3346 lines
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Entry
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- #277480 - VON WILLEBRAND DISEASE, TYPE 3; VWD3
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- OMIM
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<p>
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<span class="h4">#277480</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/277480"><strong>Clinical Synopsis</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="#otherFeatures">Other Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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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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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=VON WILLEBRAND DISEASE, TYPE" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=17617&Typ=Pat" title="Von Willebrand disease type 3" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Von Willebrand disease typ… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3497&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Von Willebrand disease </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK7014/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/7419" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=277480[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=166096" title="Von Willebrand disease type 3" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Von Willebrand disease typ…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Von Willebrand disease</a></div>
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<span class="small">
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<div style="display: table-cell;">Animal Models</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0111054" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/277480" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/results?search_type=advanced&omia_id=001056,001058" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:277480" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 128108002<br />
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<strong>ICD10CM:</strong> D68.03<br />
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<strong>ORPHA:</strong> 166096, 903<br />
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<strong>DO:</strong> 0111054<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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277480
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</span>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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VON WILLEBRAND DISEASE, TYPE 3; VWD3
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</span>
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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VON WILLEBRAND DISEASE, TYPE III<br />
|
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VWD, TYPE 3
|
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</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="phenotypeMap" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/12/45?start=-3&limit=10&highlight=45">
|
|
12p13.31
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
von Willebrand disease, type 3
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/277480"> 277480 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
VWF
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613160"> 613160 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/277480" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<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/277480" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/277480" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Nose </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Epistaxis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249366005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249366005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R04.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R04.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/784.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">784.7</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0014591&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014591</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000421" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000421</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000421" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000421</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hemarthrosis may occur <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806560&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806560</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81808003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81808003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M25.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M25.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/719.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">719.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/719.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">719.1</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005261" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005261</a>]</span><br />
|
|
|
|
</span>
|
|
</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">
|
|
|
|
- Easy bruising <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/425075004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">425075004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/424131007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">424131007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423798</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000978" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000978</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000978" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000978</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">
|
|
|
|
- Prolonged bleeding time <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R79.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R79.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151529&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151529</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003010</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003010</a>]</span><br /> -
