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Entry
- #600376 - TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2; HHT2
- OMIM
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<span class="h4">#600376</span>
<br />
<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/600376"><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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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#mapping">Mapping</a>
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<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="#clinicalManagement">Clinical Management</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<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>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=236&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="http://www.informatics.jax.org/disease/600376" 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>
</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>
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</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>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>
600376
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2; HHT2
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/393?start=-3&limit=10&highlight=393">
12q13.13
</a>
</span>
</td>
<td>
<span class="mim-font">
Telangiectasia, hereditary hemorrhagic, type 2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600376"> 600376 </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">
ACVRL1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601284"> 601284 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/600376" 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>
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</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')">
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<span class="sr-only">Toggle Dropdown</span>
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&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/600376" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/600376" 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 /> -
Choriocapillaris atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030491" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030491</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030491" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030491</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 in 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 />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Arteriovenous malformation (cerebral, spinal, pulmonary, liver) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275760&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275760</a>]</span> <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">[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 />
</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) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838170&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838170</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111289009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111289009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/303070000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">303070000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I28.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I28.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q25.72" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q25.72</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/417.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">417.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/747.32" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">747.32</a>]</span> <span class="mim-feature-ids hidden">[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 /> -
A subset of patients develop pulmonary arterial hypertension <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838171&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838171</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 /> -
Liver 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">
- Gastrointestinal hemorrhage (onset usually 5th-6th decade) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1838165&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1838165</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 /> -
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 /> -
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 /> -
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> 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, face, conjunctiva, trunk, nail beds, fingers, and finger pads) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275759&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275759</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>
<span class="h5 mim-font">
<em> Nails </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 />
</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">
- 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 /> -
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 /> -
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 /> -
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 /> -
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 /> -
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 /> -
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 />
</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">
- Intrafamilial phenotypic variability<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the activin receptor-like kinase gene (ALK1, <a href="/entry/601284#0001">601284.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Telangiectasia, hereditary hemorrhagic (see also primary pulmonary hypertension (<a href="/phenotypicSeries/PS178600">PS178600</a>)
- <a href="/phenotypicSeries/PS187300">PS187300</a>
- 4 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/152?start=-3&limit=10&highlight=152"> 7p14 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610655"> Telangiectasia, hereditary hemorrhagic, type 4 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610655"> 610655 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610655"> HHT4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610655"> 610655 </a>
</span>
</td>
</tr>
<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">
<a href="/entry/187300"> Telangiectasia, hereditary hemorrhagic, type 1 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/187300"> 187300 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/131195"> ENG </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/131195"> 131195 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/180?start=-3&limit=10&highlight=180"> 10q11.22 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615506"> Telangiectasia, hereditary hemorrhagic, type 5 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615506"> 615506 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605120"> GDF2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605120"> 605120 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/393?start=-3&limit=10&highlight=393"> 12q13.13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600376"> Telangiectasia, hereditary hemorrhagic, type 2 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600376"> 600376 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601284"> ACVRL1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601284"> 601284 </a>
</span>
</td>
</tr>
</tbody>
</table>
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<p>A number sign (#) is used with this entry because of evidence that hereditary hemorrhagic telangiectasia type 2 (HHT2) is caused by heterozygous mutation in the ACVRL1 gene (<a href="/entry/601284">601284</a>) on chromosome 12q13.</p>
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<p>Hereditary hemorrhagic telangiectasia type 2 (HHT2) is an autosomal dominant disorder characterized by telangiectases of the mucous membranes causing nasal and gastrointestinal bleeding. Angiodysplastic lesions, including angiomas and arteriovenous malformations with arteriovenous shunting, may be present in the lungs, liver, or brain, and may be associated with hemorrhage, fibrosis, and/or neurologic symptoms. Extreme intrafamilial phenotypic variability has been observed (<a href="#22" class="mim-tip-reference" title="Piantanida, M., Buscarini, E., Dellavecchia, C., Minelli, A., Rossi, A., Buscarini, L., Danesino, C. &lt;strong&gt;Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2.&lt;/strong&gt; J. Med. Genet. 33: 441-443, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8782041/&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;8782041&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.6.441&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="8782041">Piantanida et al., 1996</a>; <a href="#19" class="mim-tip-reference" title="McDonald, J. E., Miller, F. J., Hallam, S. E., Nelson, L., Marchuk, D. A., Ward, K. J. &lt;strong&gt;Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred.&lt;/strong&gt; Am. J. Med. Genet. 93: 320-327, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10946360/&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;10946360&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(20000814)93:4&lt;320::aid-ajmg12&gt;3.0.co;2-r&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="10946360">McDonald et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10946360+8782041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a general phenotypic description and a discussion of genetic heterogeneity of this disorder, see HHT1 (<a href="/entry/187300">187300</a>).</p>
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<p><a href="#22" class="mim-tip-reference" title="Piantanida, M., Buscarini, E., Dellavecchia, C., Minelli, A., Rossi, A., Buscarini, L., Danesino, C. &lt;strong&gt;Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2.&lt;/strong&gt; J. Med. Genet. 33: 441-443, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8782041/&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;8782041&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.6.441&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="8782041">Piantanida et al. (1996)</a> reported a large 5-generation Italian family in which 30 members had HHT. Angiodysplastic liver involvement was documented in 13 female patients. In 2 male patients with telangiectases, 1 also had anomalies of the splenic artery and the other showed nodular hepatic steatosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782041" 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="#19" class="mim-tip-reference" title="McDonald, J. E., Miller, F. J., Hallam, S. E., Nelson, L., Marchuk, D. A., Ward, K. J. &lt;strong&gt;Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred.&lt;/strong&gt; Am. J. Med. Genet. 93: 320-327, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10946360/&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;10946360&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(20000814)93:4&lt;320::aid-ajmg12&gt;3.0.co;2-r&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="10946360">McDonald et al. (2000)</a> reported clinical features of a large kindred in which 38 members had HHT2 confirmed by genetic analysis (see <a href="/entry/601284#0004">601284.0004</a> and <a href="#5" class="mim-tip-reference" title="Berg, J. N., Gallione, C. J., Stenzel, T. T., Johnson, D. W., Allen, W. P., Schwartz, C. E., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A. &lt;strong&gt;The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.&lt;/strong&gt; Am. J. Hum. Genet. 61: 60-67, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9245985/&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;9245985&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/513903&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="9245985">Berg et al., 1997</a>). Visceral findings of HHT2 included pulmonary arteriovenous malformations (PAVMs) (6%), cerebral AVM (7%), spinal AVM (3%), hepatic AVM (17%), gastrointestinal bleeding due to AVMs (11%), and cirrhosis (3%). Seventy-two percent of patients had onset of nosebleeds by age 15 years; however, there was overlap in frequency of epistaxis between mutation-negative and mutation-positive individuals. The findings illustrated the extreme phenotypic variability of HHT2 even in those with the same mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9245985+10946360" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="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. 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. PAVMs 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><a href="#2" class="mim-tip-reference" title="Abdalla, S. A., Geisthoff, U. W., Bonneau, D., Plauchu, H., McDonald, J., Kennedy, S., Faughnan, M. E., Letarte, M. &lt;strong&gt;Visceral manifestations in hereditary haemorrhagic telangiectasia type 2.&lt;/strong&gt; J. Med. Genet. 