysis.&lt;/strong&gt; J. Med. Genet. 29: 527-530, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1518020/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1518020&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.29.8.527&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1518020">Porteous et al. (1992)</a> asked all clinicians in the northern region of England for information regarding their patients with HHT; 79 patients were identified in a population of 3.1 million, giving a minimum point prevalence of 1 in 39,216. Given the variable expression, the true incidence is likely to be much higher than this figure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1518020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#83" class="mim-tip-reference" title="Plauchu, H., Bideau, A., Robert, J. M. &lt;strong&gt;La maladie de Rendu-Osler dans le Haut-Jura: decouverte d&#x27;une concentration geographique et etude epidemiologique.&lt;/strong&gt; Nouv. Presse Med. 9: 2921, 1980."None>Plauchu et al. (1980)</a> found a concentration of HHT patients in Haut-Jura in eastern France; 120 affected individuals from 42 families lived in a 300-km square area.</p><p><a href="#9" class="mim-tip-reference" title="Bideau, A., Brunet, G., Heyer, E., Plauchu, H., Robert, J.-M. &lt;strong&gt;An abnormal concentration of cases of Rendu-Osler disease in the Valserine valley of the French Jura: a genealogical and demographic study.&lt;/strong&gt; Ann. Hum. Biol. 19: 233-247, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1616282/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1616282&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1080/03014469200002112&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1616282">Bideau et al. (1992)</a> reported that only 17.8% of the genes of inhabitants of the Valserine valley of the French Jura could be traced to the 'original population,' although persons affected with HHT disease belonged to a subset of the population that had lived in the villages for more than 10 generations. All patients in 85 sibships were related. The smallest number of originator couples who lived at the beginning of the 18th century amounted to 16; the unique originator may, therefore, have lived approximately 4 generations earlier. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1616282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Guttmacher, A. E., McKinnon, W. C., Upton, M. D. &lt;strong&gt;Hereditary hemorrhagic telangiectasia: a disorder in search of the genetics community. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 52: 252-253, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7802026/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7802026&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320520232&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7802026">Guttmacher et al. (1994)</a> suggested that the prevalence of HHT has been underestimated at the level of 1 in 50,000 to 100,000 and that the disorder has not received the attention it deserves from the medical genetics community. He urged clinical geneticists and genetic counselors to play an active role in making the diagnosis, coordinating care, and providing genetic counseling. They estimated the minimal prevalence rate of HHT in Vermont to be 1:16,500 and suggested that this frequency is not atypical of rates elsewhere. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7802026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Dakeishi, M., Shioya, T., Wada, Y., Shindo, T., Otaka, K., Manabe, M., Nozaki, J., Inoue, S., Koizumi, A. &lt;strong&gt;Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan.&lt;/strong&gt; Hum. Mutat. 19: 140-148, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11793473/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11793473&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10026&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11793473">Dakeishi et al. (2002)</a> estimated the population prevalence of HHT in the Akita prefecture of northern Japan to be 1:5,000 to 1:8,000, roughly comparable with those reported in European and U.S. populations, which is contradictory to the traditional view that HHT is rare among Asians. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11793473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#119" class="mim-tip-reference" title="Westermann, C. J. J., Rosina, A. F., de Vries, V., de Coteau, P. A. &lt;strong&gt;The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of the Netherlands Antilles: a family screening.&lt;/strong&gt; Am. J. Med. Genet. 116A: 324-328, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12522784/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12522784&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10002&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12522784">Westermann et al. (2003)</a> studied HHT in the Afro-Caribbean population of the Netherlands Antilles and found a point prevalence of 1 in 1,331 inhabitants older than 12 years, the highest known in the world. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12522784" 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>Osler (1849-1919) described this disorder as a 'family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes' (<a href="#82" class="mim-tip-reference" title="Osler, W. &lt;strong&gt;On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes.&lt;/strong&gt; Bull. Johns Hopkins Hosp. 7: 333-337, 1901."None>Osler, 1901</a>). The only previous report he could find was that of Rendu dated 1896. Because of his prominence as a physician and author of a textbook, Osler 'put the disorder on the map.' F. Parkes Weber (1863-1962), who pronounced his name in the Germanic manner even though he was born in England and always lived there, described cases later as part of a lifelong interest in angiomas and other vascular lesions (<a href="#74" class="mim-tip-reference" title="McKusick, V. A. &lt;strong&gt;Frederick Parkes Weber: 1863-1962.&lt;/strong&gt; JAMA 183: 45-49, 1963.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13932117/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13932117&lt;/a&gt;]" pmid="13932117">McKusick, 1963</a>). The frequent eponymic sequence, although not chronologically accurate, is perhaps justified by the contribution to the nosology of the entity: Osler-Rendu-Weber (pronounced OHz-ler, ren-DYU, and VAY-ber). <a href="#45" class="mim-tip-reference" title="Hanes, F. M. &lt;strong&gt;Multiple hereditary telangiectases causes hemorrhage (hereditary hemorrhagic telangiectasia).&lt;/strong&gt; Bull. Johns Hopkins Hosp. 20: 63-73, 1909."None>Hanes (1909)</a>, then a medical resident at the Johns Hopkins Hospital, wrote a rather comprehensive discussion of this disorder, together with color illustrations of the lesions of the lips, tongue, and face, and named the disorder 'hereditary hemorrhagic telangiectasia.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13932117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p><a href="#22" class="mim-tip-reference" title="Christian, H. A. &lt;strong&gt;Osler: recollections of an undergraduate medical student at Johns Hopkins.&lt;/strong&gt; Arch. Intern. Med. 84: 77-83, 1949."None>Christian (1949)</a>, who graduated from Johns Hopkins in 1900 during Osler's time there, wrote as follows: 'At another of the dispensary clinics it fell to my lot to demonstrate the case of a young man who frequently had come to the dispensary, as well as been a patient several times in the hospital wards. He was deeply jaundiced and had a large liver and many angiectases in his nose, which bled frequently and profusely. His condition had been diagnosed as Hanot's cirrhosis. His brother, a little older, had the same disease. The patient had devised a very simple way to control his nose bleeds: He took a thin rubber finger cot, put into its end a small cork, through which passed a small glass tube, and to the glass tube he had attached a bit of thin-walled rubber tubing. He would insert the finger cot well into his bleeding nostril, expand it by blowing through the rubber tubing and clamp off the tubing between his teeth to keep the cot distended until its pressure stopped the nosebleed. I had him demonstrate this to the section, while Dr. Osler commented on how simple but ingenious methods might be useful to the physician and patient....Dr. Osler had asked me to keep track of the patient, to report on his visits to the dispensary and to make follow-up visits at his home. At a later clinic Dr. Osler asked me how the patient was, and I replied, 'I think he is about as usual. I visited him about two weeks ago.' With this, Dr. Osler, to my embarrassment, dramatically brought forth a tray containing a large liver and other organs, saying, 'Christian, he did not continue to do so well. Dr. MacCallum autopsied him this morning.' That was the only liver showing Hanot's cirrhosis that I ever saw. Obviously, it made a great impression on me, and for the subsequent fifty years I have diligently sought for another patient with similar cirrhosis of the liver, so far with no success.' The description by <a href="#22" class="mim-tip-reference" title="Christian, H. A. &lt;strong&gt;Osler: recollections of an undergraduate medical student at Johns Hopkins.&lt;/strong&gt; Arch. Intern. Med. 84: 77-83, 1949."None>Christian (1949)</a> sounds much like that given by <a href="#82" class="mim-tip-reference" title="Osler, W. &lt;strong&gt;On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes.&lt;/strong&gt; Bull. Johns Hopkins Hosp. 7: 333-337, 1901."None>Osler (1901)</a> in his classic paper but the latter concerned a man from Kentucky whom he first saw in 1896, who had no affected relatives and no sign of liver disease, and who was still alive at the time of Osler's report. <a href="#82" class="mim-tip-reference" title="Osler, W. &lt;strong&gt;On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes.&lt;/strong&gt; Bull. Johns Hopkins Hosp. 7: 333-337, 1901."None>Osler (1901)</a> wrote: 'He sent a diagram of an ingenious arrangement. He took a rubber finger-stall about three inches long, into which was tied a small bit of rubber tubing, with a stop-cock at one end. He inserted the finger-stall, relaxed, then put the tubing in his mouth, inflated it, and turned the stop-cock.' The diagram was included in a letter dated Dec. 16, 1898. In the fifth edition of his Principles and Practice of Medicine (1904; p. 574), Osler wrote concerning Hanot hypertrophic cirrhosis: 'Of four recent cases under my care, the ages were from twenty to thirty-five. Two were brothers.' Hanot cirrhosis is a vague entity at best. Did the 2 brothers in fact suffer from Osler's disease, hereditary hemorrhagic telangiectasia (as it was designated by <a href="#45" class="mim-tip-reference" title="Hanes, F. M. &lt;strong&gt;Multiple hereditary telangiectases causes hemorrhage (hereditary hemorrhagic telangiectasia).&lt;/strong&gt; Bull. Johns Hopkins Hosp. 20: 63-73, 1909."None>Hanes, 1909</a>), which is known to be accompanied by cirrhosis?</p>
<p>Reported instances of familial epistaxis (e.g., <a href="#59" class="mim-tip-reference" title="Lane, W. C. &lt;strong&gt;Hereditary nose-bleed.&lt;/strong&gt; J. Hered. 7: 132-134, 1916."None>Lane, 1916</a>) probably represented this disorder. Indeed, <a href="#82" class="mim-tip-reference" title="Osler, W. &lt;strong&gt;On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes.&lt;/strong&gt; Bull. Johns Hopkins Hosp. 7: 333-337, 1901."None>Osler (1901)</a> entitled his original report, 'A family form of recurring epistaxis.'</p>
<p><a href="#35" class="mim-tip-reference" title="Fuchizaki, U., Miyamori, H., Kitagawa, S., Kaneko, S., Kobayashi, K. &lt;strong&gt;Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease).&lt;/strong&gt; Lancet 362: 1490-1494, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14602446/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14602446&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(03)14696-X&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14602446">Fuchizaki et al. (2003)</a> provided biographical information on the individuals whose names are included in triple eponym Rendu-Osler-Weber. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14602446" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p>A comment on semantics: The individual lesion in HHT is a telangiectasis (pl., telangiectases); the process is telangiectasia. Multiple lesions should not be referred to as 'telangiectasias.' One would use the latter term only in a statement such as, 'Dr. William Bennett Bean was a student of the telangiectasias.'</p>
<p><strong><em>Hereditary Hemorrhagic Telangiectasia Type 3</em></strong>
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<div class="mim-changed mim-change"><p>There is no longer evidence for an independent HHT3 locus on chromosome 5. A pathogenic mutation in the ENG gene (HHT1) was identified in a member of the HHT3 family.</p></div>
<p>In a 4-generation HHT pedigree with pulmonary involvement, <a href="#115" class="mim-tip-reference" title="Wallace, G. M. F., Shovlin, C. L. &lt;strong&gt;A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1.&lt;/strong&gt; Thorax 55: 685-690, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10899246/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10899246&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/thorax.55.8.685&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10899246">Wallace and Shovlin (2000)</a> excluded linkage to the 2 known HHT genes, endoglin (ENG; <a href="/entry/131195">131195</a>) and ALK1 (ACVRL1; <a href="/entry/601284">601284</a>), and concluded that there is a third HHT locus that accounts for disease in some HHT patients with pulmonary involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10899246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p>In a genomewide scan of the HHT family described by <a href="#115" class="mim-tip-reference" title="Wallace, G. M. F., Shovlin, C. L. &lt;strong&gt;A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1.&lt;/strong&gt; Thorax 55: 685-690, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10899246/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10899246&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/thorax.55.8.685&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10899246">Wallace and Shovlin (2000)</a>, <a href="#23" class="mim-tip-reference" title="Cole, S. G., Begbie, M. E., Wallace, G. M. F., Shovlin, C. L. &lt;strong&gt;A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5.&lt;/strong&gt; J. Med. Genet. 42: 577-582, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15994879/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15994879&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2004.028712&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15994879">Cole et al. (2005)</a> identified a 12-cM interval on chromosome 5 where lod scores exceeded 2; supplementary adjacent markers generated a 2-point maximum lod score of 3.45 (theta = 0.0). A series of 2-point lod scores and recombination mapping identified a 5.4-cM disease interval at 5q31.3-q32 in which a single haplotype was inherited by all 12 affected members of the pedigree. <a href="#23" class="mim-tip-reference" title="Cole, S. G., Begbie, M. E., Wallace, G. M. F., Shovlin, C. L. &lt;strong&gt;A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5.&lt;/strong&gt; J. Med. Genet. 42: 577-582, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15994879/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15994879&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2004.028712&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15994879">Cole et al. (2005)</a> concluded that classic HHT with pulmonary involvement can result from mutations in an unidentified gene on chromosome 5. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15994879+10899246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p><a href="#101" class="mim-tip-reference" title="Shovlin, C. L., Almaghlouth, F. I., Alsafi, A., Coote, N., Rennie, C., Wallace, G. M., Govani, F. S., Genomics England Research Consortium. &lt;strong&gt;Updates on diagnostic criteria for hereditary haemorrhagic telangiectasia in the light of whole genome sequencing of &#x27;gene-negative&#x27; individuals recruited to the 100 000 Genomes Project.&lt;/strong&gt; J. Med. Genet. 61: 182-185, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/37586837/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;37586837&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=37586837[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg-2023-109195&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="37586837">Shovlin et al. (2024)</a> restudied the 4-generation pedigree with HHT originally reported by <a href="#115" class="mim-tip-reference" title="Wallace, G. M. F., Shovlin, C. L. &lt;strong&gt;A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1.