|
|
Mucocutaneous bleeding <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3150070&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3150070</a>]</span><br /> -
|
|
Prolonged bleeding after surgery or trauma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3554755&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3554755</a>]</span><br /> -
|
|
Menorrhagia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386692008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386692008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N92.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N92.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0025323&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025323</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000132" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000132</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000132" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000132</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Severely decreased antigen levels of VWF and factor VIII <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3550743&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3550743</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">
|
|
|
|
- Most severe type of von Willebrand disease<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 von Willebrand factor gene (VWF, <a href="/entry/613160#0015">613160.0015</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="text" class="mim-anchor"></a>
|
|
|
|
|
|
|
|
<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
|
|
<span class="mim-font">
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<p>A number sign (#) is used with this entry because von Willebrand disease (VWD) type 3 is caused by homozygous or compound heterozygous mutation in the gene encoding von Willebrand factor (VWF; <a href="/entry/613160">613160</a>), which maps to chromosome 12p13.</p>
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<p>Von Willebrand disease is a bleeding disorder resulting from a defect in platelet aggregation due to defects in the von Willebrand factor protein. Type 3 von Willebrand disease, which is inherited as an autosomal recessive disorder, is associated with a severe quantitative defect or virtual absence of VWF in plasma, a prolonged bleeding time, and more severe bleeding tendencies compared to the other types of VWD. Type 3 accounts for about 1% of patients with VWD. Bleeding usually starts in infancy and can include epistaxis, recurrent mucocutaneous bleeding, bleeding after surgery, and hemarthroses. Since VWF also serves as a carrier protein for coagulation factor VIII (F8; <a href="/entry/300841">300841</a>), affected individuals also have very low levels of plasma F8, resembling hemophilia A (<a href="/entry/306700">306700</a>) (summary by Zhang et al. (<a href="#24" class="mim-tip-reference" title="Zhang, Z. P., Lindstedt, M., Falk, G., Blomback, M., Egberg, N., Anvret, M. <strong>Nonsense mutations of the von Willebrand factor gene in patients with von Willebrand disease type III and type I.</strong> Am. J. Hum. Genet. 51: 850-858, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1415226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1415226</a>]" pmid="1415226">1992</a>, <a href="#21" class="mim-tip-reference" title="Zhang, Z. P., Blomback, M., Nyman, D., Anvret, M. <strong>Mutations of von Willebrand factor gene in families with von Willebrand disease in the Aland Islands.</strong> Proc. Nat. Acad. Sci. 90: 7937-7940, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8367445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8367445</a>] [<a href="https://doi.org/10.1073/pnas.90.17.7937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8367445">1993</a>); reviews by <a href="#11" class="mim-tip-reference" title="Sadler, J. E., Budde, U., Eikenboom, J. C. J., Favaloro, E. J., Hill, F. G. H., Holmberg, L., Ingerslev, J., Lee, C. A., Lillicrap, D., Mannucci, P. M., Mazurier, C., Meyer, D., and 9 others. <strong>Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor.</strong> J. Thromb. Haemost. 4: 2103-2114, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16889557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16889557</a>] [<a href="https://doi.org/10.1111/j.1538-7836.2006.02146.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16889557">Sadler et al., 2006</a> and <a href="#6" class="mim-tip-reference" title="Lillicrap, D. <strong>Genotype/phenotype association in von Willebrand disease: is the glass half full or empty?</strong> J. Thromb. Haemost. 7 (suppl. 1): 65-70, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19630771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19630771</a>] [<a href="https://doi.org/10.1111/j.1538-7836.2009.03367.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19630771">Lillicrap, 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19630771+16889557+8367445+1415226" 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 description and a classification of the types of von Willebrand disease, see VWD type 1 (<a href="/entry/193400">193400</a>).</p>
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<p>Von Willebrand (<a href="#18" class="mim-tip-reference" title="von Willebrand, E. A. <strong>Hereditar pseudohemofili.</strong> Finska Lakar. Hand. 68: 87-112, 1926."None>1926</a>, <a href="#19" class="mim-tip-reference" title="von Willebrand, E. A. <strong>Ueber hereditaere Pseudohaemophilie.</strong> Acta Med. Scand. 76: 521-550, 1931."None>1931</a>) discovered a hemorrhagic condition in persons living on the Aland Islands in the Sea of Bothnia between Sweden and Finland and called it 'pseudohemophilia.' (See <a href="/entry/300600">300600</a> for another Aland Island disease.) The main difference from classic hemophilia was prolonged bleeding time. Major clinical problems were gastrointestinal, urinary, and uterine bleeding; hemarthroses were rare, but present. <a href="#8" class="mim-tip-reference" title="Nyman, D., Eriksson, A. W., Blomback, M., Frants, R. R., Wahlberg, P. <strong>Recent investigations of the first bleeder family in Aland (Finland) described by von Willebrand.</strong> Thromb. Haemost. 