40: 494-502, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12843319/&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;12843319&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.40.7.494&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="12843319">Abdalla et al. (2003)</a> reported clinical data on 10 HHT2 families with known mutations in the ALK1 gene. They also summarized published data on patients and/or families with a known HHT2 genotype. Visceral manifestations were detected in 24 (26%) of 93 HHT2 patients from 9 of the families and included gastrointestinal bleeding (14%), intrahepatic shunts (6%), and arteriovenous malformations (AVMs) in the lung (4%) and brain (3%). Gastrointestinal bleeding, the most frequent visceral manifestation, was reported in 6 of the 10 families, mostly in patients over the age of 50. Identification of ALK1 mutations in subjects with a suspected diagnosis but without clinical signs of HHT argued in favor of molecular diagnosis. Visceral manifestations occurred in 27 of 44 reported families with HHT2, and affected 29% of HHT2 patients. This was considered an underestimate given incomplete and variable screening for lung, brain, and/or liver involvement in different clinical centers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12843319" 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 affected members of a family with HHT2, <a href="#1" class="mim-tip-reference" title="Abdalla, S. A., Cymerman, U., Johnson, R. M., Deber, C. M., Letarte, M. &lt;strong&gt;Disease-associated mutations in conserved residues of ALK-1 kinase domain.&lt;/strong&gt; Europ. J. Hum. Genet. 11: 279-287, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12700602/&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;12700602&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.ejhg.5200919&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="12700602">Abdalla et al. (2003)</a> identified a 1-bp insertion (1113insG) in the ACVRL1 gene (<a href="/entry/601284#0014">601284.0014</a>). In 17 of 160 unrelated patients with HHT2, <a href="#16" 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> identified the 1113insG mutation, which they referred to as a 1-bp duplication (1112dupG). The 17 patients shared a common haplotype and all originated from the Rhone-Alpes region of France, strongly suggesting a founder effect. <a href="#16" 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> stated that the family reported by <a href="#2" class="mim-tip-reference" title="Abdalla, S. A., Geisthoff, U. W., Bonneau, D., Plauchu, H., McDonald, J., Kennedy, S., Faughnan, M. E., Letarte, M. &lt;strong&gt;Visceral manifestations in hereditary haemorrhagic telangiectasia type 2.&lt;/strong&gt; J. Med. Genet. 40: 494-502, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12843319/&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;12843319&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.40.7.494&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="12843319">Abdalla et al. (2003)</a> originated from the same region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12843319+12700602+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="#24" class="mim-tip-reference" title="Rinaldi, M., Buscarini, E., Danesino, C., Chiosi, F., De Benedictis, A., Porcellini, A., Costagliola, C. &lt;strong&gt;Ocular manifestations in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease): a case-series.&lt;/strong&gt; Ophthalmic Genet. 32: 12-17, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21174526/&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;21174526&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3109/13816810.2010.535891&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="21174526">Rinaldi et al. (2011)</a> described the ocular abnormalities in 8 affected members of a family segregating HHT2. Five patients (62.5%) had conjunctival telangiectases and 3 (37.5%) had retinal abnormalities, consisting mainly of choriocapillaris atrophy. <a href="#24" class="mim-tip-reference" title="Rinaldi, M., Buscarini, E., Danesino, C., Chiosi, F., De Benedictis, A., Porcellini, A., Costagliola, C. &lt;strong&gt;Ocular manifestations in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease): a case-series.&lt;/strong&gt; Ophthalmic Genet. 32: 12-17, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21174526/&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;21174526&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3109/13816810.2010.535891&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="21174526">Rinaldi et al. (2011)</a> stated that this appeared to be the first report of the occurrence of choriocapillaris atrophy in HHT patients belonging to the same pedigree. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21174526" 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="#9" 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 (<a href="/entry/187300">187300</a>), 13 with HHT2, 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="#33" class="mim-tip-reference" title="Wooderchak-Donahue, W. L., McDonald, J., Farrell, A., Akay, G., Velinder, M., Johnson, P., VanSant-Webb, C., Margraf, R., Briggs, E., Whitehead, K. J., Thomson, J., Lin, A. E., Pyeritz, R. E., Marth, G., Bayrak-Toydemir, P. &lt;strong&gt;Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in hereditary haemorrhagic telangiectasia.&lt;/strong&gt; J. Med. Genet. 55: 824-830, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30244195/&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;30244195&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmedgenet-2018-105561&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="30244195">Wooderchak-Donahue et al. (2018)</a> reported a 4-generation family in which 9 members had HHT2. All had epistaxis and characteristic telangiectases, and 6 of the 9 had PAVMs, 5 requiring treatment by transcatheter embolization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30244195" 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>HHT-Related Pulmonary Arterial Hypertension</em></strong></p><p>
Pulmonary hypertension that is clinically and histologically indistinguishable from primary pulmonary hypertension (see <a href="/entry/178600">178600</a>) has been reported in a subset of patients with hereditary hemorrhagic telangiectasia (<a href="#29" 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.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5037289/&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;5037289&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(72)90115-5&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="5037289">Trell et al., 1972</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'})"><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 5 kindreds plus 1 individual patient with hereditary hemorrhagic telangiectasia, <a href="#30" class="mim-tip-reference" title="Trembath, R. C., Thomson, J. R., Machado, R. D., Morgan, N. V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J. E., Humbert, M., Nichols, W. C., Morrell, N. W. &lt;strong&gt;Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.&lt;/strong&gt; New Eng. J. Med. 345: 325-334, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11484689/&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;11484689&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM200108023450503&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="11484689">Trembath et al. (2001)</a> identified 10 cases of pulmonary hypertension, including 5 patients with isolated clinical PPH and 5 with clinical evidence of both PPH and HHT. Only 2 of the 10 patients were found to have PAVMs. In affected members of 4 kindreds and in the individual patient, mutations were identified in the ALK1 gene. Two patients from 1 family had isolated PPH with mutation in the in the BMPR2 gene (<a href="/entry/600799">600799</a>). <a href="#30" class="mim-tip-reference" title="Trembath, R. C., Thomson, J. R., Machado, R. D., Morgan, N. V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J. E., Humbert, M., Nichols, W. C., Morrell, N. W. &lt;strong&gt;Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.&lt;/strong&gt; New Eng. J. Med. 345: 325-334, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11484689/&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;11484689&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM200108023450503&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="11484689">Trembath et al. (2001)</a> noted that the pathophysiologic features of PPH and HHT seem to be distinct: in HHT, PAVMs lead to decreased pulmonary vascular resistance and increased cardiac output, with normal to low arterial pressures, whereas in PPH, obliteration of small pulmonary arteries leads to increased pulmonary artery pressures and decreased cardiac output. However, the histologic features of 4 patients with HHT and PPH showed pulmonary arterial lesions, including medial hypertrophy, intimal cellular proliferation, and plexiform lesions similar to those found in PPH1 patients with mutations in the BMPR2 gene. <a href="#30" class="mim-tip-reference" title="Trembath, R. C., Thomson, J. R., Machado, R. D., Morgan, N. V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J. E., Humbert, M., Nichols, W. C., Morrell, N. W. &lt;strong&gt;Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.&lt;/strong&gt; New Eng. J. Med. 345: 325-334, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11484689/&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;11484689&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM200108023450503&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="11484689">Trembath et al. (2001)</a> postulated that the pulmonary abnormalities found in the 2 disorders are related to the TGF-beta signaling pathway in the pulmonary vascular endothelium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11484689" 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>Linkage studies by <a href="#27" 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>, <a href="#23" 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>, <a href="#18" 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.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7891374/&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;7891374&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.31.12.927&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="7891374">McAllister et al. (1994)</a>, and <a href="#11" 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> indicated that in some families hereditary hemorrhagic telangiectasia is not linked to markers on 9q34. Furthermore, affected members of these families tended to escape pulmonary arteriovenous malformations, which tend to be a conspicuous feature of the 9q-linked form of HHT. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7891373+8162076+7891375+7891374" 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 2 families with HHT unlinked to chromosome 9q, <a href="#31" class="mim-tip-reference" title="Vincent, P., Plauchu, H., Hazan, J., Faure, S., Weissenbach, J., Godet, J. &lt;strong&gt;A third locus for hereditary haemorrhagic telangiectasia maps to chromosome 12q.&lt;/strong&gt; Hum. Molec. Genet. 4: 945-949, 1995. Note: Erratum: Hum. Molec. Genet. 4: 1243 only, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7633456/&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;7633456&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/4.5.945&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="7633456">Vincent et al. (1995)</a> found linkage to a series of genetic markers in the centromeric region of chromosome 12q. Using 2-point linkage analysis, a maximum lod score of 7.86 at theta = 0.05 was observed with the D12S85 microsatellite marker. In these 2 families, pulmonary arteriovenous malformations were absent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7633456" 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="Johnson, D. W., Berg, J. N., Gallione, C. J., McAllister, K. A., Warner, J. P., Helmbold, E. A., Markel, D. S., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A. &lt;strong&gt;A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12.&lt;/strong&gt; Genome Res. 5: 21-28, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8717052/&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;8717052&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1101/gr.5.1.21&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="8717052">Johnson et al. (1995)</a> reported 4 families in which HHT was linked to markers mapping to the pericentromeric region of chromosome 12. Markers D12S85 and D12S339 showed the highest maximum combined lod scores of 9.06 (theta = 0.0) and 10.77 (theta = 0.04), respectively. By haplotype analysis, they identified an 11-cM candidate region bordered by D12S345 and D12S339. The experience in these families continued to support the previously reported observation of a significantly reduced incidence of pulmonary arteriovenous malformations in non-HHT1 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8717052" 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="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.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7891374/&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;7891374&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.31.12.927&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="7891374">McAllister et al. (1994)</a> observed 1 HHT family with suggestion of linkage to markers in the 3p22 region where the tumor growth factor-beta (TGFB type II) receptor (<a href="/entry/190182">190182</a>) is located. However, <a href="#13" class="mim-tip-reference" title="Johnson, D. W., Berg, J. N., Gallione, C. J., McAllister, K. A., Warner, J. P., Helmbold, E. A., Markel, D. S., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A. &lt;strong&gt;A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12.