&lt;/strong&gt; Thorax 55: 685-690, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10899246/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10899246&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/thorax.55.8.685&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10899246">Wallace and Shovlin (2000)</a>, noting that phenotype assignment in HHT can be fraught with difficulty and that at least 1 of the individuals in the family who met 3 of the consensus clinical criteria for diagnosis of HHT was, in fact, unaffected. The authors stated that although inheritance patterns across chr5:142,963,257-147,604,706 did distinguish between members of the 4-generation pedigree with and without nosebleeds and telangiectasia, the region did not contain a new HHT-causing gene; instead, affected family members were found to be heterozygous for a pathogenic frameshift variant in the ENG gene. Based on these findings, <a href="#101" class="mim-tip-reference" title="Shovlin, C. L., Almaghlouth, F. I., Alsafi, A., Coote, N., Rennie, C., Wallace, G. M., Govani, F. S., Genomics England Research Consortium. &lt;strong&gt;Updates on diagnostic criteria for hereditary haemorrhagic telangiectasia in the light of whole genome sequencing of &#x27;gene-negative&#x27; individuals recruited to the 100 000 Genomes Project.&lt;/strong&gt; J. Med. Genet. 61: 182-185, 2024.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/37586837/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;37586837&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=37586837[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg-2023-109195&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="37586837">Shovlin et al. (2024)</a> concluded that there was no longer evidence for an independent HHT3 locus on chromosome 5. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=37586837+10899246" 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="#65" class="mim-tip-reference" title="Li, D. Y., Sorensen, L. K., Brooke, B. S., Urness, L. D., Davis, E. C., Taylor, D. G., Boak, B. B., Wendel, D. P. &lt;strong&gt;Defective angiogenesis in mice lacking endoglin.&lt;/strong&gt; Science 284: 1534-1537, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10348742/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10348742&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.284.5419.1534&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10348742">Li et al. (1999)</a> generated mice deficient for endoglin (<a href="/entry/131195">131195</a>) using homologous recombination. Eng +/- mice had normal life expectancy, fertility, and gross appearance. Eng -/- mice died by embryonic day 11.5. At embryonic day 10.5, Eng -/- mice were 3 times smaller than Eng +/+ mice and had fewer somites. The Eng -/- embryos exhibited an absence of vascular organization and the presence of multiple pockets of red blood cells on the surface of the yolk sac. Epithelial marker expression was not disrupted in Eng -/- mice. There was persistence of an immature perineural vascular plexus, indicating a failure of endothelial remodeling in Eng -/- embryos. At embryonic day 10.5, the cardiac tube did not complete rotation and was associated with a serosanguinous pericardial effusion. By embryonic day 10.5, the major vessels including the dorsal aortae, intersomitic vessels, branchial arches, and carotid arteries were atretic and disorganized in Eng -/- embryos. There was also poor vascular smooth muscle cell formation at both embryonic days 9.5 and 10.5. These vascular smooth muscle cell abnormalities preceded the differences in endothelial organization. In contrast to mice lacking TGF-beta, vasculogenesis was unaffected. <a href="#65" class="mim-tip-reference" title="Li, D. Y., Sorensen, L. K., Brooke, B. S., Urness, L. D., Davis, E. C., Taylor, D. G., Boak, B. B., Wendel, D. P. &lt;strong&gt;Defective angiogenesis in mice lacking endoglin.&lt;/strong&gt; Science 284: 1534-1537, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10348742/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10348742&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.284.5419.1534&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10348742">Li et al. (1999)</a> concluded that their results demonstrated that endoglin is essential for angiogenesis and suggest a pathogenic mechanism for HHT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10348742" 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>See Also:</strong>
</span>
</h4>
<div id="mimSeeAlsoFold" class="collapse in mimTextToggleFold">
<span class="mim-text-font">
<a href="#Bacardi1971" class="mim-tip-reference" title="Bacardi, R., Guardia, J., Rius, J. M., Angel, J., Martinez, J. M. &lt;strong&gt;Maladie de Rendu-Osler-Weber avec atteinte hepatique (telangiectasie hepatique).&lt;/strong&gt; Presse Med. 79: 1023-1024, 1971.">Bacardi et al. (1971)</a>; <a href="#Baker1980" class="mim-tip-reference" title="Baker, S. R. &lt;strong&gt;Glomus jugulare and hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Arch. Otolaryng. 106: 182-186, 1980.">Baker (1980)</a>; <a href="#Bergqvist1962" class="mim-tip-reference" title="Bergqvist, N., Hessen, I., Hey, M. &lt;strong&gt;Arteriovenous pulmonary aneurysms in Osler&#x27;s disease.&lt;/strong&gt; Acta Med. Scand. 171: 301-309, 1962.">Bergqvist et al. (1962)</a>; <a href="#Bideau1980" class="mim-tip-reference" title="Bideau, A., Plauchu, H., Jacquard, A., Robert, J. M., Brunet, G., Desjardins, B. &lt;strong&gt;La genopathie de Rendu-Osler dans le Haut-Jura: convergences des approches methodologiques de la demographie historique et de la genetique.&lt;/strong&gt; J. Genet. Hum. 28: 127-147, 1980.">Bideau
et al. (1980)</a>; <a href="#Burckhardt1973" class="mim-tip-reference" title="Burckhardt, D., Stalder, G. A., Ludin, H., Bianchi, L. &lt;strong&gt;Hyperdynamic circulatory state due to Osler-Weber-Rendu disease with intrahepatic arterio-venous fistulas.&lt;/strong&gt; Am. Heart J. 85: 797-800, 1973.">Burckhardt et al. (1973)</a>; <a href="#Chandler1965" class="mim-tip-reference" title="Chandler, D. &lt;strong&gt;Pulmonary and cerebral arteriovenous fistula with Osler&#x27;s disease.&lt;/strong&gt; Arch. Intern. Med. 116: 277-281, 1965.">Chandler (1965)</a>; <a href="#Chernelch1969" class="mim-tip-reference" title="Chernelch, M., Winchell, H. S., Pollycove, M., Sargent, T., Kusubov, N. &lt;strong&gt;Prolonged intravenous iron-dextran therapy in a patient with multiple hereditary telangiectasia.&lt;/strong&gt; Blood 34: 691-695, 1969.">Chernelch
et al. (1969)</a>; <a href="#Childers1967" class="mim-tip-reference" title="Childers, R. W., Ranniger, K., Rabinowitz, M. &lt;strong&gt;Intrahepatic arteriovenous fistula with pulmonary vascular obstruction in Osler-Rendu-Weber disease.&lt;/strong&gt; Am. J. Med. 43: 304-312, 1967.">Childers et al. (1967)</a>; <a href="#Daly1976" class="mim-tip-reference" title="Daly, J. J., Schiller, A. L. &lt;strong&gt;The liver in hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease).&lt;/strong&gt; Am. J. Med. 60: 723-726, 1976.">Daly and Schiller (1976)</a>; <a href="#Davis1971" class="mim-tip-reference" title="Davis, D. G., Smith, J. L. &lt;strong&gt;Retinal involvement in hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Arch. Ophthal. 85: 618-623, 1971.">Davis and Smith (1971)</a>; <a href="#Feizi1972" class="mim-tip-reference" title="Feizi, O. &lt;strong&gt;Hereditary hemorrhagic telangiectasia presenting with portal hypertension and cirrhosis of the liver: a case report.&lt;/strong&gt; Gastroenterology 63: 660-664, 1972.">Feizi (1972)</a>; <a href="#Foggie1928" class="mim-tip-reference" title="Foggie, W. E. &lt;strong&gt;Hereditary haemorrhagic telangiectasia with recurring haematuria.&lt;/strong&gt; Edinburgh Med. J. 35: 281-290, 1928.">Foggie (1928)</a>; <a href="#Harkonen1981" class="mim-tip-reference" title="Harkonen, M. &lt;strong&gt;Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) complicated by pulmonary arteriovenous fistula and brain abscess.&lt;/strong&gt; Acta Med. Scand. 209: 137-139, 1981.">Harkonen (1981)</a>; <a href="#Harrison1970" class="mim-tip-reference" title="Harrison, D. F. N. &lt;strong&gt;Hereditary haemorrhagic telangiectasia and oral contraceptives. (Letter)&lt;/strong&gt; Lancet 295: 721 only, 1970. Note: Originally Volume I.">Harrison (1970)</a>; <a href="#Hodgson1959" class="mim-tip-reference" title="Hodgson, C. H., Burchell, H. B., Good, C. A., Clagett, O. T. &lt;strong&gt;Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous fistula: survey of a large family.&lt;/strong&gt; New Eng. J. Med. 261: 625-636, 1959.">Hodgson et al. (1959)</a>; <a href="#Kjellberg1983" class="mim-tip-reference" title="Kjellberg, R. N., Hanamura, T., Davis, K. R., Lyons, S. L., Adams, R. D. &lt;strong&gt;Bragg-peak proton-beam therapy for arteriovenous malformations of the brain.&lt;/strong&gt; New Eng. J. Med. 309: 269-274, 1983.">Kjellberg et al. (1983)</a>; <a href="#McAllister1994" class="mim-tip-reference" title="McAllister, K. A., Lennon, F., Bowles-Biesecker, B., McKinnon, W. C., Helmbold, E. A., Markel, D. S., Jackson, C. E., Guttmacher, A. E., Pericak-Vance, M. A., Marchuk, D. A. &lt;strong&gt;Genetic heterogeneity in hereditary haemorrhagic telangiectasia: possible correlation with clinical phenotype.&lt;/strong&gt; J. Med. Genet. 31: 927-932, 1994.">McAllister et al. (1994)</a>; <a href="#McCaffrey1977" class="mim-tip-reference" title="McCaffrey, T. V., Kern, E. B., Lake, C. F. &lt;strong&gt;Management of epistaxis in hereditary hemorrhagic telangiectasia: review of 80 cases.&lt;/strong&gt; Arch. Otolaryng. 103: 627-630, 1977.">McCaffrey et al. (1977)</a>; <a href="#McCue1984" class="mim-tip-reference" title="McCue, C. M., Hartenberg, M., Nance, W. E. &lt;strong&gt;Pulmonary arteriovenous malformations related to Rendu-Osler-Weber syndrome.&lt;/strong&gt; Am. J. Med. Genet. 19: 19-27, 1984.">McCue et al.
(1984)</a>; <a href="#Mirra1973" class="mim-tip-reference" title="Mirra, J. M., Arnold, W. D. &lt;strong&gt;Skeletal hemangiomatosis in association with hereditary hemorrhagic telangiectasia. A case report.&lt;/strong&gt; J. Bone Joint Surg. Am. 55: 850-854, 1973.">Mirra and Arnold (1973)</a>; <a href="#Nyman1977" class="mim-tip-reference" title="Nyman, U. &lt;strong&gt;Angiography in hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Acta Radiol. Diagn. (Stockh.) 18: 581-592, 1977.">Nyman (1977)</a>; <a href="#Rewane1983" class="mim-tip-reference" title="Rewane, I. &lt;strong&gt;Hereditary haemorrhagic telangiectasia (Osler&#x27;s disease) with special reference to angiographic findings in liver cirrhosis.&lt;/strong&gt; Brit. J. Radiol. 56: 207-209, 1983.">Rewane (1983)</a>; <a href="#Rowley1970" class="mim-tip-reference" title="Rowley, P. T., Kurnick, J., Cheville, R. &lt;strong&gt;Hereditary haemorrhagic telangiectasia: aggravation by oral contraceptives? (Letter)&lt;/strong&gt; Lancet 295: 474-475, 1970. Note: Originally Volume I.">Rowley
et al. (1970)</a>; <a href="#Saunders1960" class="mim-tip-reference" title="Saunders, W. H. &lt;strong&gt;Permanent control of nosebleeds in patients with hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Ann. Intern. Med. 53: 147-152, 1960.">Saunders (1960)</a>; <a href="#Schuster1937" class="mim-tip-reference" title="Schuster, N. H. &lt;strong&gt;Familial haemorrhagic telangiectasia associated with multiple aneurysms of the splenic artery.&lt;/strong&gt; J. Path. 44: 29-39, 1937.">Schuster (1937)</a>; <a href="#Tedesco1975" class="mim-tip-reference" title="Tedesco, F. J., Hosty, T. A., Sumner, H. W. &lt;strong&gt;Hereditary hemorrhagic telangiectasia presenting as an unusual gastric lesion.&lt;/strong&gt; Gastroenterology 68: 384-386, 1975.">Tedesco et al.
(1975)</a>; <a href="#Terry1980" class="mim-tip-reference" title="Terry, P. B., Barth, K. H., Kaufman, S. L., White, R. I., Jr. &lt;strong&gt;Balloon embolization for treatment of pulmonary arteriovenous fistulas.&lt;/strong&gt; New Eng. J. Med. 302: 1189-1190, 1980.">Terry et al. (1980)</a>; <a href="#Terry1983" class="mim-tip-reference" title="Terry, P. B., White, R. I., Jr., Barth, K. H., Kaufman, S. L., Mitchell, S. E. &lt;strong&gt;Pulmonary arteriovenous malformations: physiologic observations and results of therapeutic balloon embolization.&lt;/strong&gt; New Eng. J. Med. 308: 1197-1200, 1983.">Terry et al. (1983)</a>; <a href="#Thomas1974" class="mim-tip-reference" title="Thomas, M. L., Carty, H. &lt;strong&gt;Hereditary haemorrhagic telangiectasia of the liver demonstrated angiographically.&lt;/strong&gt; Acta Radiol. Diagn. (Stockh.) 15: 433-439, 1974.">Thomas and Carty
(1974)</a>; <a href="#Trell1972" class="mim-tip-reference" title="Trell, E., Johansson, B. W., Linell, F., Ripa, J. &lt;strong&gt;Familial pulmonary hypertension and multiple abnormalities of large systemic arteries in Osler&#x27;s disease.&lt;/strong&gt; Am. J. Med. 53: 50-63, 1972.">Trell et al. (1972)</a>; <a href="#Whicker1972" class="mim-tip-reference" title="Whicker, J. H., Lake, C. F. &lt;strong&gt;Hemilateral rhinotomy in the treatment of hereditary hemorrhagic telangiectasia.&lt;/strong&gt; Arch. Otolaryng. 96: 319-321, 1972.">Whicker and Lake (1972)</a>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Aassar1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Aassar, O. S., Friedman, C. M., White, R. I., Jr.
<strong>The natural history of epistaxis in hereditary hemorrhagic telangiectasia.</strong>
Laryngoscope 101: 977-980, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1886446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1886446</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1886446" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1288/00005537-199109000-00008" target="_blank">Full Text</a>]
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<a id="Ahr1977" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ahr, D. J., Rickles, F. R., Hoyer, L. W., O'Leary, D. S., Conrad, M. E.
<strong>Von Willebrand's disease and hemorrhagic telangiectasia: association of two complex disorders of hemostasis resulting in life-threatening hemorrhage.</strong>
Am. J. Med. 62: 452-458, 1977.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/300225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">300225</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=300225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0002-9343(77)90846-4" target="_blank">Full Text</a>]
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<a id="Al-Samkari2024" class="mim-anchor"></a>
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Al-Samkari, H., Kasthuri, R. S., Iyer, V. N., Pishko, A. M., Decker, J. E., Weiss, C. R., Whitehead, K. J., Conrad, M. B., Zumberg, M. S., Zhou, J. Y., Parambil, J., Marsh, D., Clancy, M., Bradley, L., Wisniewski, L., Carper, B. A., Thomas, S. M., McCrae, K. R.
<strong>Pomalidomide for epistaxis in hereditary hemorrhagic telangiectasia.</strong>
New Eng. J. Med. 391: 1015-1027, 2024.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39292928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39292928</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39292928[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=39292928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa2312749" target="_blank">Full Text</a>]
</p>
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<a id="Bacardi1971" class="mim-anchor"></a>
<div class="">
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Bacardi, R., Guardia, J., Rius, J. M., Angel, J., Martinez, J. M.
<strong>Maladie de Rendu-Osler-Weber avec atteinte hepatique (telangiectasie hepatique).</strong>
Presse Med. 79: 1023-1024, 1971.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5580533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5580533</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5580533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="Baker1980" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Baker, S. R.
<strong>Glomus jugulare and hereditary hemorrhagic telangiectasia.</strong>
Arch. Otolaryng. 106: 182-186, 1980.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6243932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6243932</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6243932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archotol.1980.00790270046011" target="_blank">Full Text</a>]
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<a id="Bayrak-Toydemir2006" class="mim-anchor"></a>
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Bayrak-Toydemir, P., McDonald, J., Markewitz, B., Lewin, S., Miller, F., Chou, L.-S., Gedge, F., Tang, W., Coon, H., Mao, R.