45: 73-76, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6972630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6972630</a>]" pmid="6972630">Nyman et al. (1981)</a> followed up on the kindred originally reported by <a href="#18" class="mim-tip-reference" title="von Willebrand, E. A. <strong>Hereditar pseudohemofili.</strong> Finska Lakar. Hand. 68: 87-112, 1926."None>von Willebrand (1926)</a>. <a href="#21" class="mim-tip-reference" title="Zhang, Z. P., Blomback, M., Nyman, D., Anvret, M. <strong>Mutations of von Willebrand factor gene in families with von Willebrand disease in the Aland Islands.</strong> Proc. Nat. Acad. Sci. 90: 7937-7940, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8367445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8367445</a>] [<a href="https://doi.org/10.1073/pnas.90.17.7937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8367445">Zhang et al. (1993)</a> described patients descended from the original family reported by <a href="#18" class="mim-tip-reference" title="von Willebrand, E. A. <strong>Hereditar pseudohemofili.</strong> Finska Lakar. Hand. 68: 87-112, 1926."None>von Willebrand (1926)</a>. Only heterozygotes were found surviving. The proposita was a 5-year-old girl, who later bled to death during her fourth menstrual period. She had a normal coagulation time, but the bleeding time was prolonged, despite a normal platelet count. All but 1 of her 11 sibs had bleeding symptoms, as did both of her parents, who were third cousins, and many members of her family on both sides. Four of the proband's sisters had died of uncontrolled bleeding in early childhood; 3 died from gastrointestinal bleeding and 1 from bleeding after she bit her tongue in a fall. The predominant symptoms were bleeding from mucous membranes, such as from the nose, the gingivae after tooth extractions, the uterus, and the gastrointestinal tract. In contrast to hemophilia, hemarthroses seemed to be rare. All 5 of the girls who died from uncontrolled bleeding were probably homozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6972630+8367445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Zimmerman, T. S., Abildgaard, C. F., Meyer, D. <strong>The factor VIII abnormality in severe von Willebrand's disease.</strong> New Eng. J. Med. 301: 1307-1310, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/315519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">315519</a>] [<a href="https://doi.org/10.1056/NEJM197912133012402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="315519">Zimmerman et al. (1979)</a> studied the factor VIII abnormalities in patients with severe recessive von Willebrand disease from 8 families. In 5 families, the parents were first or second cousins. Heterozygous parents had normal to moderately decreased factor VIII-related antigen. A qualitative abnormality of the trace quantities of factor VIII-related antigen was demonstrated in 5 of 6 patients, with absence or relative decrease of the larger, less anodal forms. In addition, 5 different patterns were observed, each suggesting a different molecular abnormality. The findings indicated that severe von Willebrand disease is allelic to the dominant forms of the disorders, with different mutations responsible for the defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=315519" 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="#1" class="mim-tip-reference" title="Berliner, S. A., Seligsohn, U., Zivelin, A., Zwang, E., Sofferman, G. <strong>A relatively high frequency of severe (type III) von Willebrand's disease in Israel.</strong> Brit. J. Haemat. 62: 535-543, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3082350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3082350</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1986.tb02966.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3082350">Berliner et al. (1986)</a> observed a relatively high incidence of severe autosomal recessive VWD type 3 in Israel, especially among Arabs. In 15 obligate carriers of type 3 disease, mean levels of factor VIII clotting activity, of von Willebrand factor, and of ristocetin cofactor were significantly higher than the corresponding mean values in 31 symptomatic and 12 asymptomatic VWD type 1 patients, and in turn lower than the values observed in 30 healthy subjects. Ristocetin cofactor was the best criterion for discrimination of type 3 carriers, normals, and type 1 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3082350" 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="#13" class="mim-tip-reference" title="Sramek, A., Bucciarelli, P., Federici, A. B., Mannucci, P. M., De Rosa, V., Castaman, G., Morfini, M., Mazzucconi, M. G., Rocino, A., Schiavoni, M., Scaraggi, F. A., Reiber, J. H. C., Rosendaal, F. R. <strong>Patients with type 3 severe von Willebrand disease are not protected against atherosclerosis: results from a multicenter study in 47 patients.</strong> Circulation 109: 740-744, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14970109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14970109</a>] [<a href="https://doi.org/10.1161/01.CIR.0000112567.53841.10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14970109">Sramek et al. (2004)</a> studied atherosclerotic lesions in the carotid and femoral arteries of 47 individuals with type 3 VWD and 84 healthy controls and found no difference in intima-media thickness, proportion with atherosclerotic plaques, or thickness of plaques. There was no effect of VWF treatment on intima-media or plaque thickness in VWD patients. <a href="#13" class="mim-tip-reference" title="Sramek, A., Bucciarelli, P., Federici, A. B., Mannucci, P. M., De Rosa, V., Castaman, G., Morfini, M., Mazzucconi, M. G., Rocino, A., Schiavoni, M., Scaraggi, F. A., Reiber, J. H. C., Rosendaal, F. R. <strong>Patients with type 3 severe von Willebrand disease are not protected against atherosclerosis: results from a multicenter study in 47 patients.</strong> Circulation 109: 740-744, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14970109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14970109</a>] [<a href="https://doi.org/10.1161/01.CIR.0000112567.53841.10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14970109">Sramek et al. (2004)</a> concluded that VWF does not play a substantial role in human atherogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14970109" 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>Von Willebrand disease is inherited as an autosomal recessive trait (<a href="#6" class="mim-tip-reference" title="Lillicrap, D. <strong>Genotype/phenotype association in von Willebrand disease: is the glass half full or empty?