&lt;/strong&gt; Genome Res. 5: 21-28, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8717052/&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;8717052&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1101/gr.5.1.21&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="8717052">Johnson et al. (1995)</a> stated that in the one family studied by <a href="#18" 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.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7891374/&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;7891374&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.31.12.927&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="7891374">McAllister et al. (1994)</a>, the 2-point lod score was 1.43 with marker D3S1211; stronger statistical support for linkage to the disease locus in this family was obtained for chromosome 12 (lod score = 2.64 at theta = 0.0 for marker D12S85), suggesting this as the actual location. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8717052+7891374" 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="#12" class="mim-tip-reference" title="Johnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S.-J., Stenzel, T. T., Speer, M., Pericak-Vance, M. A., Diamond, A., Guttmacher, A. E., Jackson, C. E., Attisano, L., Kucherlapati, R., Porteous, M. E. M., Marchuk, D. A. &lt;strong&gt;Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.&lt;/strong&gt; Nature Genet. 13: 189-195, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8640225/&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;8640225&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0696-189&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="8640225">Johnson et al. (1996)</a> reported a 4-cM interval for ORW2 on chromosome 12 and a 1.38-Mb YAC contig that spanned the entire interval. The contig included ACVRLK1, also symbolized ALK1, a member of the serine-threonine kinase receptor family expressed in endothelium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8640225" 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 large Italian HHT family with 30 affected members, <a href="#22" class="mim-tip-reference" title="Piantanida, M., Buscarini, E., Dellavecchia, C., Minelli, A., Rossi, A., Buscarini, L., Danesino, C. &lt;strong&gt;Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2.&lt;/strong&gt; J. Med. Genet. 33: 441-443, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8782041/&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;8782041&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.6.441&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="8782041">Piantanida et al. (1996)</a> performed polymorphism typing and linkage analysis and excluded the previously identified HHT loci on chromosomes 9 and 12, suggesting the existence of a third HHT locus. <a href="#20" class="mim-tip-reference" title="Olivieri, C., Mira, E., Delu, G., Pagella, F., Zambelli, A., Malvezzi, L., Buscarini, E., Danesino, C. &lt;strong&gt;Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia.&lt;/strong&gt; J. Med. Genet. 39: E39, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12114496/&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;12114496&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.39.7.e39&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="12114496">Olivieri et al. (2002)</a> reevaluated the family members using updated diagnostic criteria and performed new linkage analysis; evidence for exclusion of chromosome 9 remained strong, whereas evidence for exclusion of chromosome 12 was no longer significant. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12114496+8782041" 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>Molecular Genetics</strong>
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<p>In 3 families with HHT2, <a href="#12" class="mim-tip-reference" title="Johnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S.-J., Stenzel, T. T., Speer, M., Pericak-Vance, M. A., Diamond, A., Guttmacher, A. E., Jackson, C. E., Attisano, L., Kucherlapati, R., Porteous, M. E. M., Marchuk, D. A. &lt;strong&gt;Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.&lt;/strong&gt; Nature Genet. 13: 189-195, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8640225/&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;8640225&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0696-189&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="8640225">Johnson et al. (1996)</a> identified mutations in the ALK1 gene (<a href="/entry/601284#0001">601284.0001</a>-<a href="/entry/601284#0003">601284.0003</a>). The finding suggested a critical role for ALK1 in the control of blood vessel development or repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8640225" 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="#14" class="mim-tip-reference" title="Kjeldsen, A. D., Brusgaard, K., Poulsen, L., Kruse, T., Rasmussen, K., Green, A. &lt;strong&gt;Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families.&lt;/strong&gt; Am. J. Med. Genet. 98: 298-302, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11170071/&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;11170071&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(20010201)98:4&lt;298::aid-ajmg1093&gt;3.0.co;2-k&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11170071">Kjeldsen et al. (2001)</a> used denaturing gradient gel electrophoresis (DGGE) to identify mutations in the ALK1 gene in 2 families with hereditary hemorrhagic telangiectasia. In a family with an ile398-to-asn mutation (I398N; <a href="/entry/601284#0006">601284.0006</a>) there was a high prevalence of pulmonary arteriovenous malformations and severe gastrointestinal bleeding, whereas in a family with an arg374-to-thr mutation (R374T; <a href="/entry/601284#0007">601284.0007</a>), no individuals had pulmonary arteriovenous malformations and only 1 patient had a history of severe gastrointestinal bleeding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Olivieri, C., Mira, E., Delu, G., Pagella, F., Zambelli, A., Malvezzi, L., Buscarini, E., Danesino, C. &lt;strong&gt;Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia.&lt;/strong&gt; J. Med. Genet. 39: E39, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12114496/&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;12114496&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.39.7.e39&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="12114496">Olivieri et al. (2002)</a> analyzed exons 3, 7, and 8 of the ACVRL1 gene in 52 Italian probands with HHT and identified heterozygosity for 13 different mutations in 16 (30.7%) of the probands, including an R67W substitution (<a href="/entry/601284#0017">601284.0017</a>) in 2 probands, MC and P301. The latter was a member of the large Italian family originally studied by <a href="#22" class="mim-tip-reference" title="Piantanida, M., Buscarini, E., Dellavecchia, C., Minelli, A., Rossi, A., Buscarini, L., Danesino, C. &lt;strong&gt;Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2.&lt;/strong&gt; J. Med. Genet. 33: 441-443, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8782041/&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;8782041&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.6.441&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="8782041">Piantanida et al. (1996)</a>; no relationship could be found between the 2 families up to the great-grandparents, but the authors noted that both family names originated from closely related geographical areas in northern Italy. The R67W variant segregated with disease in both families. Extensive liver involvement in the large family was confirmed, and intrahepatic arteriovenous shunts were also present in the other family sharing the R67W variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12114496+8782041" 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="#32" 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="#21" class="mim-tip-reference" title="Olivieri, C., Pagella, F., Semino, L., Lanzarini, L., Valacca, C., Pilotto, A., Corno, S., Scappaticci, S., Manfredi, G., Buscarini, E., Danesino, C. &lt;strong&gt;Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies.&lt;/strong&gt; J. Hum. Genet. 52: 820-829, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17786384/&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;17786384&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10038-007-0187-5&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="17786384">Olivieri et al. (2007)</a> identified 50 different mutations in the ACVRL1 gene in 72 of 101 Italian patients with HHT. Twenty-six different ENG mutations were identified in 29 of the 101 patients. The findings were consistent with a higher frequency of ACVRL1 mutations compared to ENG mutations in HHT patients of Mediterranean ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17786384" 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 4 of 45 probands with clinical HHT and negative results on direct sequencing, <a href="#26" 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 4 different large heterozygous deletions involving the ACVRL1 gene using quantitative real-time polymerase chain reaction (qRT-PCR). The results were confirmed by multiplex ligation-dependent probe amplification (MLPA). Affected members of 2 families had deletion of the entire ACVRL1 gene. One of these deletions spanned at least 216 kb and included 5 neighboring genes, including ACVR1B (<a href="/entry/601300">601300</a>), GRASP (<a href="/entry/612027">612027</a>), and NR4A1 (<a href="/entry/139139">139139</a>). The proband who carried this large deletion had no additional symptoms besides HHT, indicating that heterozygous loss of these genes has no obvious phenotypic effect. <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>Using whole-genome sequencing of 35 patients with HHT among 13 families and next-generation sequencing of a custom panel of genes that had been associated with HHT among 87 unrelated patients with suspected HHT, <a href="#33" class="mim-tip-reference" title="Wooderchak-Donahue, W. L., McDonald, J., Farrell, A., Akay, G., Velinder, M., Johnson, P., VanSant-Webb, C., Margraf, R., Briggs, E., Whitehead, K. J., Thomson, J., Lin, A. E., Pyeritz, R. E., Marth, G., Bayrak-Toydemir, P. &lt;strong&gt;Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in hereditary haemorrhagic telangiectasia.&lt;/strong&gt; J. Med. Genet. 55: 824-830, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30244195/&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;30244195&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmedgenet-2018-105561&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="30244195">Wooderchak-Donahue et al. (2018)</a> identified 8 patients with novel noncoding heterozygous ACVRL1 gene variants that disrupt splicing. In 1 family (family 2), an affected mother and son had an ACVRL1 intron 9:chromosome 3 translocation, t(12,3)(q13,p21), the first reported translocation to cause HHT. In the other 7 families, the variants were located within an approximately 300-bp CT-rich hotspot region of intron 9 (see, e.g., <a href="/entry/601284#0016">601284.0016</a>) that disrupted splicing. The authors suggested that adding this region to HHT molecular diagnostic testing algorithms would improve clinical sensitivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30244195" 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>HHT-Related Pulmonary Arterial Hypertension</em></strong></p><p>
In affected patients from 4 kindreds with HHT, PPH, or both, and in 1 patient with PPH and pulmonary AVMs, <a href="#30" class="mim-tip-reference" title="Trembath, R. C., Thomson, J. R., Machado, R. D., Morgan, N. V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J. E., Humbert, M., Nichols, W. C., Morrell, N. W. &lt;strong&gt;Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.&lt;/strong&gt; New Eng. J. Med. 345: 325-334, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11484689/&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;11484689&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM200108023450503&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="11484689">Trembath et al. (2001)</a> identified mutations in the ALK1 gene (see, e.g., <a href="/entry/601284#0008">601284.0008</a>-<a href="/entry/601284#0010">601284.0010</a>). No mutations in ALK1 were identified in 35 patients with isolated PPH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11484689" 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 8 unrelated probands with HHT2 and HHT-related pulmonary arterial hypertension, <a href="#10" class="mim-tip-reference" title="Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F., Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C. &lt;strong&gt;Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.&lt;/strong&gt; J. Med. Genet. 40: 865-871, 2003. Note: Erratum: J. Med. Genet. 41: 576 only, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14684682/&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;14684682&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.40.12.865&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="14684682">Harrison et al. (2003)</a> identified 7 mutations, including 3 novel mutations, in the ALK1 gene (see, e.g., <a href="/entry/601284#0011">601284.0011</a>-<a href="/entry/601284#0013">601284.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14684682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="genotypePhenotypeCorrelations" class="mim-anchor"></a>