<strong>Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.</strong>
Am. J. Med. Genet. 140A: 463-470, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16470787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16470787</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16470787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.31101" target="_blank">Full Text</a>]
</p>
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<a id="7" class="mim-anchor"></a>
<a id="Berg2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Berg, J., Porteous, M., Reinhardt, D., Gallione, C., Holloway, S., Umasunthar, T., Lux, A., McKinnon, W., Marchuk, D., Guttmacher, A.
<strong>Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations.</strong>
J. Med. Genet. 40: 585-590, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920067</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920067" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.40.8.585" target="_blank">Full Text</a>]
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<a id="Bergqvist1962" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bergqvist, N., Hessen, I., Hey, M.
<strong>Arteriovenous pulmonary aneurysms in Osler's disease.</strong>
Acta Med. Scand. 171: 301-309, 1962.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13867789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13867789</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13867789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.0954-6820.1962.tb04192.x" target="_blank">Full Text</a>]
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<a id="Bideau1992" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bideau, A., Brunet, G., Heyer, E., Plauchu, H., Robert, J.-M.
<strong>An abnormal concentration of cases of Rendu-Osler disease in the Valserine valley of the French Jura: a genealogical and demographic study.</strong>
Ann. Hum. Biol. 19: 233-247, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1616282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1616282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1616282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1080/03014469200002112" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
<a id="Bideau1980" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bideau, A., Plauchu, H., Jacquard, A., Robert, J. M., Brunet, G., Desjardins, B.
<strong>La genopathie de Rendu-Osler dans le Haut-Jura: convergences des approches methodologiques de la demographie historique et de la genetique.</strong>
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<strong>Bevacizumab in hereditary hemorrhagic telangiectasia. (Letter)</strong>
New Eng. J. Med. 360: 2143-2144, 2009.
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[<a href="https://doi.org/10.1056/NEJMc0901421" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20342" target="_blank">Full Text</a>]
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<strong>Ocular manifestations in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease).</strong>
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[<a href="https://doi.org/10.1016/0002-9394(89)90261-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/1523-1747.ep12555569" target="_blank">Full Text</a>]
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Brinkerhoff, B. T., Poetker, D. M., Choong, N. W.
<strong>Long-term therapy with bevacizumab in hereditary hemorrhagic telangiectasia. (Letter)</strong>
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[<a href="https://doi.org/10.1056/NEJMc1012774" target="_blank">Full Text</a>]
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Burckhardt, D., Stalder, G. A., Ludin, H., Bianchi, L.
<strong>Hyperdynamic circulatory state due to Osler-Weber-Rendu disease with intrahepatic arterio-venous fistulas.</strong>
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[<a href="https://doi.org/10.1016/0002-8703(73)90431-6" target="_blank">Full Text</a>]
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Canzonieri, C., Centenara, L., Ornati, F., Pagella, F., Matti, E., Alvisi, C., Danesino, C., Perego, M., Olivieri, C.
<strong>Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes.</strong>
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[<a href="https://doi.org/10.1038/gim.2013.62" target="_blank">Full Text</a>]
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<a id="Chandler1965" class="mim-anchor"></a>
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Chandler, D.
<strong>Pulmonary and cerebral arteriovenous fistula with Osler's disease.</strong>
Arch. Intern. Med. 116: 277-281, 1965.
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[<a href="https://doi.org/10.1001/archinte.1965.03870020117021" target="_blank">Full Text</a>]
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<a id="Chernelch1969" class="mim-anchor"></a>
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Chernelch, M., Winchell, H. S., Pollycove, M., Sargent, T., Kusubov, N.
<strong>Prolonged intravenous iron-dextran therapy in a patient with multiple hereditary telangiectasia.</strong>
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Childers, R. W., Ranniger, K., Rabinowitz, M.
<strong>Intrahepatic arteriovenous fistula with pulmonary vascular obstruction in Osler-Rendu-Weber disease.</strong>
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[<a href="https://doi.org/10.1016/0002-9343(67)90173-8" target="_blank">Full Text</a>]
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Christian, H. A.
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Cole, S. G., Begbie, M. E., Wallace, G. M. F., Shovlin, C. L.
<strong>A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5.</strong>
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[<a href="https://doi.org/10.1136/jmg.2004.028712" target="_blank">Full Text</a>]
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<strong>Telangiectasia and von Willebrand's disease in two families.</strong>
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[<a href="https://doi.org/10.7326/0003-4819-89-6-921" target="_blank">Full Text</a>]
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Cooke, D. A. P.
<strong>Renal arteriovenous malformation demonstrated angiographically in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease).</strong>
J. Roy. Soc. Med. 79: 744-746, 1986.
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[<a href="https://doi.org/10.1177/014107688607901220" target="_blank">Full Text</a>]
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<a id="Cronstedt1982" class="mim-anchor"></a>
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Cronstedt, J., Brechter, C., Carling, L.
<strong>Coexistent hereditary haemorrhagic telangiectasia and primary thrombocythaemia--coincidence or syndrome?</strong>
Acta Med. Scand. 212: 261-265, 1982.
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[<a href="https://doi.org/10.1111/j.0954-6820.1982.tb03210.x" target="_blank">Full Text</a>]
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<a id="Dakeishi2002" class="mim-anchor"></a>
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<p class="mim-text-font">
Dakeishi, M., Shioya, T., Wada, Y., Shindo, T., Otaka, K., Manabe, M., Nozaki, J., Inoue, S., Koizumi, A.
<strong>Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan.</strong>
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[<a href="https://doi.org/10.1002/humu.10026" target="_blank">Full Text</a>]
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Daly, J. J., Schiller, A. L.
<strong>The liver in hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease).</strong>
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[<a href="https://doi.org/10.1016/0002-9343(76)90510-6" target="_blank">Full Text</a>]
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Davis, D. G., Smith, J. L.
<strong>Retinal involvement in hereditary hemorrhagic telangiectasia.</strong>
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[<a href="https://doi.org/10.1001/archopht.1971.00990050620018" target="_blank">Full Text</a>]
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<a id="Dines1974" class="mim-anchor"></a>
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<p class="mim-text-font">
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<strong>Hereditary hemorrhagic telangiectasia presenting with portal hypertension and cirrhosis of the liver: a case report.</strong>
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Flessa, H. C., Glueck, H. I.
<strong>Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease): management of epistaxis in nine patients using systemic hormone therapy.</strong>
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[<a href="https://doi.org/10.1001/archotol.1977.00780200074007" target="_blank">Full Text</a>]
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<strong>Hereditary haemorrhagic telangiectasia with recurring haematuria.</strong>
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<strong>Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease).</strong>
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[<a href="https://doi.org/10.1016/S0140-6736(03)14696-X" target="_blank">Full Text</a>]
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Fulbright, R. K., Chaloupka, J. C., Putman, C. M., Sze, G. K., Merriam, M. M., Lee, G. K., Fayad, P. B., Awad, I. A., White, R. I., Jr.
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<strong>Liver disease in patients with hereditary hemorrhagic telangiectasia.</strong>
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[<a href="https://doi.org/10.1056/NEJM200009283431305" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ejhg.2009.35" target="_blank">Full Text</a>]
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Greenspan, D. S., Northrup, H., Au, K.-S., McAllister, K. A., Francomano, C. A., Wenstrup, R. J., Marchuk, D. A., Kwiatkowski, D. J.
<strong>COL5A1: fine genetic mapping and exclusion as a candidate gene in families with nail-patella syndrome, tuberous sclerosis 1, hereditary hemorrhagic telangiectasia, and Ehlers-Danlos syndrome type II.</strong>
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[<a href="https://doi.org/10.1016/0888-7543(95)80021-d" target="_blank">Full Text</a>]
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Guillen, B., Guizar, J., de la Cruz, J., Salamanca, F.
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[<a href="https://doi.org/10.1111/j.1399-0004.1991.tb03014.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199510053331407" target="_blank">Full Text</a>]
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Guttmacher, A. E., McKinnon, W. C., Upton, M. D.
<strong>Hereditary hemorrhagic telangiectasia: a disorder in search of the genetics community. (Letter)</strong>
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[<a href="https://doi.org/10.1002/ajmg.1320520232" target="_blank">Full Text</a>]
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<strong>Hereditary hemorrhagic telangiectasia. A visceral angiodysplasia associated with gastrointestinal hemorrhage.</strong>
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[<a href="https://doi.org/10.1148/90.6.1143" target="_blank">Full Text</a>]
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<strong>Multiple hereditary telangiectases causes hemorrhage (hereditary hemorrhagic telangiectasia).</strong>
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Hanna, W., McCarroll, D., Lin, D., Chua, W., McDonald, T. P., Chen, J., Congdon, C., Lange, R. D.
<strong>A study of a Caucasian family with variant von Willebrand's disease in association with vascular telangiectasia and haemoglobinopathy.</strong>
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<strong>Hereditary hemorrhagic telangiectasia and danazol. (Letter)</strong>
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[<a href="https://doi.org/10.7326/0003-4819-109-2-171_1" target="_blank">Full Text</a>]
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Harkonen, M.
<strong>Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) complicated by pulmonary arteriovenous fistula and brain abscess.</strong>
Acta Med. Scand. 209: 137-139, 1981.
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[<a href="https://doi.org/10.1111/j.0954-6820.1981.tb11567.x" target="_blank">Full Text</a>]
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<strong>Hereditary haemorrhagic telangiectasia and oral contraceptives. (Letter)</strong>
Lancet 295: 721 only, 1970. Note: Originally Volume I.
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[<a href="https://doi.org/10.1016/s0140-6736(70)90955-4" target="_blank">Full Text</a>]
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<strong>Use of estrogen in treatment of familial hemorrhagic telangiectasia.</strong>
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[<a href="https://doi.org/10.1288/00005537-198203000-00017" target="_blank">Full Text</a>]
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Heutink, P., Haitjema, T., Breedveld, G. J., Janssen, B., Sandkuijl, L. A., Bontekoe, C. J. M., Westerman, C. J. J., Oostra, B. A.
<strong>Linkage of hereditary haemorrhagic telangiectasia to chromosome 9q34 and evidence for locus heterogeneity.</strong>
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[<a href="https://doi.org/10.1136/jmg.31.12.933" target="_blank">Full Text</a>]
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<a id="Hodgson1959" class="mim-anchor"></a>
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<strong>Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous fistula: survey of a large family.</strong>
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[<a href="https://doi.org/10.1056/NEJM195909242611301" target="_blank">Full Text</a>]
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<strong>Analysis of the relationship of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia and identification of a potential type IIA vWD mutation (ile865-to-thr).</strong>
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Kjellberg, R. N., Hanamura, T., Davis, K. R., Lyons, S. L., Adams, R. D.
<strong>Bragg-peak proton-beam therapy for arteriovenous malformations of the brain.</strong>
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[<a href="https://doi.org/10.1056/NEJM198308043090503" target="_blank">Full Text</a>]
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<strong>Intranasal tranexamic acid treatment for severe epistaxis in hereditary hemorrhagic telangiectasia.</strong>
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[<a href="https://doi.org/10.1001/archinte.161.5.767" target="_blank">Full Text</a>]
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<strong>Cardiac tamponade in hereditary hemorrhagic telangiectasia.</strong>
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[<a href="https://doi.org/10.1016/s0002-9343(98)00238-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199411033311818" target="_blank">Full Text</a>]
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<strong>Coronary artery ectasia associated with hereditary hemorrhagic telangiectasia.</strong>
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[<a href="https://doi.org/10.1136/jmg.29.8.527" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.31.12.925" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(76)90729-7" target="_blank">Full Text</a>]
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<strong>Hereditary haemorrhagic telangiectasia (Osler's disease) with special reference to angiographic findings in liver cirrhosis.</strong>
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[<a href="https://doi.org/10.1259/0007-1285-56-663-207" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0046-8177(88)80160-6" target="_blank">Full Text</a>]
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Roman, G., Fisher, M., Perl, D. P., Poser, C. M.
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[<a href="https://doi.org/10.1002/ana.410040207" target="_blank">Full Text</a>]
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Rowley, P. T., Kurnick, J., Cheville, R.
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[<a href="https://doi.org/10.1016/s0140-6736(70)90870-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s10038-019-0564-x" target="_blank">Full Text</a>]
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<strong>Treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid.</strong>
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[<a href="https://doi.org/10.1056/NEJM199406233302504" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM200109203451216" target="_blank">Full Text</a>]
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<strong>Permanent control of nosebleeds in patients with hereditary hemorrhagic telangiectasia.</strong>
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[<a href="https://doi.org/10.7326/0003-4819-53-1-147" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00000478-199803000-00013" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1055/s-2008-1059420" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2008.00968.x" target="_blank">Full Text</a>]
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Shovlin, C. L., Guttmacher, A. E., Buscarini, E., Faughnan, M. E., Hyland, R. H., Westermann, C. J. J., Kjeldsen, A. D., Plauchu, H.
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[<a href="https://doi.org/10.1002/(sici)1096-8628(20000306)91:1&lt;66::aid-ajmg12&gt;3.0.co;2-p" target="_blank">Full Text</a>]
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<strong>Clinical and experimental studies in human inheritance: is the homozygous form of multiple telangiectasia lethal?</strong>
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[<a href="https://doi.org/10.1038/s41525-023-00378-5" target="_blank">Full Text</a>]
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Steele, J. S., Nath, P. U., Burn, J., Porteous, M. E. M.
<strong>An association between migrainous aura and hereditary haemorrhagic telangiectasia.</strong>
Headache 33: 145-148, 1993.
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[<a href="https://doi.org/10.1111/j.1526-4610.1993.hed3303145.x" target="_blank">Full Text</a>]
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<strong>Balloon embolization for treatment of pulmonary arteriovenous fistulas.</strong>
New Eng. J. Med. 302: 1189-1190, 1980.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7366659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7366659</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7366659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM198005223022107" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="109" class="mim-anchor"></a>
<a id="Terry1983" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Terry, P. B., White, R. I., Jr., Barth, K. H., Kaufman, S. L., Mitchell, S. E.
<strong>Pulmonary arteriovenous malformations: physiologic observations and results of therapeutic balloon embolization.</strong>
New Eng. J. Med. 308: 1197-1200, 1983.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6405268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6405268</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6405268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM198305193082005" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="110" class="mim-anchor"></a>
<a id="Thomas1974" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Thomas, M. L., Carty, H.
<strong>Hereditary haemorrhagic telangiectasia of the liver demonstrated angiographically.</strong>
Acta Radiol. Diagn. (Stockh.) 15: 433-439, 1974.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4413669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4413669</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4413669" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1177/028418517401500409" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="111" class="mim-anchor"></a>
<a id="Trell1972" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Trell, E., Johansson, B. W., Linell, F., Ripa, J.
<strong>Familial pulmonary hypertension and multiple abnormalities of large systemic arteries in Osler's disease.</strong>
Am. J. Med. 53: 50-63, 1972.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5037289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5037289</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5037289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0002-9343(72)90115-5" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="112" class="mim-anchor"></a>
<a id="Tuente1964" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Tuente, W.