</strong> J. Thromb. Haemost. 7 (suppl. 1): 65-70, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19630771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19630771</a>] [<a href="https://doi.org/10.1111/j.1538-7836.2009.03367.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19630771">Lillicrap, 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19630771" 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>Autosomal recessive inheritance of VWD was described by several authors, including <a href="#17" class="mim-tip-reference" title="Veltkamp, J. J., van Tilburg, N. H. <strong>Autosomal haemophilia: a variant of von Willebrand's disease.</strong> Brit. J. Haemat. 26: 141-152, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4546581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4546581</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1974.tb00457.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4546581">Veltkamp and van Tilburg (1974)</a>, <a href="#3" class="mim-tip-reference" title="Holmberg, L. <strong>Von Willebrand's disease with normal factor VIII activity in a homozygote.</strong> Haemostasis 3: 237-246, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4549210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4549210</a>] [<a href="https://doi.org/10.1159/000214059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4549210">Holmberg (1974)</a>, <a href="#14" class="mim-tip-reference" title="Sultan, Y., Simeon, J., Caen, J. P. <strong>Detection of heterozygotes in both parents of homozygous patients with von Willebrand's disease.</strong> J. Clin. Path. 28: 309-316, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/805164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">805164</a>] [<a href="https://doi.org/10.1136/jcp.28.4.309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="805164">Sultan et al. (1975)</a>, <a href="#10" class="mim-tip-reference" title="Ruggeri, Z. M., Mannucci, P. M., Jeffcoate, S. L., Ingram, G. I. C. <strong>Immunoradiometric assay of factor VIII related antigen, with observations in 32 patients with von Willebrand's disease.</strong> Brit. J. Haemat. 33: 221-223, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1083743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1083743</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1976.tb03533.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1083743">Ruggeri et al. (1976)</a>, and <a href="#4" class="mim-tip-reference" title="Ingram, G. I. C. <strong>Classification of von Willebrand's disease.</strong> Lancet 312: 1364-1365, 1978. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/82857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">82857</a>] [<a href="https://doi.org/10.1016/s0140-6736(78)91992-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="82857">Ingram (1978)</a>. <a href="#14" class="mim-tip-reference" title="Sultan, Y., Simeon, J., Caen, J. P. <strong>Detection of heterozygotes in both parents of homozygous patients with von Willebrand's disease.</strong> J. Clin. Path. 28: 309-316, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/805164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">805164</a>] [<a href="https://doi.org/10.1136/jcp.28.4.309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="805164">Sultan et al. (1975)</a> noted that the phenotype can be as severe as that observed in hemophilia. Many of the patients were born of consanguineous parents. In some instances, heterozygous parents showed minor laboratory abnormalities in the absence of clinical features of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4549210+1083743+805164+4546581+82857" 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 review of VWD, <a href="#5" class="mim-tip-reference" title="James, P., Lillicrap, D. <strong>The role of molecular genetics in diagnosing von Willebrand disease.</strong> Semin. Thromb. Hemost. 34: 502-508, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19085649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19085649</a>] [<a href="https://doi.org/10.1055/s-0028-1103361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19085649">James and Lillicrap (2008)</a> noted that VWD type 3 is associated with the development of anti-VWF alloantibodies after exposure to therapeutic VWF concentrates, representing an important issue in the clinical management of this subtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19085649" 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="#6" class="mim-tip-reference" title="Lillicrap, D. <strong>Genotype/phenotype association in von Willebrand disease: is the glass half full or empty?</strong> J. Thromb. Haemost. 7 (suppl. 1): 65-70, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19630771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19630771</a>] [<a href="https://doi.org/10.1111/j.1538-7836.2009.03367.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19630771">Lillicrap (2009)</a> stated that VWD type 3 varies in incidence from frequencies of 1 per 500,000 to 1 per million in many Western countries, to figures as high as 6 per million in countries where consanguineous marriages are more frequent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19630771" 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="#15" class="mim-tip-reference" title="Sutherland, M. S., Cumming, A. M., Bowman, M., Bolton-Maggs, P. H. B., Bowen, D. J., Collins, P. W., Hay, C. R. M., Will, A. M., Keeney, S. <strong>A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3.