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<p>From a cohort of 16 Italian probands with HHT2, <a href="#20" class="mim-tip-reference" title="Olivieri, C., Mira, E., Delu, G., Pagella, F., Zambelli, A., Malvezzi, L., Buscarini, E., Danesino, C. &lt;strong&gt;Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia.&lt;/strong&gt; J. Med. Genet. 39: E39, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12114496/&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;12114496&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.39.7.e39&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="12114496">Olivieri et al. (2002)</a> performed hepatic ultrasound in 10 patients and found intrahepatic arteriovenous shunts in 6 of them. A positive family history for similar liver involvement was present in 3 of the probands. In the same set of patients, lung x-ray and pulse oximetry consistently yielded normal results. The authors suggested that mutations in the ACVRL1 gene might be associated with higher risk of liver AVMs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12114496" 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="#4" 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>Among 18 German adults with HHT, <a href="#8" class="mim-tip-reference" title="Brakensiek, K., Frye-Boukhriss, H., Malzer, M., Abramowicz, M., Bahr, M. J., von Beckerath, N., Bergmann, C., Caselitz, M., Holinski-Feder, E., Muschke, P., Oexle, J., Strobl-Wildemann, G., Wolff, G., El-Harith, E. A., Stuhrmann, M. &lt;strong&gt;Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia.&lt;/strong&gt; Clin. Genet. 74: 171-177, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18498373/&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;18498373&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2008.01029.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="18498373">Brakensiek et al. (2008)</a> identified 9 mutations in the ACVRL1 gene and 7 in the ENG gene. Eight of the mutations were novel. Five of the 18 patients had liver involvement, including hepatomegaly, nodular hyperplasia, and massive arteriovenous shunts detected by imaging. All 5 of the patients with liver involvement had an ACVRL1 mutation, yielding a statistically significant difference in the distribution of ACVRL1 and ENG mutations among HHT patients with and without liver involvement (p = 0.0016). The positive predictive value for ACVRL1-positive patients to develop liver disease until the age of 52 years was estimated to be 68.4%. <a href="#8" class="mim-tip-reference" title="Brakensiek, K., Frye-Boukhriss, H., Malzer, M., Abramowicz, M., Bahr, M. J., von Beckerath, N., Bergmann, C., Caselitz, M., Holinski-Feder, E., Muschke, P., Oexle, J., Strobl-Wildemann, G., Wolff, G., El-Harith, E. A., Stuhrmann, M. &lt;strong&gt;Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia.&lt;/strong&gt; Clin. Genet. 74: 171-177, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18498373/&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;18498373&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2008.01029.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="18498373">Brakensiek et al. (2008)</a> concluded that molecular genetic testing of HHT patients is important for prognosis with respect to liver disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18498373" 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="#17" 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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<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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<p>In a large-scale French epidemiologic study, <a href="#7" class="mim-tip-reference" title="Bideau, A., Plauchu, H., Brunet, G., Robert, J. &lt;strong&gt;Epidemiological investigation of Rendu-Osler disease in France: its geographical distribution and prevalence.&lt;/strong&gt; Popul. 44: 3-22, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12157905/&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;12157905&lt;/a&gt;]" pmid="12157905">Bideau et al. (1989)</a> found an average prevalence of HHT to be 1 in 8,345, which was more than 10 times higher than expected at that time. The distribution of the disease varied greatly from 1 area to another. Three French administrative areas had a far higher prevalence: Ain (1 in 3,345), Jura (1 in 5,062) and Deux-Sevres (1 in 4,287). <a href="#15" class="mim-tip-reference" title="Lesca, G., Genin, E., Blachier, C., Olivieri, C., Coulet, F., Brunet, G., Dupuis-Girod, S., Buscarini, E., Soubrier, F., Calender, A., Danesino, C., Giraud, S., Plauchu, H. &lt;strong&gt;Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients.&lt;/strong&gt; Europ. J. Hum. Genet. 16: 742-749, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18285823/&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;18285823&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ejhg.2008.3&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18285823">Lesca et al. (2008)</a> found that the 1112dupG mutation (<a href="/entry/601284#0014">601284.0014</a>) was responsible for the very high frequency of the disease observed in the Ain and Jura administrative areas. The mutation was likely to have occurred in a common ancestor living in a valley of the Haut-Jura mountains more than 3 centuries ago and to have spread over the generations, mainly in the Rhone-Alpes region but also outside. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12157905+18285823" 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="#28" class="mim-tip-reference" title="Srinivasan, S., Hanes, M. A., Dickens, T., Porteous, M. E. M., Oh, S. P., Hale, L. P., Marchuk, D. A. &lt;strong&gt;A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2.&lt;/strong&gt; Hum. Molec. Genet. 12: 473-482, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12588795/&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;12588795&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddg050&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="12588795">Srinivasan et al. (2003)</a> created mice heterozygous for a loss-of-function mutation in Acvrl1 (<a href="/entry/601284">601284</a>). The mice developed age-dependent vascular lesions in the skin, extremities, oral cavity, and internal organs (lung, liver, intestine, spleen, and brain), as well as occult gastrointestinal bleeding. Major histopathologic features of the lesions included thin-walled dilated vessels in close proximity to each other, hemorrhage, and fibrosis. An Acvrl1 +/- mouse with profound liver involvement also displayed a secondary cardiac phenotype, similar to that observed in human patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12588795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a novel Acvrl1 null mutant mouse line in which a beta-galactosidase (see <a href="/entry/230500">230500</a>) reporter gene (lacZ) was inserted into the Acvrl1 locus, <a href="#25" class="mim-tip-reference" title="Seki, T., Yun, J., Oh, S. P. &lt;strong&gt;Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling.&lt;/strong&gt; Circ. Res. 93: 682-689, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12970115/&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;12970115&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1161/01.RES.0000095246.40391.3B&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="12970115">Seki et al. (2003)</a> showed that Acvrl1 was predominantly expressed in developing arterial, but not venous, endothelium. They concluded that, contrary to the view of HHT as a venous disease, their findings suggested that arterioles rather than venules are the primary vessels affected by the loss of an ACVRL1 allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12970115" 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>REFERENCES</strong>
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<a id="Abdalla2003" class="mim-anchor"></a>
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<p class="mim-text-font">
Abdalla, S. A., Cymerman, U., Johnson, R. M., Deber, C. M., Letarte, M.
<strong>Disease-associated mutations in conserved residues of ALK-1 kinase domain.</strong>
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[<a href="https://doi.org/10.1038/sj.ejhg.5200919" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
<a id="Abdalla2003" class="mim-anchor"></a>
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<p class="mim-text-font">
Abdalla, S. A., Geisthoff, U. W., Bonneau, D., Plauchu, H., McDonald, J., Kennedy, S., Faughnan, M. E., Letarte, M.
<strong>Visceral manifestations in hereditary haemorrhagic telangiectasia type 2.</strong>
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[<a href="https://doi.org/10.1136/jmg.40.7.494" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
<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.
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[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>]
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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>]
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<a id="Berg1997" class="mim-anchor"></a>
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Berg, J. N., Gallione, C. J., Stenzel, T. T., Johnson, D. W., Allen, W. P., Schwartz, C. E., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A.
<strong>The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.</strong>
Am. J. Hum. Genet. 61: 60-67, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9245985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9245985</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9245985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/513903" target="_blank">Full Text</a>]
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<a id="Berg2003" class="mim-anchor"></a>
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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="Bideau1989" class="mim-anchor"></a>
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Bideau, A., Plauchu, H., Brunet, G., Robert, J.
<strong>Epidemiological investigation of Rendu-Osler disease in France: its geographical distribution and prevalence.</strong>
Popul. 44: 3-22, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12157905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12157905</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12157905" 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="8" class="mim-anchor"></a>
<a id="Brakensiek2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Brakensiek, K., Frye-Boukhriss, H., Malzer, M., Abramowicz, M., Bahr, M. J., von Beckerath, N., Bergmann, C., Caselitz, M., Holinski-Feder, E., Muschke, P., Oexle, J., Strobl-Wildemann, G., Wolff, G., El-Harith, E. A., Stuhrmann, M.
<strong>Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18498373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18498373</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18498373" 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.1399-0004.2008.01029.x" target="_blank">Full Text</a>]
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<a id="Canzonieri2014" class="mim-anchor"></a>
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<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: <a href="https://pubmed.ncbi.nlm.nih.gov/23722869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23722869</a>, <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'})">related citations</a>]
[<a href="https://doi.org/10.1038/gim.2013.62" target="_blank">Full Text</a>]
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<a id="Harrison2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F., Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C.
<strong>Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.</strong>
J. Med. Genet. 40: 865-871, 2003. Note: Erratum: J. Med. Genet. 41: 576 only, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14684682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14684682</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14684682" 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.40.12.865" target="_blank">Full Text</a>]
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<a id="Heutink1994" class="mim-anchor"></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>
J. Med. Genet. 31: 933-936, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7891375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7891375</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7891375" 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.31.12.933" target="_blank">Full Text</a>]
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<a id="Johnson1996" class="mim-anchor"></a>
<div class="">
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Johnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S.-J., Stenzel, T. T., Speer, M., Pericak-Vance, M. A., Diamond, A., Guttmacher, A. E., Jackson, C. E., Attisano, L., Kucherlapati, R., Porteous, M. E. M., Marchuk, D. A.