<strong>Klinik und Genetik der Oslerschen Krankheit.</strong>
Z. Mensch. Vererb. Konstitutionsl. 37: 221-250, 1964.
</p>
</div>
</li>
<li>
<a id="113" class="mim-anchor"></a>
<a id="Vase1985" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vase, P., Holm, M., Arendrup, H.
<strong>Pulmonary arteriovenous fistules in hereditary haemorrhagic telangiectasia.</strong>
Acta Med. Scand. 218: 105-109, 1985.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4050544/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4050544</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4050544" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.0954-6820.1985.tb08832.x" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="114" class="mim-anchor"></a>
<a id="Vase1981" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vase, P.
<strong>Estrogen treatment of hereditary hemorrhagic telangiectasia: a double-blind controlled clinical trial.</strong>
Acta Med. Scand. 209: 393-396, 1981.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7018182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7018182</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7018182" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.0954-6820.1981.tb11614.x" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="115" class="mim-anchor"></a>
<a id="Wallace2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wallace, G. M. F., Shovlin, C. L.
<strong>A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1.</strong>
Thorax 55: 685-690, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10899246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10899246</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10899246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/thorax.55.8.685" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="116" class="mim-anchor"></a>
<a id="Ward1996" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ward, K.
<strong>Personal Communication.</strong>
Salt Lake City, Utah 2/24/1996.
</p>
</div>
</li>
<li>
<a id="117" class="mim-anchor"></a>
<a id="Wehner2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wehner, L.-E., Folz, B. J., Argyriou, L., Twelkemeyer, S., Teske, U., Geisthoff, U. W., Werner, J. A., Engel, W., Nayernia, K.
<strong>Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations.</strong>
Clin. Genet. 69: 239-245, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16542389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16542389</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16542389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.2006.00574.x" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="118" class="mim-anchor"></a>
<a id="Weik1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Weik, C., Greiner, L.
<strong>The liver in hereditary hemorrhagic telangiectasia (Weber-Rendu-Osler disease).</strong>
Scand. J. Gastroent. 34: 1241-1246, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10636073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10636073</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10636073" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1080/003655299750024779" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="119" class="mim-anchor"></a>
<a id="Westermann2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Westermann, C. J. J., Rosina, A. F., de Vries, V., de Coteau, P. A.
<strong>The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of the Netherlands Antilles: a family screening.</strong>
Am. J. Med. Genet. 116A: 324-328, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522784</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12522784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.10002" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="120" class="mim-anchor"></a>
<a id="Whicker1972" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Whicker, J. H., Lake, C. F.
<strong>Hemilateral rhinotomy in the treatment of hereditary hemorrhagic telangiectasia.</strong>
Arch. Otolaryng. 96: 319-321, 1972.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4563055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4563055</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4563055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archotol.1972.00770090495004" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="121" class="mim-anchor"></a>
<a id="White1988" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
White, R. I., Jr., Lynch-Nyhan, A., Terry, P., Buescher, P. C., Farmlett, E. J., Charnas, L., Shuman, K., Kim, W., Kinnison, M., Mitchell, S. E.
<strong>Pulmonary arteriovenous malformations: techniques and long-term outcome of embolotherapy.</strong>
Radiology 169: 663-669, 1988.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3186989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3186989</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3186989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1148/radiology.169.3.3186989" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="122" class="mim-anchor"></a>
<a id="Winterbauer1964" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Winterbauer, R. H.
<strong>Multiple telangiectasia, Raynaud's phenomenon, sclerodactyly and subcutaneous calcinosis: a syndrome mimicking hereditary hemorrhagic telangiectasia.</strong>
Bull. Johns Hopkins Hosp. 114: 361-383, 1964.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14171636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14171636</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14171636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
</ol>
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</div>
<div>
<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
</span>
</div>
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Marla J. F. O'Neill - updated : 11/18/2024
</span>
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</div>
<div class="row collapse" id="mimCollapseContributors">
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Ada Hamosh - updated : 10/18/2024<br>Ada Hamosh - updated : 1/31/2014<br>Ada Hamosh - updated : 6/20/2012<br>Marla J. F. O'Neill - updated : 7/26/2010<br>Cassandra L. Kniffin - updated : 5/27/2010<br>Marla J. F. O'Neill - updated : 10/5/2009<br>Cassandra L. Kniffin - updated : 7/21/2009<br>Cassandra L. Kniffin - updated : 9/16/2008<br>Victor A. McKusick - updated : 9/29/2006<br>Marla J. F. O'Neill - updated : 7/7/2006<br>Cassandra L. Kniffin - updated : 4/27/2006<br>Cassandra L. Kniffin - updated : 3/21/2006<br>Deborah L. Stone - updated : 7/23/2004<br>Victor A. McKusick - updated : 5/5/2004<br>Victor A. McKusick - updated : 12/23/2003<br>John A. Phillips, III - updated : 11/7/2002<br>Victor A. McKusick - updated : 2/21/2002<br>Victor A. McKusick - updated : 10/2/2001<br>Gary A. Bellus - updated : 4/5/2001<br>Victor A. McKusick - updated : 10/23/2000<br>Victor A. McKusick - updated : 3/23/2000<br>Victor A. McKusick - updated : 3/15/2000<br>Victor A. McKusick - updated : 8/12/1999<br>Ada Hamosh - updated : 6/1/1999<br>Victor A. McKusick - updated : 1/20/1999<br>Victor A. McKusick - updated : 6/12/1998<br>Victor A. McKusick - updated : 5/19/1998
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<div>
<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
<span class="text-nowrap mim-text-font">
Creation Date:
</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Victor A. McKusick : 6/2/1986
</span>
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</div>
<div>
<a id="editHistory" class="mim-anchor"></a>
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carol : 12/20/2024
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<span class="mim-text-font">
alopez : 11/22/2024<br>carol : 11/20/2024<br>alopez : 11/19/2024<br>alopez : 11/18/2024<br>carol : 10/22/2024<br>alopez : 10/18/2024<br>carol : 09/29/2021<br>carol : 08/22/2019<br>carol : 05/16/2019<br>alopez : 05/15/2019<br>carol : 12/06/2017<br>carol : 11/22/2017<br>alopez : 09/21/2015<br>carol : 6/26/2015<br>alopez : 1/31/2014<br>alopez : 1/31/2014<br>carol : 10/31/2013<br>carol : 9/16/2013<br>alopez : 6/26/2012<br>terry : 6/20/2012<br>joanna : 4/25/2012<br>carol : 8/29/2011<br>carol : 8/29/2011<br>terry : 8/26/2011<br>terry : 1/13/2011<br>carol : 12/22/2010<br>carol : 10/4/2010<br>wwang : 7/30/2010<br>terry : 7/26/2010<br>wwang : 6/15/2010<br>ckniffin : 5/27/2010<br>wwang : 10/22/2009<br>terry : 10/5/2009<br>terry : 10/5/2009<br>wwang : 9/4/2009<br>ckniffin : 7/21/2009<br>terry : 6/3/2009<br>terry : 4/8/2009<br>ckniffin : 3/20/2009<br>terry : 2/9/2009<br>terry : 2/9/2009<br>wwang : 9/24/2008<br>ckniffin : 9/16/2008<br>wwang : 12/21/2006<br>ckniffin : 12/15/2006<br>carol : 11/10/2006<br>alopez : 10/13/2006<br>terry : 9/29/2006<br>wwang : 7/7/2006<br>wwang : 5/3/2006<br>ckniffin : 4/27/2006<br>wwang : 3/23/2006<br>ckniffin : 3/21/2006<br>terry : 2/18/2005<br>tkritzer : 7/26/2004<br>terry : 7/23/2004<br>carol : 6/8/2004<br>tkritzer : 6/1/2004<br>terry : 5/5/2004<br>carol : 4/29/2004<br>cwells : 12/24/2003<br>terry : 12/23/2003<br>tkritzer : 10/8/2003<br>tkritzer : 10/1/2003<br>alopez : 11/7/2002<br>terry : 3/5/2002<br>cwells : 2/25/2002<br>terry : 2/21/2002<br>carol : 10/2/2001<br>terry : 10/2/2001<br>cwells : 4/11/2001<br>cwells : 4/5/2001<br>terry : 3/26/2001<br>carol : 11/9/2000<br>mcapotos : 11/6/2000<br>terry : 10/23/2000<br>mcapotos : 3/28/2000<br>mcapotos : 3/28/2000<br>terry : 3/23/2000<br>terry : 3/15/2000<br>carol : 8/16/1999<br>alopez : 8/12/1999<br>terry : 8/12/1999<br>terry : 6/11/1999<br>alopez : 6/1/1999<br>carol : 1/28/1999<br>terry : 1/20/1999<br>carol : 6/19/1998<br>dholmes : 6/12/1998<br>carol : 5/30/1998<br>terry : 5/28/1998<br>terry : 5/19/1998<br>alopez : 5/8/1998<br>dholmes : 5/7/1998<br>dholmes : 5/7/1998<br>terry : 7/10/1997<br>terry : 10/30/1996<br>jamie : 10/23/1996<br>jamie : 10/16/1996<br>mark : 9/26/1996<br>terry : 9/23/1996<br>carol : 8/22/1996<br>marlene : 8/2/1996<br>terry : 7/25/1996<br>mark : 2/19/1996<br>terry : 2/15/1996<br>mark : 11/1/1995<br>carol : 2/7/1995<br>jburn : 10/27/1994<br>terry : 7/27/1994<br>jason : 7/19/1994<br>warfield : 4/21/1994
</span>
</div>
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<div class="container visible-print-block">
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<div class="col-md-8 col-md-offset-1">
<div>
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<h3>
<span class="mim-font">
<strong>#</strong> 187300
</span>
</h3>
</div>
<div>
<h3>
<span class="mim-font">
TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 1; HHT1
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<div >
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
HHT<br />
TELANGIECTASIA, HEREDITARY HEMORRHAGIC, OF RENDU, OSLER, AND WEBER<br />
OSLER-RENDU-WEBER DISEASE<br />
ORW DISEASE
</span>
</h4>
</div>
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<div>
<br />
</div>
</div>
<div>
<p>
<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 21877004; &nbsp;
<strong>ICD10CM:</strong> I78.0; &nbsp;
<strong>ICD9CM:</strong> 448.0; &nbsp;
<strong>ORPHA:</strong> 774; &nbsp;
<strong>DO:</strong> 1270; &nbsp;
</span>
</p>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
9q34.11
</span>
</td>
<td>
<span class="mim-font">
Telangiectasia, hereditary hemorrhagic, type 1
</span>
</td>
<td>
<span class="mim-font">
187300
</span>
</td>
<td>
<span class="mim-font">
Autosomal dominant
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
ENG
</span>
</td>
<td>
<span class="mim-font">
131195
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>TEXT</strong>
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</h4>
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<p>A number sign (#) is used with this entry because hereditary hemorrhagic telangiectasia type 1 (HHT1) is caused by heterozygous mutation in the gene encoding endoglin (ENG; 131195) on chromosome 9q34.</p>
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<strong>Description</strong>
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<p>Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia leading to telangiectases and arteriovenous malformations of skin, mucosa, and viscera. Epistaxis and gastrointestinal bleeding are frequent complications of mucosal involvement. Visceral involvement includes that of the lung, liver, and brain. The most frequent form of hereditary hemorrhagic telangiectasia maps to the long arm of chromosome 9.</p><p><strong><em>Genetic Heterogeneity of Hereditary Hemorrhagic Telangiectasia</em></strong></p><p>
See also HHT2 (600376), caused by mutation in the ALK1 gene (ACVRL1; 601284) on chromosome 12q13; HHT4 (610655), mapped to chromosome 7p14; and HHT5 (615506), caused by mutation in the GDF2 gene (605120) on chromosome 10q11.</p><p>A locus formerly designated HHT3 and mapped to chromosome 5 was found to be in error; see HISTORY. Affected members of the family in which the HHT3 locus was mapped were found to have a mutation in ENG (see MOLECULAR GENETICS) and have been included in HHT1.</p><p>See also juvenile polyposis/HHT syndrome (175050), caused by mutation in the SMAD4 gene (600993).</p>
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<strong>Clinical Features</strong>
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<p>HHT is highly penetrant; in a series of 384 patients, Plauchu et al. (1989) found at least 1 manifestation in 97%, while Porteous et al. (1992) found complete penetrance by 40 years of age in a series of 35 British families with 98 affected members. Sixty-two percent of these were clinically affected by age 16, with epistaxes being the presenting feature in 90% of cases. Aassar et al. (1991) found that the mean age of onset of epistaxis in HHT was 12 years, with more than 90% becoming manifest before 21 years. Blood loss from the nasal mucosa may become severe. Telangiectases also occur on the mucosal surface of the tongue (where bleeding may prove difficult to control), lips, face, conjunctiva, ears and fingers. Plauchu et al. (1989) noted facial involvement in 33% and lesions on the hands or wrists of 41% of their patients </p><p>Porteous et al. (1992) found significant gastrointestinal hemorrhage in 16% of patients, with half of these requiring transfusion. The preponderance of upper GI involvement may have reflected the reliance on upper GI endoscopy. </p><p>By angiographic methods, various types of visceral angiodysplasias have been demonstrated (Halpern et al., 1968). These include arterial aneurysm, arteriovenous communication including discrete arteriovenous fistula, conglomerate masses of angiectasia, phlebectasia, and angioma. Pulmonary arteriovenous malformations (PAVMs) are a significant cause of morbidity. Some are sufficiently large to cause heart failure leading to polycythaemia and clubbing. Paradoxical emboli may cause infarction or abscess formation in the brain and elsewhere. Vase et al. (1985) reported PAVMs in 20% of their series. Plauchu et al. (1989) found PAVMs in 4.6% with an age range of 1 to 78 years. In the study of Porteous et al. (1992) 13 (23%) of those who had undergone chest radiography had a visible PAVM; 4 suffered embolic complications, 3 cerebral abscesses, and one a stroke. In one 17-year-old, 50% of the circulating volume was passing through a single PAVM. Reyes-Mujica et al. (1988) described HHT in a 23-month-old girl who died of massive pulmonary hemorrhage. There were no skin lesions but vascular anomalies of varying severity were found in the tongue, esophagus, liver, kidney, central nervous system, ovaries, spleen, and lymph nodes. Before death, the child had 15 episodes of hemoptysis and 2 of epistaxis. The parents, by contrast, had no evidence of the disease but 1 grandfather had died after bleeding from the mouth following physical exertion. Dines et al. (1974) reviewed 63 cases of pulmonary arteriovenous fistula seen at the Mayo Clinic; HHT was recognized in 38 (60%). </p><p>Cirrhosis of the liver may occur; Plauchu et al. (1989) found liver involvement in 27 patients (8%); 17 of these had cirrhosis, which was the cause of death in 5. Michaeli et al. (1968) described a 47-year-old woman with HHT disease and hepatic portacaval shunts of sufficient magnitude to cause repeated episodes of encephalopathy. The liver was not scarred. Nikolopoulos et al. (1988) raised the question of familial tendency to hepatic involvement in HHT. They described 2 brothers with intrahepatic arteriovenous shunts of sufficient size to cause hyperdynamic circulation, leading to cirrhosis; the mother and 3 maternal uncles died of cirrhosis with rupture of esophageal varices. Members of the previous generation also had a history of hyperdynamic circulation. Selmaier et al. (1993) described the case of a 50-year-old woman with heart failure resulting from calcified hemangiomatosis of the liver with a high shunt volume. Saxena et al. (1998) reported the case of a 43-year-old woman who received a transplant for end-stage liver disease due to HHT and fibropolycystic liver disease. The liver showed extensive vascular malformations of arteries and veins, as well as telangiectasia and fibrosis. In addition, there were cystically dilated ducts containing inspissated bile and extensive von Meyenburg complexes. The case raised the question of a possible relationship between polycystic liver disease (174050) and HHT. (A von Meyenburg complex consists of clusters of small bile ducts occurring in polycystic livers, separate from the portal areas.) </p><p>In the liver, the vascular abnormalities of HHT are associated with marked fibrosis and/or cirrhosis. Weik and Greiner (1999) found hepatic manifestations of HHT in 4 women and 1 man (51 to 63 years of age) presenting initially with slight disturbances of liver function. In 3 patients, progressive liver insufficiency developed. </p><p>Garcia-Tsao et al. (2000) described the clinical findings and results of hemodynamic, angiographic, and imaging studies in 19 patients with HHT and symptomatic liver involvement. Ages ranged from 34 to 74 years in the 14 women and 5 men. All but 1 had a hyperdynamic circulation (cardiac index, 4.2 to 7.3 liters per minute per square meter of body-surface area). In 8 patients, the clinical findings were consistent with the presence of high-output heart failure. Manifestations of portal hypertension such as ascites or variceal bleeding were present in 6 patients. Manifestations of biliary disease, such as an elevated alkaline phosphatase level and abnormalities on bile duct imaging, were present in 5 patients. One of these patients died after an unsuccessful attempt at liver transplantation. </p><p>Cooke (1986) described renal arteriovenous malformations in a patient with episodic hematuria