</strong> Blood 114: 1091-1098, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19372260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19372260</a>] [<a href="https://doi.org/10.1182/blood-2008-08-173278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19372260">Sutherland et al. (2009)</a> identified a recurrent 8.6-kb deletion of exons 4 and 5 of the VWF gene (<a href="/entry/613160#0038">613160.0038</a>) in Caucasian British patients with VWD type 3 and VWD type 1 (<a href="/entry/193400">193400</a>). The deletion was not found in VWD patients of Asian origin, and haplotype analysis confirmed a founder effect in the white British population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19372260" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Ngo, K. Y., Glotz, V. T., Koziol, J. A., Lynch, D. C., Gitschier, J., Ranieri, P., Ciavarella, N., Ruggeri, Z. M., Zimmerman, T. S. <strong>Homozygous and heterozygous deletions of the von Willebrand factor gene in patients and carriers of severe von Willebrand disease.</strong> Proc. Nat. Acad. Sci. 85: 2753-2757, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3258663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3258663</a>] [<a href="https://doi.org/10.1073/pnas.85.8.2753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3258663">Ngo et al. (1988)</a> studied the genomic DNA from 10 affected persons from 6 families with severe von Willebrand disease, characterized by undetectable or trace quantities of VWF in plasma and tissue stores. Four patients from 1 family showed complete homozygous deletion of the VWF gene. Gene dosage analysis was consistent with heterozygous deletion in both of the asymptomatic parents and in 4 asymptomatic sibs. A second family had complete heterozygous deletion of the VWF gene in the proband and in 1 asymptomatic parent, suggesting that a different type of genetic abnormality was inherited from the other parent, consistent with compound heterozygosity. Alloantibodies to VWF after treatment developed only in the kindred with homozygous deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3258663" 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 patient with severe type 3 von Willebrand disease, <a href="#9" class="mim-tip-reference" title="Peake, I. R., Liddell, M. B., Moodie, P., Standen, G., Mancuso, D. J., Tuley, E. A., Westfield, L. A., Sorace, J. M., Sadler, J. E., Verweij, C. L., Bloom, A. L. <strong>Severe type III von Willebrand's disease caused by deletion of exon 42 of the von Willebrand factor gene: family studies that identify carriers of the condition and a compound heterozygous individual.</strong> Blood 75: 654-661, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2297569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2297569</a>]" pmid="2297569">Peake et al. (1990)</a> found a homozygous 2.3-kb deletion in the VWF gene which included exon 42; a novel 182-bp insertion was found between the breakpoints. The patient had an alloantibody inhibitor to VWF. The insertion was detected by PCR amplification both in the patient's DNA and in his carrier relatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2297569" 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 patients with VWD type 3, Zhang et al. (<a href="#23" class="mim-tip-reference" title="Zhang, Z. P., Falk, G., Blomback, M., Egberg, N., Anvret, M. <strong>Identification of a new nonsense mutation in the von Willebrand factor gene in patients with von Willebrand disease type III.</strong> Hum. Molec. Genet. 1: 61-62, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301136</a>] [<a href="https://doi.org/10.1093/hmg/1.1.61" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301136">1992</a>, <a href="#22" class="mim-tip-reference" " title="Zhang, Z. P., Falk, G., Blomback, M., Egberg, N., Anvret, M. <strong>A single cytosine deletion in exon 18 of the von Willebrand factor gene is the most common mutation in Swedish vWD type III patients.</strong> Hum. Molec. Genet. 1: 767-768, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302613</a>] [<a href="https://doi.org/10.1093/hmg/1.9.767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302613">1992</a>, <a href="#24" class="mim-tip-reference" title="Zhang, Z. P., Lindstedt, M., Falk, G., Blomback, M., Egberg, N., Anvret, M. <strong>Nonsense mutations of the von Willebrand factor gene in patients with von Willebrand disease type III and type I.</strong> Am. J. Hum. Genet. 51: 850-858, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1415226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1415226</a>]" pmid="1415226">1992</a>) identified homozygous or compound heterozygous mutations in the VWF gene (see, e.g., <a href="/entry/613160#0015">613160.0015</a>-<a href="/entry/613160#0017">613160.0017</a>). Some heterozygous family members had a less severe phenotype, consistent with VWD type 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1301136+1415226+1302613" 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="Zhang, Z. P., Blomback, M., Nyman, D., Anvret, M. <strong>Mutations of von Willebrand factor gene in families with von Willebrand disease in the Aland Islands.</strong> Proc. Nat. Acad. Sci. 90: 7937-7940, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8367445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8367445</a>] [<a href="https://doi.org/10.1073/pnas.90.17.7937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8367445">Zhang et al. (1993)</a> found that the original family with VWD reported by <a href="#18" class="mim-tip-reference" title="von Willebrand, E. A. <strong>Hereditar pseudohemofili.</strong> Finska Lakar. Hand. 68: 87-112, 1926."None>von Willebrand (1926)</a> carried a common 1-bp deletion in the VWF gene (<a href="/entry/613160#0021">613160.0021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8367445" 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="Eikenboom, J. C. J., Castaman, G., Vos, H. L., Bertina, R. M., Rodeghiero, F. <strong>Characterization of the genetic defects in recessive type 1 and type 3 von Willebrand disease patients of Italian origin.</strong> Thromb. Haemost. 79: 709-717, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9569178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9569178</a>]" pmid="9569178">Eikenboom et al. (1998)</a> reviewed families with recessive VWD type 3 from northern Italy. Several mutations located throughout the gene were identified, indicating diverse molecular defects (see, e.g., C2362F, <a href="/entry/613160#0034">613160.0034</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9569178" 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="#12" class="mim-tip-reference" title="Shelton-Inloes, B. B., Chehab, F. F., Mannucci, P. M., Federici, A. B., Sadler, J. E. <strong>Gene deletions correlate with the development of alloantibodies in von Willebrand disease.