<strong>Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.</strong>
Nature Genet. 13: 189-195, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640225</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8640225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng0696-189" target="_blank">Full Text</a>]
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<a id="Johnson1995" class="mim-anchor"></a>
<div class="">
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Johnson, D. W., Berg, J. N., Gallione, C. J., McAllister, K. A., Warner, J. P., Helmbold, E. A., Markel, D. S., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A.
<strong>A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12.</strong>
Genome Res. 5: 21-28, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8717052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8717052</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8717052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1101/gr.5.1.21" target="_blank">Full Text</a>]
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<a id="Kjeldsen2001" class="mim-anchor"></a>
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Kjeldsen, A. D., Brusgaard, K., Poulsen, L., Kruse, T., Rasmussen, K., Green, A.
<strong>Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families.</strong>
Am. J. Med. Genet. 98: 298-302, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170071</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/1096-8628(20010201)98:4&lt;298::aid-ajmg1093&gt;3.0.co;2-k" target="_blank">Full Text</a>]
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<a id="Lesca2008" class="mim-anchor"></a>
<div class="">
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Lesca, G., Genin, E., Blachier, C., Olivieri, C., Coulet, F., Brunet, G., Dupuis-Girod, S., Buscarini, E., Soubrier, F., Calender, A., Danesino, C., Giraud, S., Plauchu, H.
<strong>Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients.</strong>
Europ. J. Hum. Genet. 16: 742-749, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285823</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ejhg.2008.3" target="_blank">Full Text</a>]
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<a id="Lesca2004" class="mim-anchor"></a>
<div class="">
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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.
<strong>Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.</strong>
Hum. Mutat. 23: 289-299, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15024723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15024723</a>, <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'})">related citations</a>]
[<a href="https://doi.org/10.1002/humu.20017" target="_blank">Full Text</a>]
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<a id="Letteboer2008" class="mim-anchor"></a>
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Letteboer, T. G. W., Mager, H.-J., Snijder, R. J., Lindhout, D., van Amstel, H.-K. P., Zanen, P., Westermann, K. J. J.
<strong>Genotype-phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia.</strong>
Am. J. Med. Genet. 146A: 2733-2739, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18831062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18831062</a>, <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'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.32243" target="_blank">Full Text</a>]
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<li>
<a id="18" class="mim-anchor"></a>
<a id="McAllister1994" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
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.
<strong>Genetic heterogeneity in hereditary haemorrhagic telangiectasia: possible correlation with clinical phenotype.</strong>
J. Med. Genet. 31: 927-932, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7891374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7891374</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7891374" 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.31.12.927" target="_blank">Full Text</a>]
</p>
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<a id="19" class="mim-anchor"></a>
<a id="McDonald2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
McDonald, J. E., Miller, F. J., Hallam, S. E., Nelson, L., Marchuk, D. A., Ward, K. J.
<strong>Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred.</strong>
Am. J. Med. Genet. 93: 320-327, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10946360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10946360</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10946360" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/1096-8628(20000814)93:4&lt;320::aid-ajmg12&gt;3.0.co;2-r" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
<a id="Olivieri2002" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Olivieri, C., Mira, E., Delu, G., Pagella, F., Zambelli, A., Malvezzi, L., Buscarini, E., Danesino, C.
<strong>Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia.</strong>
J. Med. Genet. 39: E39, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114496</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12114496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.39.7.e39" target="_blank">Full Text</a>]
</p>
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<li>
<a id="21" class="mim-anchor"></a>
<a id="Olivieri2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Olivieri, C., Pagella, F., Semino, L., Lanzarini, L., Valacca, C., Pilotto, A., Corno, S., Scappaticci, S., Manfredi, G., Buscarini, E., Danesino, C.
<strong>Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies.</strong>
J. Hum. Genet. 52: 820-829, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17786384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17786384</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17786384" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s10038-007-0187-5" target="_blank">Full Text</a>]
</p>
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<a id="22" class="mim-anchor"></a>
<a id="Piantanida1996" class="mim-anchor"></a>
<div class="">
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Piantanida, M., Buscarini, E., Dellavecchia, C., Minelli, A., Rossi, A., Buscarini, L., Danesino, C.
<strong>Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2.</strong>
J. Med. Genet. 33: 441-443, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782041</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782041" 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.33.6.441" target="_blank">Full Text</a>]
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<a id="23" class="mim-anchor"></a>
<a id="Porteous1994" class="mim-anchor"></a>
<div class="">
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Porteous, M. E. M., Curtis, A., Williams, O., Marchuk, D., Bhattacharya, S. S., Burn, J.
<strong>Genetic heterogeneity in hereditary haemorrhagic telangiectasia.</strong>
J. Med. Genet. 31: 925-926, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7891373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7891373</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7891373" 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.31.12.925" target="_blank">Full Text</a>]
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<a id="Rinaldi2011" class="mim-anchor"></a>
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Rinaldi, M., Buscarini, E., Danesino, C., Chiosi, F., De Benedictis, A., Porcellini, A., Costagliola, C.
<strong>Ocular manifestations in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease): a case-series.</strong>
Ophthalmic Genet. 32: 12-17, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21174526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21174526</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21174526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.3109/13816810.2010.535891" target="_blank">Full Text</a>]
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<a id="Seki2003" class="mim-anchor"></a>
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Seki, T., Yun, J., Oh, S. P.
<strong>Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling.</strong>
Circ. Res. 93: 682-689, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12970115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12970115</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12970115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1161/01.RES.0000095246.40391.3B" target="_blank">Full Text</a>]
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<a id="Shoukier2008" class="mim-anchor"></a>
<div class="">
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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: <a href="https://pubmed.ncbi.nlm.nih.gov/18312453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18312453</a>, <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'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.2008.00968.x" target="_blank">Full Text</a>]
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<a id="Shovlin1994" class="mim-anchor"></a>
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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: <a href="https://pubmed.ncbi.nlm.nih.gov/8162076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162076</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng0294-205" target="_blank">Full Text</a>]
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<a id="Srinivasan2003" class="mim-anchor"></a>
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Srinivasan, S., Hanes, M. A., Dickens, T., Porteous, M. E. M., Oh, S. P., Hale, L. P., Marchuk, D. A.
<strong>A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2.</strong>
Hum. Molec. Genet. 12: 473-482, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12588795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12588795</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12588795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/ddg050" target="_blank">Full Text</a>]
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<a id="Trell1972" class="mim-anchor"></a>
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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>]
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<a id="Trembath2001" class="mim-anchor"></a>
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Trembath, R. C., Thomson, J. R., Machado, R. D., Morgan, N. V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J. E., Humbert, M., Nichols, W. C., Morrell, N. W.
<strong>Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.</strong>
New Eng. J. Med. 345: 325-334, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11484689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11484689</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11484689" 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/NEJM200108023450503" target="_blank">Full Text</a>]
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<a id="31" class="mim-anchor"></a>
<a id="Vincent1995" class="mim-anchor"></a>
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Vincent, P., Plauchu, H., Hazan, J., Faure, S., Weissenbach, J., Godet, J.
<strong>A third locus for hereditary haemorrhagic telangiectasia maps to chromosome 12q.</strong>
Hum. Molec. Genet. 4: 945-949, 1995. Note: Erratum: Hum. Molec. Genet. 4: 1243 only, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7633456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7633456</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7633456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/4.5.945" target="_blank">Full Text</a>]
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<a id="Wehner2006" class="mim-anchor"></a>
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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>]
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<a id="Wooderchak-Donahue2018" class="mim-anchor"></a>
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Wooderchak-Donahue, W. L., McDonald, J., Farrell, A., Akay, G., Velinder, M., Johnson, P., VanSant-Webb, C., Margraf, R., Briggs, E., Whitehead, K. J., Thomson, J., Lin, A. E., Pyeritz, R. E., Marth, G., Bayrak-Toydemir, P.