and renal colic due to clots. </p><p>Telangiectases may occur in the bladder, although Plauchu et al. (1989) found only 2 symptomatic patients among their 324 cases. Kurnik and Heymann (1989) described 3-vessel coronary artery ectasia without evidence of atherosclerosis in a 51-year-old man with classic HHT disease. This manifestation had not previously been described although ectasia of other vessels such as intraabdominal ones is well known. In a study of 20 patients with HHT, Brant et al. (1989) found conjunctival telangiectases in 7 and retinal vascular malformations in 2. Visual loss from the intraocular lesions is a rare complication. Bloody tears sometimes occur in patients with conjunctival telangiectases and bleeding from the eyes may also result from the backing up of blood in the lacrimal duct during epistaxis with packing of the nostrils. </p><p>Most of the neurologic morbidity is related to emboli but vascular malformations may occur; Guillen et al. (1991) found 1 individual, in a Mexican family with 15 affected members, who needed surgical treatment for a cerebral lesion, while 3 of the patients seen by Porteous et al. (1992) had symptomatic cerebral lesions. In the latter report, 46.3% of patients with no known CNS pathology described visual symptoms suggestive of migrainous aura in the absence of headache and nausea compared to 5.7% of controls. Steele et al. (1993) investigated migraine prevalence in 58 British adult HHT gene carriers without known neurologic deficits; 40 carriers of the gene for familial adenomatous polyposis (FAP; 175100) were used as controls. They found that 50% of the HHT carriers fulfill diagnostic criteria for migraine with aura, 4 times the disease control group and 10 times the estimated population prevalence. White had observed this symptom separately and noted that headaches improved in patients who had undergone balloon occlusion of PAVMs (White et al., 1988). This raises the possibility of vasoactive substances which would normally be removed in the pulmonary vascular bed reaching the central nervous system, though if this is the explanation it would suggest that almost half of gene carriers have pulmonary involvement. Another factor may be occult intracranial AVMs; 6 to 8% of HHT patients with PAVMs also have intracranial lesions (Roman et al., 1978). </p><p>Fulbright et al. (1998) reviewed brain magnetic resonance imaging (MRI) of 184 consecutive patients with HHT. Catheter angiography was performed in 17 patients in whom cerebrovascular malformations (CVMs) were detected on MRIs. They found 63 CVMs in 42 patients. Classic arteriovenous malformations (n = 10) had a conspicuous network of vessels with flow voids and enlarged adjacent pial vessels. Apparent venous malformations (n = 5) were best seen after administration of contrast material as a prominent vessel coursing through normal brain parenchyma. Indeterminate vascular malformations (n = 48) had a spectrum of appearances characterized by variable combinations of heterogeneous signal intensity, enhancement, or hemosiderin. Angiography in 17 patients revealed 47 CVMs. Forty-six were arteriovenous malformations (AVMs), including 25 CVMs not seen with MRI and 21 CVMs that by MR criteria included 8 AVMs and 13 indeterminate vascular malformations. Angiography confirmed 1 venous malformation seen with MRI but failed to detect 3 indeterminate lesions revealed by MRI. Thus, MRI revealed a CVM prevalence of 23% (42 of 184). Most CVMs (48 of 63) had an atypical appearance for vascular malformations on MR images. Angiographic correlation suggests that MRI underestimates the prevalence of CVMs and that the majority of indeterminate CVMs, despite their variable MRI appearance, are AVMs. </p><p>Kopel and Lage (1998) described a 37-year-old woman with HHT who developed a large pericardial effusion with cardiac tamponade. Pericardiocentesis yielded a large amount of hemorrhagic pericardial fluid. Because of recurrent cardiac tamponade, the patient underwent partial surgical pericardial excision. Histologic examination of the pericardium showed vascular dysplasia with signs of hemorrhage and inflammation. </p><p>Canzonieri et al. (2014) examined the gastrointestinal tract of consecutive HHT patients to assess distribution, number, size, and type of telangiectases in relation to genotype. Twenty-two patients (13 men; mean age 59 +/- 9 years) were analyzed, 7 with HHT1, 13 with HHT2 (600376), and 2 undefined. Gastrointestinal telangiectases were identified in 86% of HHT1 patients and in 77% of HHT2 patients. </p><p>Ruiz-Llorente et al. (2019) reported a 3-generation Spanish family with HHT and mutation in the ENG gene. All 6 affected individuals exhibited telangiectasias, and all but the youngest (a 9-year-old girl) also experienced epistaxis. In addition, 4 of the 5 affected adults had PAVM, and 1 also had CVM. One patient, a 66-year-old woman, had no solid organ involvement detected by pulmonary or brain imaging, but her 2 affected sons had PAVM and CVM at ages 25 and 34 years. </p><p><strong><em>Reviews</em></strong></p><p>
Guttmacher et al. (1995) reviewed all aspects of HHT. They emphasized that it is important for those affected to be aware of their diagnosis and its implications and to inform health care providers of their condition. Guttmacher et al. (1995) announced that educational materials for patients and providers are available from the HHT Foundation International, Inc. </p><p>Haitjema et al. (1996) provided a review. Marchuk et al. (1998) reported on a 1997 workshop on hereditary hemorrhagic telangiectasia. </p><p>Govani and Shovlin (2009) reviewed the molecular and genetic basis of hereditary hemorrhagic telangiectasia and discussed approaches for diagnosis and clinical management. </p>
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<strong>Inheritance</strong>
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<p>HHT disease is inherited as an autosomal dominant trait. Snyder and Doan (1944) reported a possible instance of homozygosity, 2 affected parents had a stillborn offspring who had extensive angiomatous malformation of the viscera.</p><p>In a large Arab family in the Sahara, Muller et al. (1978) found 87 cases in 6 generations. Because of the extensive consanguinity in the kindred, a person considered to be homozygous was identified. In the case of 4 couples indicated in the pedigree, both partners were affected. The son of one such couple had a total of 13 children by 4 different wives. All the wives were unaffected; all the children were affected. According to the Bayes theory, the probability of homozygosity was estimated to be 0.99975. The father, who was the presumed homozygote and also the proband, had severe but no exceptionally unusual manifestations of the disease. </p>
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<strong>Mapping</strong>
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<p>Using microsatellite markers in a study of 2 extensively affected families, McDonald et al. (1993) showed that the HHT gene maps to 9q. D9S164 showed a combined maximum lod score of 4.39 at a recombination fraction of 0.14, and D9S103 showed a combined maximum lod score of 3.53 at a recombination fraction of 0.11. The probable location of the HHT gene, otherwise symbolized ORW, is 9q33-q34.1. McDonald et al. (1994) estimated that the closest marker, D9S65, is within 1 cM of the gene; it showed a combined lod score of 11.41 with HHT. Shovlin et al. (1994) independently assigned HHT to 9q. </p>
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<strong>Molecular Genetics</strong>
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<p>McAllister et al. (1994) examined endoglin (ENG; 131195), a transforming growth factor-beta (TGF-beta) binding protein, as a candidate gene for HHT because of its chromosomal location, expression pattern, and function. They identified heterozygous mutations in the ENG gene (131195.0001-131195.0003) in 3 affected individuals from different families. This was the first human disease defined as due to a mutation in a member of the TGF-beta receptor complex. Primary pulmonary hypertension (PPH1; 178600) is another autosomal dominant inherited vascular disorder that is caused by a defect in BMPR2 (600799), which is a member of the TGF-beta signaling pathway. </p><p>In 160 unrelated cases of HHT, Lesca et al. (2004) screened the coding sequences of the ENG and ALK1 genes. Germline mutations were identified in 100 patients (62.5%); 36 of the mutations were in ENG and 64 were in ALK1. </p><p>Wehner et al. (2006) identified mutations in 32 (62.7%) of 51 unrelated German patients with HHT. Thirteen mutations were in the ENG gene, consistent with HHT1, and 17 mutations were in the ACVRL1 gene, consistent with HHT2. Analysis of genotype/phenotype correlations was consistent with a more common frequency of PAVMs in patients with HHT1. </p><p>Bossler et al. (2006) described the results of mutation analysis on a consecutive series of 200 individuals undergoing clinical genetic testing for HHT. A total of 127 probands were found, with sequence changes consisting of 103 unique alterations, 68 of which were novel. In addition 8 intragenic rearrangements in the ENG gene (131195), and 2 in ACVRL1 gene (601284) were identified. Surprisingly, almost 50% of the individuals with a single symptom were found to have a significant sequence alteration; 3 of these reported only nosebleeds. </p><p>In a German woman with clinical features of HHT and negative direct sequencing results, Shoukier et al. (2008) identified a deletion of exon 4 of the ENG gene using quantitative real-time polymerase chain reaction (qRT-PCR) and confirmed by multiplex ligation-dependent probe amplification (MLPA). </p><p>In a 3-generation Spanish family with HHT that was negative for mutation after screening with an HHT gene panel, Ruiz-Llorente et al. (2019) sequenced the 5-prime UTR of the ENG gene and identified a variant (c.-142A-T; 131195.0010) that creates a putative AUG initiation codon at -141 bases from the constitutive translation initiation codon. The mutation segregated with disease in the family, and was not found in the dbSNP or gnomAD databases. </p><p>From a cohort of 274 sequenced patients with genetically unresolved HHT, Soukarieh et al. (2023) identified 2 patients with mutations in the 5-prime UTR of the ENG gene, c.-79C-T and c.-68G-A, which were confirmed by Sanger sequencing. Functional analysis of these 2 variants as well as 3 additional previously published 5-prime UTR ENG variants identified in HHT patients, including the c.-142A-T mutation, revealed that all 5 variants created upstream AUGs at the origin of upstream overlapping open reading frames (uoORFs) ending at the same stop codon (c.125), and all showed altered protein levels and function. Experiments using constructs in which the canonical start site had been deleted revealed that the identified upstream AUGs could initiate translation, suggesting that the associated effects were translation-dependent. The authors noted that all of the uoORF-creating variants studied showed ENG protein levels and BMP response element (BRE) activity that were less than 40% and 50%, respectively, compared to wildtype ENG, and were associated with severe HHT symptoms. </p><p>In a whole-genome sequencing study performed prospectively for HHT gene-negative patients as part of the British National Health Service 100,000 Genomes Project, Shovlin et al. (2024) restudied a 4-generation pedigree with HHT that was originally reported by Wallace and Shovlin (2000) and mapped to chromosome 5q31-q32 by Cole et al. (2005), a locus that was designated HHT3. However, Shovlin et al. (2024) identified a pathogenic frameshift variant in the ENG gene in an affected member of that family. The ENG mutation was not present in all family members who were previously designated as affected in the earlier linkage analyses: the authors noted that at least 1 of the individuals in the family who met 3 of the consensus clinical criteria for diagnosis of HHT was, in fact, unaffected. Thus, in addition to awareness that there may be a paucity of clinical signs in individuals with genetically confirmed HHT, the authors emphasized the importance of being cognizant of the potential for overdiagnosis in relatives of patients with HHT who also have recurrent nosebleeds and telangiectasia at characteristic sites. </p><p><strong><em>Exclusion Studies</em></strong></p><p>
Greenspan et al. (1995) excluded the COL5A1 gene as a candidate for HHT mapping to chromosome 9q. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Berg et al. (2003) performed a questionnaire-based study to delineate phenotypic differences between HHT1 and HHT2, which are caused by mutation in the ENG gene and ALK1 (601284) gene, respectively. The questionnaires were completed by 83 patients with known mutations (49 had HHT1 and 34 had HHT2). Patients with HHT1 reported an earlier onset of epistaxis and telangiectasis than those with HHT2. Pulmonary arteriovenous malformations were reported only in the group of HHT1 patients. </p><p>Among 14 kindreds with HHT1 and 12 with HHT2 confirmed by genetic analysis, Bayrak-Toydemir et al. (2006) found that HHT2 was associated with later onset and more hepatic involvement than HHT1. </p><p>Letteboer et al. (2006) analyzed phenotype in relation to sex in 584 Dutch probands and affected family members with HHT1 and HHT2 confirmed by genetic analysis. For the HHT1 group, they found a significantly higher prevalence of PAVM and hepatic AVM in women than in men. </p><p>In a study of 268 Dutch patients with HHT1 and 130 Dutch patients with HHT2, Letteboer et al. (2008) found that oral and nasal mucosal telangiectases were present earlier in life in patients with HHT1 compared to patients with HHT2, whereas dermal lesions were more frequent and appeared earlier in life in patients with HHT2. In both groups, telangiectases of the nasal mucosa were present at a higher prevalence and started to appear earlier in life than those of the oral mucosa or dermal sites. The number of sites affected increased with age in both groups. In patients with HHT1, more women than men had skin telangiectases, particularly on the face. These results confirmed that the frequency of AVMs differ between patients with HHT1 and HHT2, and that these differences can be detected on physical examination. </p>
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<strong>Heterogeneity</strong>
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<p>Genetic heterogeneity was indicated by the results of linkage studies by several groups. Shovlin et al. (1994) found one family that did not map to 9q3. Porteous et al. (1994) pointed out that all of the previously reported 9q34-linked families contained at least 1 affected member with a symptomatic PAVM. Porteous et al. (1994) reported 4 families apparently unlinked to 9q34 and with no evidence of PAVMs. In a study by McAllister et al. (1994), 4 of 7 families gave a posterior probability of more than 99% being of the linked type and 3 families appeared unlinked to 9q34. They were impressed also by the absence of PAVMs in the 3 9q3-unlinked families. In 3 unrelated families of Dutch origin, Heutink et al. (1994) confirmed the linkage to 9q, and in a fourth unrelated family in which 'considerably fewer pulmonary arteriovenous malformations' were present, there was evidence for nonlinkage to this region. </p><p>Cronstedt et al. (1982) observed the coexistence of HHT disease and primary thrombocythemia (187950) in 2 patients, both men in their 70s. </p><p>The observation of a family with both type IIA von Willebrand disease (VWF2A; see 613554) and HHT prompted Iannuzzi et al. (1991) to study genetic linkage of the 2 conditions. No linkage was detected and the VWF gene (613160) was ruled out as a candidate gene for HHT because of the finding of segregation in linkage studies. </p><p>Ward (1996) suggested that there may be a form of hereditary hemorrhagic telangiectasia, unlinked to either chromosome 9 (HHT1) or chromosome 12 (HHT2; 600376), in which the frequency of pulmonary arteriovenous fistulas is intermediate between the high frequency in HHT1 and the low frequency in HHT2.</p>
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<strong>Pathogenesis</strong>
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<p>Braverman et al. (1990) reconstructed representative cutaneous telangiectases by computer from serial 1- or 2-mm plastic embedded sections. The earliest clinically detectable lesion was a focal dilatation of postcapillary venules, which continued to enlarge and eventually connect with dilated arterioles through capillaries. As the vascular lesion increased in size, the capillary segments disappeared and a direct arteriovenous communication was formed. This sequence of events was associated with a perivascular mononuclear cell infiltrate in which most of the cells were lymphocytes and a minority are monocytes/macrophages by ultrastructural characteristics. The telangiectatic lesions of scleroderma are also composed of dilated postcapillary venules and also associated with perivascular infiltrates. Cherry angiomas, however, which are produced by capillary loop aneurysms, are not associated with infiltrates. </p>
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<strong>Diagnosis</strong>
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<p>An important phenocopy is the CRST syndrome (calcinosis, Raynaud syndrome, sclerodactyly, telangiectasia; 181750), a probable 'collagen vascular disease.' The mucosal and cutaneous telangiectases are indistinguishable from those of the hereditary disorder (Winterbauer, 1964). Conlon et al. (1978) described 2 families in which telangiectasia like that of HHT disease occurred with von Willebrand disease. Other families with combined von Willebrand disease and HHT disease were described by Ramsay et al. (1976), Ahr et al. (1977), Hanna et al. (1984), and Iannuzzi et al. (1991). Since the CRST syndrome is occasionally familial (Frayha et al., 1977), a positive family history is not a conclusive differentiating feature of HHT disease. </p><p>On behalf of the Scientific Advisory Board of the HHT Foundation International, Inc., Shovlin et al. (2000) presented consensus clinical diagnostic criteria. The 4 criteria (epistaxes, telangiectasia, visceral lesions, and an appropriate family history) were carefully delineated. They considered the HHT diagnosis to be definite if 3 criteria were present. They suggested that a diagnosis of HHT cannot be established in patients with only 2 criteria, but should be recorded as possible or suspected in order to maintain a high index of clinical suspicion. If fewer than 2 criteria are present, HHT is unlikely, although children of affected individuals should be considered at risk in view of age-related penetrance in this disorder. They pointed out that these criteria may be refined as molecular diagnostic tests become available in the future. </p><p>Mager and Westermann (2000) used capillary microscopy to compare the capillary pattern of the fingernail folds in 54 patients with confirmed diagnoses of HHT and 40 healthy controls. Forty-five (83%) of the 54 patients with HHT had giant loops between the normal capillaries in the nail fold and 2 patients had enlargement of the draining limb of the capillary only. Seven patients (13%) had no vascular abnormalities in the nail fold. Seven of 9 patients with HHT but without cutaneous telangiectases had microvascular abnormalities. None of the volunteers had vascular abnormalities. The difference between both groups was significant (chi square, P less than 0.001). Mager and Westermann (2000) concluded that capillary microscopy can be useful in diagnosing HHT, especially in children with an affected parent and cases where there are few or atypical telangiectases present. </p>