</strong> J. Clin. Invest. 79: 1459-1465, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3033024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3033024</a>] [<a href="https://doi.org/10.1172/JCI112974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3033024">Shelton-Inloes et al. (1987)</a> found a correlation between the development of alloantibodies to VWF and the nature of the genetic lesion in VWD. Alloantibodies to VWF have been described only in the severe type 3 disease. <a href="#12" class="mim-tip-reference" title="Shelton-Inloes, B. B., Chehab, F. F., Mannucci, P. M., Federici, A. B., Sadler, J. E. <strong>Gene deletions correlate with the development of alloantibodies in von Willebrand disease.</strong> J. Clin. Invest. 79: 1459-1465, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3033024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3033024</a>] [<a href="https://doi.org/10.1172/JCI112974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3033024">Shelton-Inloes et al. (1987)</a> studied 19 patients with severe recessive VWD type 3 by Southern blotting with probes encompassing the full 9 kb of the VWF cDNA. Two presumably unrelated patients with type 3 who had large deletions within the VWF gene were the only ones among those studied who developed inhibitory alloantibodies to VWF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3033024" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Veltkamp1973" class="mim-tip-reference" title="Veltkamp, J. J., Van Tilburg, N. H. <strong>Detection of heterozygotes for recessive von Willebrand's disease by the assay of antihemophilic-factor-like antigen.</strong> New Eng. J. Med. 289: 882-885, 1973.">Veltkamp and Van Tilburg (1973)</a>; <a href="#Wise1993" class="mim-tip-reference" title="Wise, R. J., Ewenstein, B. M., Gorlin, J., Narins, S. C., Jesson, M., Handin, R. I. <strong>Autosomal recessive transmission of hemophilia A due to a von Willebrand factor mutation.</strong> Hum. Genet. 91: 367-372, 1993.">Wise et al. (1993)</a>
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Berliner, S. A., Seligsohn, U., Zivelin, A., Zwang, E., Sofferman, G.
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<strong>A relatively high frequency of severe (type III) von Willebrand's disease in Israel.</strong>
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Brit. J. Haemat. 62: 535-543, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3082350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3082350</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3082350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.1986.tb02966.x" target="_blank">Full Text</a>]
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<strong>Characterization of the genetic defects in recessive type 1 and type 3 von Willebrand disease patients of Italian origin.</strong>
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Thromb. Haemost. 79: 709-717, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9569178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9569178</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9569178" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Haemostasis 3: 237-246, 1974.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4549210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4549210</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4549210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1159/000214059" target="_blank">Full Text</a>]
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<strong>Classification of von Willebrand's disease.</strong>
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Lancet 312: 1364-1365, 1978. Note: Originally Volume II.
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[<a href="https://doi.org/10.1016/s0140-6736(78)91992-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1055/s-0028-1103361" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1538-7836.2009.03367.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.85.8.2753" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.1976.tb03533.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1538-7836.2006.02146.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI112974" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.CIR.0000112567.53841.10" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jcp.28.4.309" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197310252891703" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00217358" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302613</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/1.9.767" target="_blank">Full Text</a>]
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<a id="23" class="mim-anchor"></a>
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<a id="Zhang1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, Z. P., Falk, G., Blomback, M., Egberg, N., Anvret, M.
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<strong>Identification of a new nonsense mutation in the von Willebrand factor gene in patients with von Willebrand disease type III.</strong>
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Hum. Molec. Genet. 1: 61-62, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301136</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/1.1.61" target="_blank">Full Text</a>]
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<a id="24" class="mim-anchor"></a>
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<a id="Zhang1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, Z. P., Lindstedt, M., Falk, G., Blomback, M., Egberg, N., Anvret, M.
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<strong>Nonsense mutations of the von Willebrand factor gene in patients with von Willebrand disease type III and type I.</strong>
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Am. J. Hum. Genet. 51: 850-858, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1415226/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1415226</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1415226" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="25" class="mim-anchor"></a>
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<a id="Zimmerman1979" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zimmerman, T. S., Abildgaard, C. F., Meyer, D.