<strong>Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in hereditary haemorrhagic telangiectasia.</strong>
J. Med. Genet. 55: 824-830, 2018.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30244195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30244195</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30244195" 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/jmedgenet-2018-105561" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 11/22/2024
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Ada Hamosh - updated : 10/18/2024<br>Sonja A. Rasmussen - updated : 02/05/2019<br>Ada Hamosh - updated : 01/31/2014<br>Jane Kelly - updated : 8/29/2011<br>Cassandra L. Kniffin - updated : 7/21/2009<br>Cassandra L. Kniffin - updated : 9/16/2008<br>Cassandra L. Kniffin - updated : 9/5/2008<br>Cassandra L. Kniffin - updated : 8/18/2008<br>Cassandra L. Kniffin - updated : 2/29/2008<br>Cassandra L. Kniffin - updated : 4/27/2006<br>Cassandra L. Kniffin - updated : 3/21/2006<br>Cassandra L. Kniffin - updated : 10/10/2005<br>George E. Tiller - updated : 1/5/2005<br>Cassandra L. Kniffin - reorganized : 4/29/2004<br>Cassandra L. Kniffin - updated : 4/12/2004<br>Marla J. F. O'Neill - updated : 3/17/2004<br>Victor A. McKusick - updated : 1/9/2004<br>Victor A. McKusick - updated : 10/22/2003<br>Sonja A. Rasmussen - updated : 3/12/2001<br>John Burn - edited : 12/14/1995
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Victor A. McKusick : 2/7/1995
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alopez : 10/18/2024<br>carol : 07/11/2023<br>carol : 08/22/2019<br>carol : 02/06/2019<br>carol : 02/05/2019<br>alopez : 01/02/2019<br>carol : 12/06/2017<br>alopez : 01/31/2014<br>terry : 8/17/2012<br>carol : 8/29/2011<br>carol : 12/22/2010<br>wwang : 3/23/2010<br>wwang : 9/4/2009<br>ckniffin : 7/21/2009<br>wwang : 9/24/2008<br>ckniffin : 9/16/2008<br>wwang : 9/9/2008<br>ckniffin : 9/5/2008<br>wwang : 8/25/2008<br>ckniffin : 8/18/2008<br>wwang : 3/19/2008<br>ckniffin : 2/29/2008<br>wwang : 5/3/2006<br>ckniffin : 4/27/2006<br>wwang : 3/23/2006<br>ckniffin : 3/21/2006<br>wwang : 10/24/2005<br>ckniffin : 10/10/2005<br>wwang : 1/5/2005<br>tkritzer : 6/2/2004<br>ckniffin : 4/30/2004<br>ckniffin : 4/30/2004<br>carol : 4/29/2004<br>carol : 4/29/2004<br>ckniffin : 4/12/2004<br>tkritzer : 3/17/2004<br>alopez : 1/14/2004<br>terry : 1/9/2004<br>tkritzer : 10/22/2003<br>mcapotos : 3/15/2001<br>mcapotos : 3/12/2001<br>alopez : 4/7/2000<br>alopez : 4/7/2000<br>alopez : 7/30/1997<br>alopez : 7/8/1997<br>joanna : 9/17/1996<br>mark : 5/31/1996<br>mark : 5/30/1996<br>terry : 5/28/1996<br>joanna : 12/14/1995<br>mark : 12/7/1995<br>mark : 11/14/1995<br>mimadm : 9/23/1995<br>carol : 2/7/1995
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<strong>#</strong> 600376
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TELANGIECTASIA, HEREDITARY HEMORRHAGIC, TYPE 2; HHT2
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Other entities represented in this entry:
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PULMONARY ARTERIAL HYPERTENSION, HEREDITARY HEMORRHAGIC TELANGIECTASIA-RELATED, INCLUDED
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<strong>ORPHA:</strong> 774; &nbsp;
<strong>DO:</strong> 1270; &nbsp;
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</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">
12q13.13
</span>
</td>
<td>
<span class="mim-font">
Telangiectasia, hereditary hemorrhagic, type 2
</span>
</td>
<td>
<span class="mim-font">
600376
</span>
</td>
<td>
<span class="mim-font">
Autosomal dominant
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
ACVRL1
</span>
</td>
<td>
<span class="mim-font">
601284
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because of evidence that hereditary hemorrhagic telangiectasia type 2 (HHT2) is caused by heterozygous mutation in the ACVRL1 gene (601284) on chromosome 12q13.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Hereditary hemorrhagic telangiectasia type 2 (HHT2) is an autosomal dominant disorder characterized by telangiectases of the mucous membranes causing nasal and gastrointestinal bleeding. Angiodysplastic lesions, including angiomas and arteriovenous malformations with arteriovenous shunting, may be present in the lungs, liver, or brain, and may be associated with hemorrhage, fibrosis, and/or neurologic symptoms. Extreme intrafamilial phenotypic variability has been observed (Piantanida et al., 1996; McDonald et al., 2000). </p><p>For a general phenotypic description and a discussion of genetic heterogeneity of this disorder, see HHT1 (187300).</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Piantanida et al. (1996) reported a large 5-generation Italian family in which 30 members had HHT. Angiodysplastic liver involvement was documented in 13 female patients. In 2 male patients with telangiectases, 1 also had anomalies of the splenic artery and the other showed nodular hepatic steatosis. </p><p>McDonald et al. (2000) reported clinical features of a large kindred in which 38 members had HHT2 confirmed by genetic analysis (see 601284.0004 and Berg et al., 1997). Visceral findings of HHT2 included pulmonary arteriovenous malformations (PAVMs) (6%), cerebral AVM (7%), spinal AVM (3%), hepatic AVM (17%), gastrointestinal bleeding due to AVMs (11%), and cirrhosis (3%). Seventy-two percent of patients had onset of nosebleeds by age 15 years; however, there was overlap in frequency of epistaxis between mutation-negative and mutation-positive individuals. The findings illustrated the extreme phenotypic variability of HHT2 even in those with the same mutation. </p><p>Berg et al. (2003) performed a questionnaire-based study to delineate phenotypic differences between HHT1 and HHT2. 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. PAVMs were reported only in the group of HHT1 patients. </p><p>Abdalla et al. (2003) reported clinical data on 10 HHT2 families with known mutations in the ALK1 gene. They also summarized published data on patients and/or families with a known HHT2 genotype. Visceral manifestations were detected in 24 (26%) of 93 HHT2 patients from 9 of the families and included gastrointestinal bleeding (14%), intrahepatic shunts (6%), and arteriovenous malformations (AVMs) in the lung (4%) and brain (3%). Gastrointestinal bleeding, the most frequent visceral manifestation, was reported in 6 of the 10 families, mostly in patients over the age of 50. Identification of ALK1 mutations in subjects with a suspected diagnosis but without clinical signs of HHT argued in favor of molecular diagnosis. Visceral manifestations occurred in 27 of 44 reported families with HHT2, and affected 29% of HHT2 patients. This was considered an underestimate given incomplete and variable screening for lung, brain, and/or liver involvement in different clinical centers. </p><p>In affected members of a family with HHT2, Abdalla et al. (2003) identified a 1-bp insertion (1113insG) in the ACVRL1 gene (601284.0014). In 17 of 160 unrelated patients with HHT2, Lesca et al. (2004) identified the 1113insG mutation, which they referred to as a 1-bp duplication (1112dupG). The 17 patients shared a common haplotype and all originated from the Rhone-Alpes region of France, strongly suggesting a founder effect. Lesca et al. (2004) stated that the family reported by Abdalla et al. (2003) originated from the same region. </p><p>Rinaldi et al. (2011) described the ocular abnormalities in 8 affected members of a family segregating HHT2. Five patients (62.5%) had conjunctival telangiectases and 3 (37.5%) had retinal abnormalities, consisting mainly of choriocapillaris atrophy. Rinaldi et al. (2011) stated that this appeared to be the first report of the occurrence of choriocapillaris atrophy in HHT patients belonging to the same pedigree. </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 (187300), 13 with HHT2, and 2 undefined. Gastrointestinal telangiectases were identified in 86% of HHT1 patients and in 77% of HHT2 patients. </p><p>Wooderchak-Donahue et al. (2018) reported a 4-generation family in which 9 members had HHT2. All had epistaxis and characteristic telangiectases, and 6 of the 9 had PAVMs, 5 requiring treatment by transcatheter embolization. </p><p><strong><em>HHT-Related Pulmonary Arterial Hypertension</em></strong></p><p>
Pulmonary hypertension that is clinically and histologically indistinguishable from primary pulmonary hypertension (see 178600) has been reported in a subset of patients with hereditary hemorrhagic telangiectasia (Trell et al., 1972). </p><p>Among 5 kindreds plus 1 individual patient with hereditary hemorrhagic telangiectasia, Trembath et al. (2001) identified 10 cases of pulmonary hypertension, including 5 patients with isolated clinical PPH and 5 with clinical evidence of both PPH and HHT. Only 2 of the 10 patients were found to have PAVMs. In affected members of 4 kindreds and in the individual patient, mutations were identified in the ALK1 gene. Two patients from 1 family had isolated PPH with mutation in the in the BMPR2 gene (600799). Trembath et al. (2001) noted that the pathophysiologic features of PPH and HHT seem to be distinct: in HHT, PAVMs lead to decreased pulmonary vascular resistance and increased cardiac output, with normal to low arterial pressures, whereas in PPH, obliteration of small pulmonary arteries leads to increased pulmonary artery pressures and decreased cardiac output. However, the histologic features of 4 patients with HHT and PPH showed pulmonary arterial lesions, including medial hypertrophy, intimal cellular proliferation, and plexiform lesions similar to those found in PPH1 patients with mutations in the BMPR2 gene. Trembath et al. (2001) postulated that the pulmonary abnormalities found in the 2 disorders are related to the TGF-beta signaling pathway in the pulmonary vascular endothelium. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Linkage studies by Shovlin et al. (1994), Porteous et al. (1994), McAllister et al. (1994), and Heutink et al. (1994) indicated that in some families hereditary hemorrhagic telangiectasia is not linked to markers on 9q34. Furthermore, affected members of these families tended to escape pulmonary arteriovenous malformations, which tend to be a conspicuous feature of the 9q-linked form of HHT. </p><p>In 2 families with HHT unlinked to chromosome 9q, Vincent et al. (1995) found linkage to a series of genetic markers in the centromeric region of chromosome 12q. Using 2-point linkage analysis, a maximum lod score of 7.86 at theta = 0.05 was observed with the D12S85 microsatellite marker. In these 2 families, pulmonary arteriovenous malformations were absent. </p><p>Johnson et al. (1995) reported 4 families in which HHT was linked to markers mapping to the pericentromeric region of chromosome 12. Markers D12S85 and D12S339 showed the highest maximum combined lod scores of 9.06 (theta = 0.0) and 10.77 (theta = 0.04), respectively. By haplotype analysis, they identified an 11-cM candidate region bordered by D12S345 and D12S339. The experience in these families continued to support the previously reported observation of a significantly reduced incidence of pulmonary arteriovenous malformations in non-HHT1 families. </p><p>McAllister et al. (1994) observed 1 HHT family with suggestion of linkage to markers in the 3p22 region where the tumor growth factor-beta (TGFB type II) receptor (190182) is located. However, Johnson et al. (1995) stated that in the one family studied by McAllister et al. (1994), the 2-point lod score was 1.43 with marker D3S1211; stronger statistical support for linkage to the disease locus in this family was obtained for chromosome 12 (lod score = 2.64 at theta = 0.0 for marker D12S85), suggesting this as the actual location. </p><p>Johnson et al. (1996) reported a 4-cM interval for ORW2 on chromosome 12 and a 1.38-Mb YAC contig that spanned the entire interval. The contig included ACVRLK1, also symbolized ALK1, a member of the serine-threonine kinase receptor family expressed in endothelium. </p><p>In a large Italian HHT family with 30 affected members, Piantanida et al. (1996) performed polymorphism typing and linkage analysis and excluded the previously identified HHT loci on chromosomes 9 and 12, suggesting the existence of a third HHT locus. Olivieri et al. (2002) reevaluated the family members using updated diagnostic criteria and performed new linkage analysis; evidence for exclusion of chromosome 9 remained strong, whereas evidence for exclusion of chromosome 12 was no longer significant. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In 3 families with HHT2, Johnson et al. (1996) identified mutations in the ALK1 gene (601284.0001-601284.0003). The finding suggested a critical role for ALK1 in the control of blood vessel development or repair. </p><p>Kjeldsen et al. (2001) used denaturing gradient gel electrophoresis (DGGE) to identify mutations in the ALK1 gene in 2 families with hereditary hemorrhagic telangiectasia. In a family with an ile398-to-asn mutation (I398N; 601284.0006) there was a high prevalence of pulmonary arteriovenous malformations and severe gastrointestinal bleeding, whereas in a family with an arg374-to-thr mutation (R374T; 601284.0007), no individuals had pulmonary arteriovenous malformations and only 1 patient had a history of severe gastrointestinal bleeding. </p><p>Olivieri et al. (2002) analyzed exons 3, 7, and 8 of the ACVRL1 gene in 52 Italian probands with HHT and identified heterozygosity for 13 different mutations in 16 (30.7%) of the probands, including an R67W substitution (601284.0017) in 2 probands, MC and P301. The latter was a member of the large Italian family originally studied by Piantanida et al. (1996); no relationship could be found between the 2 families up to the great-grandparents, but the authors noted that both family names originated from closely related geographical areas in northern Italy. The R67W variant segregated with disease in both families. Extensive liver involvement in the large family was confirmed, and intrahepatic arteriovenous shunts were also present in the other family sharing the R67W variant. </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>Olivieri et al. (2007) identified 50 different mutations in the ACVRL1 gene in 72 of 101 Italian patients with HHT. Twenty-six different ENG mutations were identified in 29 of the 101 patients. The findings were consistent with a higher frequency of ACVRL1 mutations compared to ENG mutations in HHT patients of Mediterranean ancestry. </p><p>In 4 of 45 probands with clinical HHT and negative results on direct sequencing, Shoukier et al. (2008) identified 4 different large heterozygous deletions involving the ACVRL1 gene using quantitative real-time polymerase chain reaction (qRT-PCR). The results were confirmed by multiplex ligation-dependent probe amplification (MLPA). Affected members of 2 families had deletion of the entire ACVRL1 gene. One of these deletions spanned at least 216 kb and included 5 neighboring genes, including ACVR1B (601300), GRASP (612027), and NR4A1 (139139). The proband who carried this large deletion had no additional symptoms besides HHT, indicating that heterozygous loss of these genes has no obvious phenotypic effect. </p><p>Using whole-genome sequencing of 35 patients with HHT among 13 families and next-generation sequencing of a custom panel of genes that had been associated with HHT among 87 unrelated patients with suspected HHT, Wooderchak-Donahue et al. (2018) identified 8 patients with novel noncoding heterozygous ACVRL1 gene variants that disrupt splicing. In 1 family (family 2), an affected mother and son had an ACVRL1 intron 9:chromosome 3 translocation, t(12,3)(q13,p21), the first reported translocation to cause HHT. In the other 7 families, the variants were located within an approximately 300-bp CT-rich hotspot region of intron 9 (see, e.g., 601284.0016) that disrupted splicing. The authors suggested that adding this region to HHT molecular diagnostic testing algorithms would improve clinical sensitivity. </p><p><strong><em>HHT-Related Pulmonary Arterial Hypertension</em></strong></p><p>
In affected patients from 4 kindreds with HHT, PPH, or both, and in 1 patient with PPH and pulmonary AVMs, Trembath et al. (2001) identified mutations in the ALK1 gene (see, e.g., 601284.0008-601284.0010). No mutations in ALK1 were identified in 35 patients with isolated PPH. </p><p>In 8 unrelated probands with HHT2 and HHT-related pulmonary arterial hypertension, Harrison et al. (2003) identified 7 mutations, including 3 novel mutations, in the ALK1 gene (see, e.g., 601284.0011-601284.0013). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>From a cohort of 16 Italian probands with HHT2, Olivieri et al. (2002) performed hepatic ultrasound in 10 patients and found intrahepatic arteriovenous shunts in 6 of them. A positive family history for similar liver involvement was present in 3 of the probands. In the same set of patients, lung x-ray and pulse oximetry consistently yielded normal results. The authors suggested that mutations in the ACVRL1 gene might be associated with higher risk of liver AVMs. </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>Among 18 German adults with HHT, Brakensiek et al. (2008) identified 9 mutations in the ACVRL1 gene and 7 in the ENG gene. Eight of the mutations were novel. Five of the 18 patients had liver involvement, including hepatomegaly, nodular hyperplasia, and massive arteriovenous shunts detected by imaging. All 5 of the patients with liver involvement had an ACVRL1 mutation, yielding a statistically significant difference in the distribution of ACVRL1 and ENG mutations among HHT patients with and without liver involvement (p = 0.0016). The positive predictive value for ACVRL1-positive patients to develop liver disease until the age of 52 years was estimated to be 68.4%. Brakensiek et al. (2008) concluded that molecular genetic testing of HHT patients is important for prognosis with respect to liver disease. </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>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<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 large-scale French epidemiologic study, Bideau et al. (1989) found an average prevalence of HHT to be 1 in 8,345, which was more than 10 times higher than expected at that time. The distribution of the disease varied greatly from 1 area to another. Three French administrative areas had a far higher prevalence: Ain (1 in 3,345), Jura (1 in 5,062) and Deux-Sevres (1 in 4,287). Lesca et al. (2008) found that the 1112dupG mutation (601284.0014) was responsible for the very high frequency of the disease observed in the Ain and Jura administrative areas. The mutation was likely to have occurred in a common ancestor living in a valley of the Haut-Jura mountains more than 3 centuries ago and to have spread over the generations, mainly in the Rhone-Alpes region but also outside. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Srinivasan et al. (2003) created mice heterozygous for a loss-of-function mutation in Acvrl1 (601284). The mice developed age-dependent vascular lesions in the skin, extremities, oral cavity, and internal organs (lung, liver, intestine, spleen, and brain), as well as occult gastrointestinal bleeding. Major histopathologic features of the lesions included thin-walled dilated vessels in close proximity to each other, hemorrhage, and fibrosis. An Acvrl1 +/- mouse with profound liver involvement also displayed a secondary cardiac phenotype, similar to that observed in human patients. </p><p>Using a novel Acvrl1 null mutant mouse line in which a beta-galactosidase (see 230500) reporter gene (lacZ) was inserted into the Acvrl1 locus, Seki et al. (2003) showed that Acvrl1 was predominantly expressed in developing arterial, but not venous, endothelium. They concluded that, contrary to the view of HHT as a venous disease, their findings suggested that arterioles rather than venules are the primary vessels affected by the loss of an ACVRL1 allele. </p>
</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">
Abdalla, S. A., Cymerman, U., Johnson, R. M., Deber, C. M., Letarte, M.
<strong>Disease-associated mutations in conserved residues of ALK-1 kinase domain.</strong>
Europ. J. Hum. Genet. 11: 279-287, 2003.
[PubMed: 12700602]
[Full Text: https://doi.org/10.1038/sj.ejhg.5200919]
</p>
</li>
<li>
<p class="mim-text-font">
Abdalla, S. A., Geisthoff, U. W., Bonneau, D., Plauchu, H., McDonald, J., Kennedy, S., Faughnan, M. E., Letarte, M.