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<strong>Clinical Management</strong>
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<p>Flessa and Glueck (1977) recommended Enovid (a combination of a progestogen and an estrogen) for control of severe nosebleeds. They described experience with 9 patients of whom 1 was male. Vase (1981) could demonstrate no benefit of estrogen therapy. Oral estrogen has been found useful in controlling the frequency and severity of epistaxis (Harrison, 1982). It improves the continuity of telangiectatic endothelium and induces metaplasia of overlying epithelium (Menefee et al., 1975). Haq et al. (1988) used danazol, a synthetic weak androgen, with highly satisfactory results in a single patient, a 41-year-old man. </p><p>Aminocoporic acid, an antifibrinolytic drug, can reduce epistaxis in HHT (Saba et al., 1994), but its effect is inconsistent (Korzenik et al., 1994). Sabba et al. (2001) successfully treated 3 HHT patients with tranexamic acid, another antifibrinolytic drug which is 10 times as potent as aminocaproic acid and has a longer half-life. Klepfish et al. (2001) reported successful use of topical tranexamic acid for severe epistaxis in HHT. </p><p>White et al. (1988) reported embolotherapy of pulmonary arteriovenous malformations in 67 patients with HHT. Eleven of the patients had been discovered by means of family screening with measurements of arterial blood gases and chest radiography. Hypoxemia in the upright position is a clue to the presence of PAVMs. The AV fistulae are most often found in the lower lobes. </p><p>Lee et al. (1997) reported the long-term results of transcatheter embolotherapy of large pulmonary arteriovenous malformations in 221 consecutive patients, many of them with HHT, treated over a period of 18 years by a single physician, Robert I. White, Jr. The follow-up focused particularly on 45 patients with 52 PAVMs supplied by feeding arteries 8 mm in diameter or larger. Of these 45 patients, 38 (84%) with 44 PAVMs (85%) were cured by the first embolotherapy (mean follow-up, 4.7 years). Acute periprocedural complications included self-limited pleurisy (31%), angina secondary to air embolus (2%), and paradoxical embolization of a device during deployment (4%). None of these events led to short- or long-term sequelae. Seven patients (16%) had persistence of the PAVM, attributable to recanalization in 4 patients and to interim accessory artery growth in 3. Two of these patients presented with ischemic stroke several years after the initial treatment. Eight persistent PAVMs were re-treated successfully, 7 by a second procedure and 1 with a third procedure (mean follow-up, 5.9 and 5.3 years, respectively). Thus, embolotherapy was successful in a great majority of cases. Continued patency due to recanalization or accessory artery growth was easily detected and treated. </p><p>Bose et al. (2009) reported a 42-year-old man with a 3-generation family history of HHT who presented with longstanding epistaxis, hemoptysis, and a hemoglobin level half that of normal. After unsuccessful treatment with oral and intravenous iron, he received 4 cycles over 8 weeks of an anti-VEGF (see 192240) antibody, bevacizumab. After treatment, the patient's episodes of epistaxis were fewer in number and of shorter duration, and his hemoglobin level remained stable without transfusion. </p><p>Oosting et al. (2009) reported treatment with bevacizumab in a 55-year-old man with HHT who had intractable pain and frequent episodes of pancreatitis related to pancreatic AVMs. The treatment immediately stopped the patient's epistaxis, skin vascular signs became less pronounced, and the frequency and severity of pancreatitis diminished to the point where morphine and tube feeding could be discontinued. No change in the volume of AVMs was observed on CT scan. Retornaz et al. (2009) administered bevacizumab to a 65-year-old woman with HHT and life-threatening, recurrent hemorrhage, for which she had received 27 blood transfusions over a 6-month period. After treatment, blood transfusions were not required for 2 months; subsequently, hemorrhage recurred but with a reduced need for blood transfusion. Bose et al. (2009) noted that these cases provided further evidence of the efficacy of bevacizumab in patients with HHT, with improvement in symptoms and transfusion requirements without appreciable change in AVMs; they stated that although there was no difference in the size of their patient's pulmonary AVMs on CT scan before and after bevacizumab, he continued to report symptomatic benefit more than a year after completing therapy. </p><p>Lebrin et al. (2010) found that treatment with thalidomide, which has antiangiogenic activity, reduced nosebleed frequency in 6 of 7 individuals with HHT, and reduced the duration of nosebleeds in 3 of 4 for whom data were available. There were some side effects, including constipation and drowsiness. In vitro studies of mouse tissue showed that thalidomide stimulated the recruitment of mural cells to the vessel branches, resulting in a stabilization of blood vessels. Studies in Eng +/- mice also showed that thalidomide normalized inappropriate vessel formation and promoted pericyte and mural cell activation and vessel maturation via increased expression of Pdgfb (190040). </p><p>Brinkerhoff et al. (2011) described the long-term outcome of a patient who received multiple repeat courses of intravenous bevacizumab, a potent VEGF antagonist, for treatment of severe HHT. The patient was a 62-year-old male with severe HHT-related epistaxis who required blood transfusions and intravenous iron therapy to maintain a baseline hemoglobin level ranging from 5 to 7 grams per deciliter. Treatment with 4 intravenous infusions every 2 weeks resolved the epistaxis and improved his hemoglobin level to 13 grams per deciliter. After 1 year without treatment, he had a progressive relapse. Retreatment again resulted in cessation of epistaxis and a concomitant rise in hemoglobin. Subsequently a third course was required. In each case, there was a favorable response and no adverse events. </p><p>Al-Samkari et al. (2024) conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide, a safer thalidomide derivative, for the treatment of HHT. Patients were randomly assigned, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more was considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations). The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (+/- SD) Epistaxis Severity Score was 5.0+/-1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; p = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash. Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In a study of 18 families, Tuente (1964) estimated the frequency of the condition to be 1 or 2 in 100,000. The mutation rate was estimated to be 2 x 10(-6) to 3 x 10(-6).</p><p>Porteous et al. (1992) asked all clinicians in the northern region of England for information regarding their patients with HHT; 79 patients were identified in a population of 3.1 million, giving a minimum point prevalence of 1 in 39,216. Given the variable expression, the true incidence is likely to be much higher than this figure. </p><p>Plauchu et al. (1980) found a concentration of HHT patients in Haut-Jura in eastern France; 120 affected individuals from 42 families lived in a 300-km square area.</p><p>Bideau et al. (1992) reported that only 17.8% of the genes of inhabitants of the Valserine valley of the French Jura could be traced to the 'original population,' although persons affected with HHT disease belonged to a subset of the population that had lived in the villages for more than 10 generations. All patients in 85 sibships were related. The smallest number of originator couples who lived at the beginning of the 18th century amounted to 16; the unique originator may, therefore, have lived approximately 4 generations earlier. </p><p>Guttmacher et al. (1994) suggested that the prevalence of HHT has been underestimated at the level of 1 in 50,000 to 100,000 and that the disorder has not received the attention it deserves from the medical genetics community. He urged clinical geneticists and genetic counselors to play an active role in making the diagnosis, coordinating care, and providing genetic counseling. They estimated the minimal prevalence rate of HHT in Vermont to be 1:16,500 and suggested that this frequency is not atypical of rates elsewhere. </p><p>Dakeishi et al. (2002) estimated the population prevalence of HHT in the Akita prefecture of northern Japan to be 1:5,000 to 1:8,000, roughly comparable with those reported in European and U.S. populations, which is contradictory to the traditional view that HHT is rare among Asians. </p><p>Westermann et al. (2003) studied HHT in the Afro-Caribbean population of the Netherlands Antilles and found a point prevalence of 1 in 1,331 inhabitants older than 12 years, the highest known in the world. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Osler (1849-1919) described this disorder as a 'family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes' (Osler, 1901). The only previous report he could find was that of Rendu dated 1896. Because of his prominence as a physician and author of a textbook, Osler 'put the disorder on the map.' F. Parkes Weber (1863-1962), who pronounced his name in the Germanic manner even though he was born in England and always lived there, described cases later as part of a lifelong interest in angiomas and other vascular lesions (McKusick, 1963). The frequent eponymic sequence, although not chronologically accurate, is perhaps justified by the contribution to the nosology of the entity: Osler-Rendu-Weber (pronounced OHz-ler, ren-DYU, and VAY-ber). Hanes (1909), then a medical resident at the Johns Hopkins Hospital, wrote a rather comprehensive discussion of this disorder, together with color illustrations of the lesions of the lips, tongue, and face, and named the disorder 'hereditary hemorrhagic telangiectasia.' </p><p>Christian (1949), who graduated from Johns Hopkins in 1900 during Osler's time there, wrote as follows: 'At another of the dispensary clinics it fell to my lot to demonstrate the case of a young man who frequently had come to the dispensary, as well as been a patient several times in the hospital wards. He was deeply jaundiced and had a large liver and many angiectases in his nose, which bled frequently and profusely. His condition had been diagnosed as Hanot's cirrhosis. His brother, a little older, had the same disease. The patient had devised a very simple way to control his nose bleeds: He took a thin rubber finger cot, put into its end a small cork, through which passed a small glass tube, and to the glass tube he had attached a bit of thin-walled rubber tubing. He would insert the finger cot well into his bleeding nostril, expand it by blowing through the rubber tubing and clamp off the tubing between his teeth to keep the cot distended until its pressure stopped the nosebleed. I had him demonstrate this to the section, while Dr. Osler commented on how simple but ingenious methods might be useful to the physician and patient....Dr. Osler had asked me to keep track of the patient, to report on his visits to the dispensary and to make follow-up visits at his home. At a later clinic Dr. Osler asked me how the patient was, and I replied, 'I think he is about as usual. I visited him about two weeks ago.' With this, Dr. Osler, to my embarrassment, dramatically brought forth a tray containing a large liver and other organs, saying, 'Christian, he did not continue to do so well. Dr. MacCallum autopsied him this morning.' That was the only liver showing Hanot's cirrhosis that I ever saw. Obviously, it made a great impression on me, and for the subsequent fifty years I have diligently sought for another patient with similar cirrhosis of the liver, so far with no success.' The description by Christian (1949) sounds much like that given by Osler (1901) in his classic paper but the latter concerned a man from Kentucky whom he first saw in 1896, who had no affected relatives and no sign of liver disease, and who was still alive at the time of Osler's report. Osler (1901) wrote: 'He sent a diagram of an ingenious arrangement. He took a rubber finger-stall about three inches long, into which was tied a small bit of rubber tubing, with a stop-cock at one end. He inserted the finger-stall, relaxed, then put the tubing in his mouth, inflated it, and turned the stop-cock.' The diagram was included in a letter dated Dec. 16, 1898. In the fifth edition of his Principles and Practice of Medicine (1904; p. 574), Osler wrote concerning Hanot hypertrophic cirrhosis: 'Of four recent cases under my care, the ages were from twenty to thirty-five. Two were brothers.' Hanot cirrhosis is a vague entity at best. Did the 2 brothers in fact suffer from Osler's disease, hereditary hemorrhagic telangiectasia (as it was designated by Hanes, 1909), which is known to be accompanied by cirrhosis?</p><p>Reported instances of familial epistaxis (e.g., Lane, 1916) probably represented this disorder. Indeed, Osler (1901) entitled his original report, 'A family form of recurring epistaxis.'</p><p>Fuchizaki et al. (2003) provided biographical information on the individuals whose names are included in triple eponym Rendu-Osler-Weber. </p><p>A comment on semantics: The individual lesion in HHT is a telangiectasis (pl., telangiectases); the process is telangiectasia. Multiple lesions should not be referred to as 'telangiectasias.' One would use the latter term only in a statement such as, 'Dr. William Bennett Bean was a student of the telangiectasias.'</p><p><strong><em>Hereditary Hemorrhagic Telangiectasia Type 3</em></strong></p><p>
There is no longer evidence for an independent HHT3 locus on chromosome 5. A pathogenic mutation in the ENG gene (HHT1) was identified in a member of the HHT3 family.</p><p>In a 4-generation HHT pedigree with pulmonary involvement, Wallace and Shovlin (2000) excluded linkage to the 2 known HHT genes, endoglin (ENG; 131195) and ALK1 (ACVRL1; 601284), and concluded that there is a third HHT locus that accounts for disease in some HHT patients with pulmonary involvement. </p><p>In a genomewide scan of the HHT family described by Wallace and Shovlin (2000), Cole et al. (2005) identified a 12-cM interval on chromosome 5 where lod scores exceeded 2; supplementary adjacent markers generated a 2-point maximum lod score of 3.45 (theta = 0.0). A series of 2-point lod scores and recombination mapping identified a 5.4-cM disease interval at 5q31.3-q32 in which a single haplotype was inherited by all 12 affected members of the pedigree. Cole et al. (2005) concluded that classic HHT with pulmonary involvement can result from mutations in an unidentified gene on chromosome 5. </p><p>Shovlin et al. (2024) restudied the 4-generation pedigree with HHT originally reported by Wallace and Shovlin (2000), noting that phenotype assignment in HHT can be fraught with difficulty and that at least 1 of the individuals in the family who met 3 of the consensus clinical criteria for diagnosis of HHT was, in fact, unaffected. The authors stated that although inheritance patterns across chr5:142,963,257-147,604,706 did distinguish between members of the 4-generation pedigree with and without nosebleeds and telangiectasia, the region did not contain a new HHT-causing gene; instead, affected family members were found to be heterozygous for a pathogenic frameshift variant in the ENG gene. Based on these findings, Shovlin et al. (2024) concluded that there was no longer evidence for an independent HHT3 locus on chromosome 5. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Li et al. (1999) generated mice deficient for endoglin (131195) using homologous recombination. Eng +/- mice had normal life expectancy, fertility, and gross appearance. Eng -/- mice died by embryonic day 11.5. At embryonic day 10.5, Eng -/- mice were 3 times smaller than Eng +/+ mice and had fewer somites. The Eng -/- embryos exhibited an absence of vascular organization and the presence of multiple pockets of red blood cells on the surface of the yolk sac. Epithelial marker expression was not disrupted in Eng -/- mice. There was persistence of an immature perineural vascular plexus, indicating a failure of endothelial remodeling in Eng -/- embryos. At embryonic day 10.5, the cardiac tube did not complete rotation and was associated with a serosanguinous pericardial effusion. By embryonic day 10.5, the major vessels including the dorsal aortae, intersomitic vessels, branchial arches, and carotid arteries were atretic and disorganized in Eng -/- embryos. There was also poor vascular smooth muscle cell formation at both embryonic days 9.5 and 10.5. These vascular smooth muscle cell abnormalities preceded the differences in endothelial organization. In contrast to mice lacking TGF-beta, vasculogenesis was unaffected. Li et al. (1999) concluded that their results demonstrated that endoglin is essential for angiogenesis and suggest a pathogenic mechanism for HHT1. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Bacardi et al. (1971); Baker (1980); Bergqvist et al. (1962); Bideau
et al. (1980); Burckhardt et al. (1973); Chandler (1965); Chernelch
et al. (1969); Childers et al. (1967); Daly and Schiller (1976);
Davis and Smith (1971); Feizi (1972); Foggie (1928); Harkonen (1981);
Harrison (1970); Hodgson et al. (1959); Kjellberg et al. (1983);
McAllister et al. (1994); McCaffrey et al. (1977); McCue et al.