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<strong>The factor VIII abnormality in severe von Willebrand's disease.</strong>
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New Eng. J. Med. 301: 1307-1310, 1979.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/315519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">315519</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=315519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM197912133012402" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/27/2010
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - reorganized : 10/4/2010<br>Cassandra L. Kniffin - updated : 9/29/2010<br>Victor A. McKusick - updated : 7/10/1998
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 09/19/2016
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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terry : 07/31/2012<br>carol : 4/7/2011<br>wwang : 1/5/2011<br>ckniffin : 12/27/2010<br>terry : 10/8/2010<br>carol : 10/4/2010<br>ckniffin : 9/29/2010<br>terry : 3/25/2009<br>terry : 2/12/2009<br>carol : 7/15/1998<br>terry : 7/10/1998<br>warfield : 4/4/1994<br>mimadm : 3/12/1994<br>carol : 9/8/1992<br>supermim : 3/17/1992<br>carol : 3/2/1992<br>supermim : 3/20/1990
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<h3>
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<span class="mim-font">
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<strong>#</strong> 277480
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<h3>
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VON WILLEBRAND DISEASE, TYPE 3; VWD3
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<em>Alternative titles; symbols</em>
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<h4>
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VON WILLEBRAND DISEASE, TYPE III<br />
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VWD, TYPE 3
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 128108002;
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<strong>ICD10CM:</strong> D68.03;
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<strong>ORPHA:</strong> 166096, 903;
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<strong>DO:</strong> 0111054;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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</th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<tbody>
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<td>
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<span class="mim-font">
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12p13.31
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<td>
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<span class="mim-font">
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von Willebrand disease, type 3
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</td>
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<td>
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<span class="mim-font">
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277480
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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<td>
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<span class="mim-font">
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VWF
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</td>
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<td>
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<span class="mim-font">
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613160
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</table>
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<br />
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because von Willebrand disease (VWD) type 3 is caused by homozygous or compound heterozygous mutation in the gene encoding von Willebrand factor (VWF; 613160), which maps to chromosome 12p13.</p>
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</span>
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<div>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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<span class="mim-text-font">
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<p>Von Willebrand disease is a bleeding disorder resulting from a defect in platelet aggregation due to defects in the von Willebrand factor protein. Type 3 von Willebrand disease, which is inherited as an autosomal recessive disorder, is associated with a severe quantitative defect or virtual absence of VWF in plasma, a prolonged bleeding time, and more severe bleeding tendencies compared to the other types of VWD. Type 3 accounts for about 1% of patients with VWD. Bleeding usually starts in infancy and can include epistaxis, recurrent mucocutaneous bleeding, bleeding after surgery, and hemarthroses. Since VWF also serves as a carrier protein for coagulation factor VIII (F8; 300841), affected individuals also have very low levels of plasma F8, resembling hemophilia A (306700) (summary by Zhang et al. (1992, 1993); reviews by Sadler et al., 2006 and Lillicrap, 2009). </p><p>For a general description and a classification of the types of von Willebrand disease, see VWD type 1 (193400).</p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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<span class="mim-text-font">
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<p>Von Willebrand (1926, 1931) discovered a hemorrhagic condition in persons living on the Aland Islands in the Sea of Bothnia between Sweden and Finland and called it 'pseudohemophilia.' (See 300600 for another Aland Island disease.) The main difference from classic hemophilia was prolonged bleeding time. Major clinical problems were gastrointestinal, urinary, and uterine bleeding; hemarthroses were rare, but present. Nyman et al. (1981) followed up on the kindred originally reported by von Willebrand (1926). Zhang et al. (1993) described patients descended from the original family reported by von Willebrand (1926). Only heterozygotes were found surviving. The proposita was a 5-year-old girl, who later bled to death during her fourth menstrual period. She had a normal coagulation time, but the bleeding time was prolonged, despite a normal platelet count. All but 1 of her 11 sibs had bleeding symptoms, as did both of her parents, who were third cousins, and many members of her family on both sides. Four of the proband's sisters had died of uncontrolled bleeding in early childhood; 3 died from gastrointestinal bleeding and 1 from bleeding after she bit her tongue in a fall. The predominant symptoms were bleeding from mucous membranes, such as from the nose, the gingivae after tooth extractions, the uterus, and the gastrointestinal tract. In contrast to hemophilia, hemarthroses seemed to be rare. All 5 of the girls who died from uncontrolled bleeding were probably homozygotes. </p><p>Zimmerman et al. (1979) studied the factor