<strong>Visceral manifestations in hereditary haemorrhagic telangiectasia type 2.</strong>
J. Med. Genet. 40: 494-502, 2003.
[PubMed: 12843319]
[Full Text: https://doi.org/10.1136/jmg.40.7.494]
</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">
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. N., Gallione, C. J., Stenzel, T. T., Johnson, D. W., Allen, W. P., Schwartz, C. E., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A.
<strong>The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2.</strong>
Am. J. Hum. Genet. 61: 60-67, 1997.
[PubMed: 9245985]
[Full Text: https://doi.org/10.1086/513903]
</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">
Bideau, A., Plauchu, H., Brunet, G., Robert, J.
<strong>Epidemiological investigation of Rendu-Osler disease in France: its geographical distribution and prevalence.</strong>
Popul. 44: 3-22, 1989.
[PubMed: 12157905]
</p>
</li>
<li>
<p class="mim-text-font">
Brakensiek, K., Frye-Boukhriss, H., Malzer, M., Abramowicz, M., Bahr, M. J., von Beckerath, N., Bergmann, C., Caselitz, M., Holinski-Feder, E., Muschke, P., Oexle, J., Strobl-Wildemann, G., Wolff, G., El-Harith, E. A., Stuhrmann, M.
<strong>Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia.</strong>
Clin. Genet. 74: 171-177, 2008.
[PubMed: 18498373]
[Full Text: https://doi.org/10.1111/j.1399-0004.2008.01029.x]
</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">
Harrison, R. E., Flanagan, J. A., Sankelo, M., Abdalla, S. A., Rowell, J., Machado, R. D., Elliott, C. G., Robbins, I. M., Olschewski, H., McLaughlin, V., Gruenig, E., Kermeen, F., Halme, M., Raisanen-Sokolowski, A., Laitinen, T., Morrell, N. W., Trembath, R. C.
<strong>Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.</strong>
J. Med. Genet. 40: 865-871, 2003. Note: Erratum: J. Med. Genet. 41: 576 only, 2004.
[PubMed: 14684682]
[Full Text: https://doi.org/10.1136/jmg.40.12.865]
</p>
</li>
<li>
<p class="mim-text-font">
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>
J. Med. Genet. 31: 933-936, 1994.
[PubMed: 7891375]
[Full Text: https://doi.org/10.1136/jmg.31.12.933]
</p>
</li>
<li>
<p class="mim-text-font">
Johnson, D. W., Berg, J. N., Baldwin, M. A., Gallione, C. J., Marondel, I., Yoon, S.-J., Stenzel, T. T., Speer, M., Pericak-Vance, M. A., Diamond, A., Guttmacher, A. E., Jackson, C. E., Attisano, L., Kucherlapati, R., Porteous, M. E. M., Marchuk, D. A.
<strong>Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.</strong>
Nature Genet. 13: 189-195, 1996.
[PubMed: 8640225]
[Full Text: https://doi.org/10.1038/ng0696-189]
</p>
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<p class="mim-text-font">
Johnson, D. W., Berg, J. N., Gallione, C. J., McAllister, K. A., Warner, J. P., Helmbold, E. A., Markel, D. S., Jackson, C. E., Porteous, M. E. M., Marchuk, D. A.
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Lesca, G., Genin, E., Blachier, C., Olivieri, C., Coulet, F., Brunet, G., Dupuis-Girod, S., Buscarini, E., Soubrier, F., Calender, A., Danesino, C., Giraud, S., Plauchu, H.
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Europ. J. Hum. Genet. 16: 742-749, 2008.
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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.
<strong>Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France.</strong>
Hum. Mutat. 23: 289-299, 2004.
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[Full Text: https://doi.org/10.1002/ajmg.a.32243]
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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.
<strong>Genetic heterogeneity in hereditary haemorrhagic telangiectasia: possible correlation with clinical phenotype.</strong>
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[PubMed: 7891374]
[Full Text: https://doi.org/10.1136/jmg.31.12.927]
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McDonald, J. E., Miller, F. J., Hallam, S. E., Nelson, L., Marchuk, D. A., Ward, K. J.
<strong>Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred.</strong>
Am. J. Med. Genet. 93: 320-327, 2000.
[PubMed: 10946360]
[Full Text: https://doi.org/10.1002/1096-8628(20000814)93:4&lt;320::aid-ajmg12&gt;3.0.co;2-r]
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Olivieri, C., Mira, E., Delu, G., Pagella, F., Zambelli, A., Malvezzi, L., Buscarini, E., Danesino, C.
<strong>Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia.</strong>
J. Med. Genet. 39: E39, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.
[PubMed: 12114496]
[Full Text: https://doi.org/10.1136/jmg.39.7.e39]
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Olivieri, C., Pagella, F., Semino, L., Lanzarini, L., Valacca, C., Pilotto, A., Corno, S., Scappaticci, S., Manfredi, G., Buscarini, E., Danesino, C.
<strong>Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies.</strong>
J. Hum. Genet. 52: 820-829, 2007.
[PubMed: 17786384]
[Full Text: https://doi.org/10.1007/s10038-007-0187-5]
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Piantanida, M., Buscarini, E., Dellavecchia, C., Minelli, A., Rossi, A., Buscarini, L., Danesino, C.
<strong>Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2.</strong>
J. Med. Genet. 33: 441-443, 1996.
[PubMed: 8782041]
[Full Text: https://doi.org/10.1136/jmg.33.6.441]
</p>
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Porteous, M. E. M., Curtis, A., Williams, O., Marchuk, D., Bhattacharya, S. S., Burn, J.
<strong>Genetic heterogeneity in hereditary haemorrhagic telangiectasia.</strong>
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[Full Text: https://doi.org/10.1136/jmg.31.12.925]
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Rinaldi, M., Buscarini, E., Danesino, C., Chiosi, F., De Benedictis, A., Porcellini, A., Costagliola, C.
<strong>Ocular manifestations in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease): a case-series.</strong>
Ophthalmic Genet. 32: 12-17, 2011.
[PubMed: 21174526]
[Full Text: https://doi.org/10.3109/13816810.2010.535891]
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Seki, T., Yun, J., Oh, S. P.
<strong>Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling.</strong>
Circ. Res. 93: 682-689, 2003.
[PubMed: 12970115]
[Full Text: https://doi.org/10.1161/01.RES.0000095246.40391.3B]
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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]
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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>
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Srinivasan, S., Hanes, M. A., Dickens, T., Porteous, M. E. M., Oh, S. P., Hale, L. P., Marchuk, D. A.
<strong>A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2.</strong>
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[PubMed: 12588795]
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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>
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[PubMed: 5037289]
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Trembath, R. C., Thomson, J. R., Machado, R. D., Morgan, N. V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J. E., Humbert, M., Nichols, W. C., Morrell, N. W.
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Vincent, P., Plauchu, H., Hazan, J., Faure, S., Weissenbach, J., Godet, J.
<strong>A third locus for hereditary haemorrhagic telangiectasia maps to chromosome 12q.</strong>
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[PubMed: 7633456]
[Full Text: https://doi.org/10.1093/hmg/4.5.945]
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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>
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[PubMed: 16542389]
[Full Text: https://doi.org/10.1111/j.1399-0004.2006.00574.x]
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<p class="mim-text-font">
Wooderchak-Donahue, W. L., McDonald, J., Farrell, A., Akay, G., Velinder, M., Johnson, P., VanSant-Webb, C., Margraf, R., Briggs, E., Whitehead, K. J., Thomson, J., Lin, A. E., Pyeritz, R. E., Marth, G., Bayrak-Toydemir, P.
<strong>Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in hereditary haemorrhagic telangiectasia.</strong>
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[PubMed: 30244195]
[Full Text: https://doi.org/10.1136/jmedgenet-2018-105561]
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Marla J. F. O&#x27;Neill - updated : 11/22/2024<br>Ada Hamosh - updated : 10/18/2024<br>Sonja A. Rasmussen - updated : 02/05/2019<br>Ada Hamosh - updated : 01/31/2014<br>Jane Kelly - updated : 8/29/2011<br>Cassandra L. Kniffin - updated : 7/21/2009<br>Cassandra L. Kniffin - updated : 9/16/2008<br>Cassandra L. Kniffin - updated : 9/5/2008<br>Cassandra L. Kniffin - updated : 8/18/2008<br>Cassandra L. Kniffin - updated : 2/29/2008<br>Cassandra L. Kniffin - updated : 4/27/2006<br>Cassandra L. Kniffin - updated : 3/21/2006<br>Cassandra L. Kniffin - updated : 10/10/2005<br>George E. Tiller - updated : 1/5/2005<br>Cassandra L. Kniffin - reorganized : 4/29/2004<br>Cassandra L. Kniffin - updated : 4/12/2004<br>Marla J. F. O&#x27;Neill - updated : 3/17/2004<br>Victor A. McKusick - updated : 1/9/2004<br>Victor A. McKusick - updated : 10/22/2003<br>Sonja A. Rasmussen - updated : 3/12/2001<br>John Burn - edited : 12/14/1995
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