(1984); Mirra and Arnold (1973); Nyman (1977); Rewane (1983); Rowley
et al. (1970); Saunders (1960); Schuster (1937); Tedesco et al.
(1975); Terry et al. (1980); Terry et al. (1983); Thomas and Carty
(1974); Trell et al. (1972); Whicker and Lake (1972)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Aassar, O. S., Friedman, C. M., White, R. I., Jr.
<strong>The natural history of epistaxis in hereditary hemorrhagic telangiectasia.</strong>
Laryngoscope 101: 977-980, 1991.
[PubMed: 1886446]
[Full Text: https://doi.org/10.1288/00005537-199109000-00008]
</p>
</li>
<li>
<p class="mim-text-font">
Ahr, D. J., Rickles, F. R., Hoyer, L. W., O'Leary, D. S., Conrad, M. E.
<strong>Von Willebrand&#x27;s disease and hemorrhagic telangiectasia: association of two complex disorders of hemostasis resulting in life-threatening hemorrhage.</strong>
Am. J. Med. 62: 452-458, 1977.
[PubMed: 300225]
[Full Text: https://doi.org/10.1016/0002-9343(77)90846-4]
</p>
</li>
<li>
<p class="mim-text-font">
Al-Samkari, H., Kasthuri, R. S., Iyer, V. N., Pishko, A. M., Decker, J. E., Weiss, C. R., Whitehead, K. J., Conrad, M. B., Zumberg, M. S., Zhou, J. Y., Parambil, J., Marsh, D., Clancy, M., Bradley, L., Wisniewski, L., Carper, B. A., Thomas, S. M., McCrae, K. R.
<strong>Pomalidomide for epistaxis in hereditary hemorrhagic telangiectasia.</strong>
New Eng. J. Med. 391: 1015-1027, 2024.
[PubMed: 39292928]
[Full Text: https://doi.org/10.1056/NEJMoa2312749]
</p>
</li>
<li>
<p class="mim-text-font">
Bacardi, R., Guardia, J., Rius, J. M., Angel, J., Martinez, J. M.
<strong>Maladie de Rendu-Osler-Weber avec atteinte hepatique (telangiectasie hepatique).</strong>
Presse Med. 79: 1023-1024, 1971.
[PubMed: 5580533]
</p>
</li>
<li>
<p class="mim-text-font">
Baker, S. R.
<strong>Glomus jugulare and hereditary hemorrhagic telangiectasia.</strong>
Arch. Otolaryng. 106: 182-186, 1980.
[PubMed: 6243932]
[Full Text: https://doi.org/10.1001/archotol.1980.00790270046011]
</p>
</li>
<li>
<p class="mim-text-font">
Bayrak-Toydemir, P., McDonald, J., Markewitz, B., Lewin, S., Miller, F., Chou, L.-S., Gedge, F., Tang, W., Coon, H., Mao, R.
<strong>Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.</strong>
Am. J. Med. Genet. 140A: 463-470, 2006.
[PubMed: 16470787]
[Full Text: https://doi.org/10.1002/ajmg.a.31101]
</p>
</li>
<li>
<p class="mim-text-font">
Berg, J., Porteous, M., Reinhardt, D., Gallione, C., Holloway, S., Umasunthar, T., Lux, A., McKinnon, W., Marchuk, D., Guttmacher, A.
<strong>Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations.</strong>
J. Med. Genet. 40: 585-590, 2003.
[PubMed: 12920067]
[Full Text: https://doi.org/10.1136/jmg.40.8.585]
</p>
</li>
<li>
<p class="mim-text-font">
Bergqvist, N., Hessen, I., Hey, M.
<strong>Arteriovenous pulmonary aneurysms in Osler&#x27;s disease.</strong>
Acta Med. Scand. 171: 301-309, 1962.
[PubMed: 13867789]
[Full Text: https://doi.org/10.1111/j.0954-6820.1962.tb04192.x]
</p>
</li>
<li>
<p class="mim-text-font">
Bideau, A., Brunet, G., Heyer, E., Plauchu, H., Robert, J.-M.
<strong>An abnormal concentration of cases of Rendu-Osler disease in the Valserine valley of the French Jura: a genealogical and demographic study.</strong>
Ann. Hum. Biol. 19: 233-247, 1992.
[PubMed: 1616282]
[Full Text: https://doi.org/10.1080/03014469200002112]
</p>
</li>
<li>
<p class="mim-text-font">
Bideau, A., Plauchu, H., Jacquard, A., Robert, J. M., Brunet, G., Desjardins, B.
<strong>La genopathie de Rendu-Osler dans le Haut-Jura: convergences des approches methodologiques de la demographie historique et de la genetique.</strong>
J. Genet. Hum. 28: 127-147, 1980.
[PubMed: 7007573]
</p>
</li>
<li>
<p class="mim-text-font">
Bose, P., Holter, J. L., Selby, G. B.
<strong>Bevacizumab in hereditary hemorrhagic telangiectasia. (Letter)</strong>
New Eng. J. Med. 360: 2143-2144, 2009.
[PubMed: 19439755]
[Full Text: https://doi.org/10.1056/NEJMc0901421]
</p>
</li>
<li>
<p class="mim-text-font">
Bose, P., Holter J. L., Selby, G. B.
<strong>Reply to Oosting et al. and Restornaz et al. (Letter)</strong>
New Eng. J. Med. 361: 931-932, 2009.
</p>
</li>
<li>
<p class="mim-text-font">
Bossler, A. D., Richards, J., George, C., Godmilow, L., Ganguly, A.
<strong>Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype.</strong>
Hum. Mutat. 27: 667-675, 2006.
[PubMed: 16752392]
[Full Text: https://doi.org/10.1002/humu.20342]
</p>
</li>
<li>
<p class="mim-text-font">
Brant, A. M., Schachat, A. P., White, R. I.
<strong>Ocular manifestations in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease).</strong>
Am. J. Ophthal. 107: 642-646, 1989.
[PubMed: 2658618]
[Full Text: https://doi.org/10.1016/0002-9394(89)90261-4]
</p>
</li>
<li>
<p class="mim-text-font">
Braverman, I. M., Keh, A., Jacobson, B. S.
<strong>Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia.</strong>
J. Invest. Derm. 95: 422-427, 1990.
[PubMed: 2212727]
[Full Text: https://doi.org/10.1111/1523-1747.ep12555569]
</p>
</li>
<li>
<p class="mim-text-font">
Brinkerhoff, B. T., Poetker, D. M., Choong, N. W.
<strong>Long-term therapy with bevacizumab in hereditary hemorrhagic telangiectasia. (Letter)</strong>
New Eng. J. Med. 364: 688-689, 2011.
[PubMed: 21323562]
[Full Text: https://doi.org/10.1056/NEJMc1012774]
</p>
</li>
<li>
<p class="mim-text-font">
Burckhardt, D., Stalder, G. A., Ludin, H., Bianchi, L.
<strong>Hyperdynamic circulatory state due to Osler-Weber-Rendu disease with intrahepatic arterio-venous fistulas.</strong>
Am. Heart J. 85: 797-800, 1973.
[PubMed: 4702667]
[Full Text: https://doi.org/10.1016/0002-8703(73)90431-6]
</p>
</li>
<li>
<p class="mim-text-font">
Canzonieri, C., Centenara, L., Ornati, F., Pagella, F., Matti, E., Alvisi, C., Danesino, C., Perego, M., Olivieri, C.
<strong>Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes.</strong>
Genet. Med. 16: 3-10, 2014.
[PubMed: 23722869]
[Full Text: https://doi.org/10.1038/gim.2013.62]
</p>
</li>
<li>
<p class="mim-text-font">
Chandler, D.
<strong>Pulmonary and cerebral arteriovenous fistula with Osler&#x27;s disease.</strong>
Arch. Intern. Med. 116: 277-281, 1965.
[PubMed: 14315661]
[Full Text: https://doi.org/10.1001/archinte.1965.03870020117021]
</p>
</li>
<li>
<p class="mim-text-font">
Chernelch, M., Winchell, H. S., Pollycove, M., Sargent, T., Kusubov, N.
<strong>Prolonged intravenous iron-dextran therapy in a patient with multiple hereditary telangiectasia.</strong>
Blood 34: 691-695, 1969.
[PubMed: 5352657]
</p>
</li>
<li>
<p class="mim-text-font">
Childers, R. W., Ranniger, K., Rabinowitz, M.
<strong>Intrahepatic arteriovenous fistula with pulmonary vascular obstruction in Osler-Rendu-Weber disease.</strong>
Am. J. Med. 43: 304-312, 1967.
[PubMed: 6034960]
[Full Text: https://doi.org/10.1016/0002-9343(67)90173-8]
</p>
</li>
<li>
<p class="mim-text-font">
Christian, H. A.
<strong>Osler: recollections of an undergraduate medical student at Johns Hopkins.</strong>
Arch. Intern. Med. 84: 77-83, 1949.
</p>
</li>
<li>
<p class="mim-text-font">
Cole, S. G., Begbie, M. E., Wallace, G. M. F., Shovlin, C. L.
<strong>A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5.</strong>
J. Med. Genet. 42: 577-582, 2005.
[PubMed: 15994879]
[Full Text: https://doi.org/10.1136/jmg.2004.028712]
</p>
</li>
<li>
<p class="mim-text-font">
Conlon, C. L., Weinger, R. S., Cimo, P. L., Moake, J. L., Olson, J. D.
<strong>Telangiectasia and von Willebrand&#x27;s disease in two families.</strong>
Ann. Intern. Med. 89: 921-924, 1978.
[PubMed: 309746]
[Full Text: https://doi.org/10.7326/0003-4819-89-6-921]
</p>
</li>
<li>
<p class="mim-text-font">
Cooke, D. A. P.
<strong>Renal arteriovenous malformation demonstrated angiographically in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease).</strong>
J. Roy. Soc. Med. 79: 744-746, 1986.
[PubMed: 3806547]
[Full Text: https://doi.org/10.1177/014107688607901220]
</p>
</li>
<li>
<p class="mim-text-font">
Cronstedt, J., Brechter, C., Carling, L.
<strong>Coexistent hereditary haemorrhagic telangiectasia and primary thrombocythaemia--coincidence or syndrome?</strong>
Acta Med. Scand. 212: 261-265, 1982.
[PubMed: 6890752]
[Full Text: https://doi.org/10.1111/j.0954-6820.1982.tb03210.x]
</p>
</li>
<li>
<p class="mim-text-font">
Dakeishi, M., Shioya, T., Wada, Y., Shindo, T., Otaka, K., Manabe, M., Nozaki, J., Inoue, S., Koizumi, A.
<strong>Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan.</strong>
Hum. Mutat. 19: 140-148, 2002.
[PubMed: 11793473]
[Full Text: https://doi.org/10.1002/humu.10026]
</p>
</li>
<li>
<p class="mim-text-font">
Daly, J. J., Schiller, A. L.
<strong>The liver in hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease).</strong>
Am. J. Med. 60: 723-726, 1976.
[PubMed: 1020760]
[Full Text: https://doi.org/10.1016/0002-9343(76)90510-6]
</p>
</li>
<li>
<p class="mim-text-font">
Davis, D. G., Smith, J. L.
<strong>Retinal involvement in hereditary hemorrhagic telangiectasia.</strong>
Arch. Ophthal. 85: 618-623, 1971.
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Brit. J. Radiol. 56: 207-209, 1983.
[PubMed: 6824845]
[Full Text: https://doi.org/10.1259/0007-1285-56-663-207]
</p>
</li>
<li>
<p class="mim-text-font">
Reyes-Mujica, M., Lopez-Corella, E., Perez-Fernandez, L., Cuevas-Schacht, F., Carrillo-Farga, J.
<strong>Osler-Weber-Rendu disease in an infant.</strong>
Hum. Path. 19: 1243-1246, 1988.
[PubMed: 3169731]
[Full Text: https://doi.org/10.1016/s0046-8177(88)80160-6]
</p>
</li>
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<p class="mim-text-font">
Roman, G., Fisher, M., Perl, D. P., Poser, C. M.
<strong>Manifestations of hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber Disease): report of 2 cases and review of the literature.</strong>
Ann. Neurol. 4: 130-144, 1978.
[PubMed: 707984]
[Full Text: https://doi.org/10.1002/ana.410040207]
</p>
</li>
<li>
<p class="mim-text-font">
Rowley, P. T., Kurnick, J., Cheville, R.
<strong>Hereditary haemorrhagic telangiectasia: aggravation by oral contraceptives? (Letter)</strong>
Lancet 295: 474-475, 1970. Note: Originally Volume I.
[PubMed: 4189787]
[Full Text: https://doi.org/10.1016/s0140-6736(70)90870-6]
</p>
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Ruiz-Llorente, L., McDonald, J., Wooderchak-Donahue, W., Briggs, E., Chesnutt, M., Bayrak-Toydemir, P., Bernabeu, C.
<strong>Characterization of a family mutation in the 5-prime untranslated region of the endoglin gene causative of hereditary hemorrhagic telangiectasia.</strong>
J. Hum. Genet. 64: 333-339, 2019.
[PubMed: 30728427]
[Full Text: https://doi.org/10.1038/s10038-019-0564-x]
</p>
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<li>
<p class="mim-text-font">
Saba, H. I., Morelli, G. A., Logrono, L. A.
<strong>Treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid.</strong>
New Eng. J. Med. 330: 1789-1790, 1994.
[PubMed: 8190155]
[Full Text: https://doi.org/10.1056/NEJM199406233302504]
</p>
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<p class="mim-text-font">
Sabba, C., Gallitelli, M., Palasciano, G.
<strong>Efficacy of unusually high doses of tranexamic acid for the treatment of epistaxis in hereditary hemorrhagic telangiectasia. (Letter)</strong>
New Eng. J. Med. 345: 926 only, 2001.
[PubMed: 11565536]
[Full Text: https://doi.org/10.1056/NEJM200109203451216]
</p>
</li>
<li>
<p class="mim-text-font">
Saunders, W. H.
<strong>Permanent control of nosebleeds in patients with hereditary hemorrhagic telangiectasia.</strong>
Ann. Intern. Med. 53: 147-152, 1960.
[PubMed: 14441968]
[Full Text: https://doi.org/10.7326/0003-4819-53-1-147]
</p>
</li>
<li>
<p class="mim-text-font">
Saxena, R., Hytiroglou, P., Atillasoy, E. O., Cakaloglu, Y., Emre, S., Thung, S. N.
<strong>Coexistence of hereditary hemorrhagic telangiectasia and fibropolycystic liver disease.</strong>
Am. J. Surg. Path. 22: 368-372, 1998.
[PubMed: 9500780]
[Full Text: https://doi.org/10.1097/00000478-199803000-00013]
</p>
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Schuster, N. H.
<strong>Familial haemorrhagic telangiectasia associated with multiple aneurysms of the splenic artery.</strong>
J. Path. 44: 29-39, 1937.
</p>
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Selmaier, M., Cidlinsky, K., Ell, C., Hahn, E. G.
<strong>Haemangiomatose der Leber bei Morbus Osler.</strong>
Dtsch. Med. Wschr. 118: 1015-1019, 1993.
[PubMed: 8334948]
[Full Text: https://doi.org/10.1055/s-2008-1059420]
</p>
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Shoukier, M., Teske, U., Weise, A., Engel, W., Argyriou, L.
<strong>Characterization of five novel large deletions causing hereditary haemorrhagic telangiectasia.</strong>
Clin. Genet. 73: 320-330, 2008.
[PubMed: 18312453]
[Full Text: https://doi.org/10.1111/j.1399-0004.2008.00968.x]
</p>
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<li>
<p class="mim-text-font">
Shovlin, C. L., Almaghlouth, F. I., Alsafi, A., Coote, N., Rennie, C., Wallace, G. M., Govani, F. S., Genomics England Research Consortium.
<strong>Updates on diagnostic criteria for hereditary haemorrhagic telangiectasia in the light of whole genome sequencing of &#x27;gene-negative&#x27; individuals recruited to the 100 000 Genomes Project.</strong>
J. Med. Genet. 61: 182-185, 2024.
[PubMed: 37586837]
[Full Text: https://doi.org/10.1136/jmg-2023-109195]
</p>
</li>
<li>
<p class="mim-text-font">
Shovlin, C. L., Guttmacher, A. E., Buscarini, E., Faughnan, M. E., Hyland, R. H., Westermann, C. J. J., Kjeldsen, A. D., Plauchu, H.
<strong>Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).</strong>
Am. J. Med. Genet. 91: 66-67, 2000.
[PubMed: 10751092]
[Full Text: https://doi.org/10.1002/(sici)1096-8628(20000306)91:1&lt;66::aid-ajmg12&gt;3.0.co;2-p]
</p>
</li>
<li>
<p class="mim-text-font">
Shovlin, C. L., Hughes, J. M. B., Tuddenham, E. G. D., Temperley, I., Perembelon, Y. F. N., Scott, J., Seidman, C. E., Seidman, J. G.
<strong>A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3.</strong>
Nature Genet. 6: 205-209, 1994.
[PubMed: 8162076]
[Full Text: https://doi.org/10.1038/ng0294-205]
</p>
</li>
<li>
<p class="mim-text-font">
Snyder, L. H., Doan, C. A.
<strong>Clinical and experimental studies in human inheritance: is the homozygous form of multiple telangiectasia lethal?</strong>
J. Lab. Clin. Med. 29: 1211-1216, 1944.
</p>
</li>
<li>
<p class="mim-text-font">
Soukarieh, O., Tillet, E., Proust, C., Dupont, C., Jaspard-Vinassa, B., Soubrier, F., Goyenvalle, A., Eyries, M., Tregouet, D. A.
<strong>uAUG creating variants in the 5-prime-UTR of ENG causing hereditary hemorrhagic telangiectasia.</strong>
NPJ Genomic Med. 8: 32, 2023.
[PubMed: 37848456]
[Full Text: https://doi.org/10.1038/s41525-023-00378-5]
</p>
</li>
<li>
<p class="mim-text-font">
Steele, J. S., Nath, P. U., Burn, J., Porteous, M. E. M.
<strong>An association between migrainous aura and hereditary haemorrhagic telangiectasia.</strong>
Headache 33: 145-148, 1993.
[PubMed: 8486513]
[Full Text: https://doi.org/10.1111/j.1526-4610.1993.hed3303145.x]
</p>
</li>
<li>
<p class="mim-text-font">
Tedesco, F. J., Hosty, T. A., Sumner, H. W.
<strong>Hereditary hemorrhagic telangiectasia presenting as an unusual gastric lesion.</strong>
Gastroenterology 68: 384-386, 1975.
[PubMed: 1116683]
</p>
</li>
<li>
<p class="mim-text-font">
Terry, P. B., Barth, K. H., Kaufman, S. L., White, R. I., Jr.
<strong>Balloon embolization for treatment of pulmonary arteriovenous fistulas.</strong>
New Eng. J. Med. 302: 1189-1190, 1980.
[PubMed: 7366659]
[Full Text: https://doi.org/10.1056/NEJM198005223022107]
</p>
</li>
<li>
<p class="mim-text-font">
Terry, P. B., White, R. I., Jr., Barth, K. H., Kaufman, S. L., Mitchell, S. E.
<strong>Pulmonary arteriovenous malformations: physiologic observations and results of therapeutic balloon embolization.</strong>
New Eng. J. Med. 308: 1197-1200, 1983.
[PubMed: 6405268]
[Full Text: https://doi.org/10.1056/NEJM198305193082005]
</p>
</li>
<li>
<p class="mim-text-font">
Thomas, M. L., Carty, H.
<strong>Hereditary haemorrhagic telangiectasia of the liver demonstrated angiographically.</strong>
Acta Radiol. Diagn. (Stockh.) 15: 433-439, 1974.
[PubMed: 4413669]
[Full Text: https://doi.org/10.1177/028418517401500409]
</p>
</li>
<li>
<p class="mim-text-font">
Trell, E., Johansson, B. W., Linell, F., Ripa, J.
<strong>Familial pulmonary hypertension and multiple abnormalities of large systemic arteries in Osler&#x27;s disease.</strong>
Am. J. Med. 53: 50-63, 1972.
[PubMed: 5037289]
[Full Text: https://doi.org/10.1016/0002-9343(72)90115-5]
</p>
</li>
<li>
<p class="mim-text-font">
Tuente, W.
<strong>Klinik und Genetik der Oslerschen Krankheit.</strong>
Z. Mensch. Vererb. Konstitutionsl. 37: 221-250, 1964.
</p>
</li>
<li>
<p class="mim-text-font">
Vase, P., Holm, M., Arendrup, H.
<strong>Pulmonary arteriovenous fistules in hereditary haemorrhagic telangiectasia.</strong>
Acta Med. Scand. 218: 105-109, 1985.
[PubMed: 4050544]
[Full Text: https://doi.org/10.1111/j.0954-6820.1985.tb08832.x]
</p>
</li>
<li>
<p class="mim-text-font">
Vase, P.
<strong>Estrogen treatment of hereditary hemorrhagic telangiectasia: a double-blind controlled clinical trial.</strong>
Acta Med. Scand. 209: 393-396, 1981.
[PubMed: 7018182]
[Full Text: https://doi.org/10.1111/j.0954-6820.1981.tb11614.x]
</p>
</li>
<li>
<p class="mim-text-font">
Wallace, G. M. F., Shovlin, C. L.
<strong>A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1.</strong>
Thorax 55: 685-690, 2000.
[PubMed: 10899246]
[Full Text: https://doi.org/10.1136/thorax.55.8.685]
</p>
</li>
<li>
<p class="mim-text-font">
Ward, K.
<strong>Personal Communication.</strong>
Salt Lake City, Utah 2/24/1996.
</p>
</li>
<li>
<p class="mim-text-font">
Wehner, L.-E., Folz, B. J., Argyriou, L., Twelkemeyer, S., Teske, U., Geisthoff, U. W., Werner, J. A., Engel, W., Nayernia, K.
<strong>Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations.</strong>
Clin. Genet. 69: 239-245, 2006.
[PubMed: 16542389]
[Full Text: https://doi.org/10.1111/j.1399-0004.2006.00574.x]
</p>
</li>
<li>
<p class="mim-text-font">
Weik, C., Greiner, L.
<strong>The liver in hereditary hemorrhagic telangiectasia (Weber-Rendu-Osler disease).</strong>
Scand. J. Gastroent. 34: 1241-1246, 1999.
[PubMed: 10636073]
[Full Text: https://doi.org/10.1080/003655299750024779]
</p>
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<li>
<p class="mim-text-font">
Westermann, C. J. J., Rosina, A. F., de Vries, V., de Coteau, P. A.
<strong>The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of the Netherlands Antilles: a family screening.</strong>
Am. J. Med. Genet. 116A: 324-328, 2003.
[PubMed: 12522784]
[Full Text: https://doi.org/10.1002/ajmg.a.10002]
</p>
</li>
<li>
<p class="mim-text-font">
Whicker, J. H., Lake, C. F.
<strong>Hemilateral rhinotomy in the treatment of hereditary hemorrhagic telangiectasia.</strong>
Arch. Otolaryng. 96: 319-321, 1972.
[PubMed: 4563055]
[Full Text: https://doi.org/10.1001/archotol.1972.00770090495004]
</p>
</li>
<li>
<p class="mim-text-font">
White, R. I., Jr., Lynch-Nyhan, A., Terry, P., Buescher, P. C., Farmlett, E. J., Charnas, L., Shuman, K., Kim, W., Kinnison, M., Mitchell, S. E.
<strong>Pulmonary arteriovenous malformations: techniques and long-term outcome of embolotherapy.</strong>
Radiology 169: 663-669, 1988.
[PubMed: 3186989]
[Full Text: https://doi.org/10.1148/radiology.169.3.3186989]
</p>
</li>
<li>
<p class="mim-text-font">
Winterbauer, R. H.
<strong>Multiple telangiectasia, Raynaud&#x27;s phenomenon, sclerodactyly and subcutaneous calcinosis: a syndrome mimicking hereditary hemorrhagic telangiectasia.</strong>
Bull. Johns Hopkins Hosp. 114: 361-383, 1964.
[PubMed: 14171636]
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Marla J. F. O&#x27;Neill - updated : 11/18/2024<br>Ada Hamosh - updated : 10/18/2024<br>Ada Hamosh - updated : 1/31/2014<br>Ada Hamosh - updated : 6/20/2012<br>Marla J. F. O&#x27;Neill - updated : 7/26/2010<br>Cassandra L. Kniffin - updated : 5/27/2010<br>Marla J. F. O&#x27;Neill - updated : 10/5/2009<br>Cassandra L. Kniffin - updated : 7/21/2009<br>Cassandra L. Kniffin - updated : 9/16/2008<br>Victor A. McKusick - updated : 9/29/2006<br>Marla J. F. O&#x27;Neill - updated : 7/7/2006<br>Cassandra L. Kniffin - updated : 4/27/2006<br>Cassandra L. Kniffin - updated : 3/21/2006<br>Deborah L. Stone - updated : 7/23/2004<br>Victor A. McKusick - updated : 5/5/2004<br>Victor A. McKusick - updated : 12/23/2003<br>John A. Phillips, III - updated : 11/7/2002<br>Victor A. McKusick - updated : 2/21/2002<br>Victor A. McKusick - updated : 10/2/2001<br>Gary A. Bellus - updated : 4/5/2001<br>Victor A. McKusick - updated : 10/23/2000<br>Victor A. McKusick - updated : 3/23/2000<br>Victor A. McKusick - updated : 3/15/2000<br>Victor A. McKusick - updated : 8/12/1999<br>Ada Hamosh - updated : 6/1/1999<br>Victor A. McKusick - updated : 1/20/1999<br>Victor A. McKusick - updated : 6/12/1998<br>Victor A. McKusick - updated : 5/19/1998
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Victor A. McKusick : 6/2/1986
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