VIII abnormalities in patients with severe recessive von Willebrand disease from 8 families. In 5 families, the parents were first or second cousins. Heterozygous parents had normal to moderately decreased factor VIII-related antigen. A qualitative abnormality of the trace quantities of factor VIII-related antigen was demonstrated in 5 of 6 patients, with absence or relative decrease of the larger, less anodal forms. In addition, 5 different patterns were observed, each suggesting a different molecular abnormality. The findings indicated that severe von Willebrand disease is allelic to the dominant forms of the disorders, with different mutations responsible for the defect. </p><p>Berliner et al. (1986) observed a relatively high incidence of severe autosomal recessive VWD type 3 in Israel, especially among Arabs. In 15 obligate carriers of type 3 disease, mean levels of factor VIII clotting activity, of von Willebrand factor, and of ristocetin cofactor were significantly higher than the corresponding mean values in 31 symptomatic and 12 asymptomatic VWD type 1 patients, and in turn lower than the values observed in 30 healthy subjects. Ristocetin cofactor was the best criterion for discrimination of type 3 carriers, normals, and type 1 patients. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Other Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sramek et al. (2004) studied atherosclerotic lesions in the carotid and femoral arteries of 47 individuals with type 3 VWD and 84 healthy controls and found no difference in intima-media thickness, proportion with atherosclerotic plaques, or thickness of plaques. There was no effect of VWF treatment on intima-media or plaque thickness in VWD patients. Sramek et al. (2004) concluded that VWF does not play a substantial role in human atherogenesis. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Inheritance</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Von Willebrand disease is inherited as an autosomal recessive trait (Lillicrap, 2009). </p><p>Autosomal recessive inheritance of VWD was described by several authors, including Veltkamp and van Tilburg (1974), Holmberg (1974), Sultan et al. (1975), Ruggeri et al. (1976), and Ingram (1978). Sultan et al. (1975) noted that the phenotype can be as severe as that observed in hemophilia. Many of the patients were born of consanguineous parents. In some instances, heterozygous parents showed minor laboratory abnormalities in the absence of clinical features of the disorder. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Management</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a review of VWD, James and Lillicrap (2008) noted that VWD type 3 is associated with the development of anti-VWF alloantibodies after exposure to therapeutic VWF concentrates, representing an important issue in the clinical management of this subtype. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>Lillicrap (2009) stated that VWD type 3 varies in incidence from frequencies of 1 per 500,000 to 1 per million in many Western countries, to figures as high as 6 per million in countries where consanguineous marriages are more frequent. </p><p>Sutherland et al. (2009) identified a recurrent 8.6-kb deletion of exons 4 and 5 of the VWF gene (613160.0038) in Caucasian British patients with VWD type 3 and VWD type 1 (193400). The deletion was not found in VWD patients of Asian origin, and haplotype analysis confirmed a founder effect in the white British population. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ngo et al. (1988) studied the genomic DNA from 10 affected persons from 6 families with severe von Willebrand disease, characterized by undetectable or trace quantities of VWF in plasma and tissue stores. Four patients from 1 family showed complete homozygous deletion of the VWF gene. Gene dosage analysis was consistent with heterozygous deletion in both of the asymptomatic parents and in 4 asymptomatic sibs. A second family had complete heterozygous deletion of the VWF gene in the proband and in 1 asymptomatic parent, suggesting that a different type of genetic abnormality was inherited from the other parent, consistent with compound heterozygosity. Alloantibodies to VWF after treatment developed only in the kindred with homozygous deletions. </p><p>In a patient with severe type 3 von Willebrand disease, Peake et al. (1990) found a homozygous 2.3-kb deletion in the VWF gene which included exon 42; a novel 182-bp insertion was found between the breakpoints. The patient had an alloantibody inhibitor to VWF. The insertion was detected by PCR amplification both in the patient's DNA and in his carrier relatives. </p><p>In patients with VWD type 3, Zhang et al. (1992, 1992, 1992) identified homozygous or compound heterozygous mutations in the VWF gene (see, e.g., 613160.0015-613160.0017). Some heterozygous family members had a less severe phenotype, consistent with VWD type 1. </p><p>Zhang et al. (1993) found that the original family with VWD reported by von Willebrand (1926) carried a common 1-bp deletion in the VWF gene (613160.0021). </p><p>Eikenboom et al. (1998) reviewed families with recessive VWD type 3 from northern Italy. Several mutations located throughout the gene were identified, indicating diverse molecular defects (see, e.g., C2362F, 613160.0034). </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Shelton-Inloes et al. (1987) found a correlation between the development of alloantibodies to VWF and the nature of the genetic lesion in VWD. Alloantibodies to VWF have been described only in the severe type 3 disease. Shelton-Inloes et al. (1987) studied 19 patients with severe recessive VWD type 3 by Southern blotting with probes encompassing the full 9 kb of the VWF cDNA. Two presumably unrelated patients with type 3 who had large deletions within the VWF gene were the only ones among those studied who developed inhibitory alloantibodies to VWF. </p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Veltkamp and Van Tilburg (1973); Wise et al. (1993)
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</span>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<strong>Severe type III von Willebrand's disease caused by deletion of exon 42 of the von Willebrand factor gene: family studies that identify carriers of the condition and a compound heterozygous individual.</strong>
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<strong>Detection of heterozygotes for recessive von Willebrand's disease by the assay of antihemophilic-factor-like antigen.</strong>
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Zhang, Z. P., Falk, G., Blomback, M., Egberg, N., Anvret, M.
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<strong>A single cytosine deletion in exon 18 of the von Willebrand factor gene is the most common mutation in Swedish vWD type III patients.</strong>
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Zhang, Z. P., Falk, G., Blomback, M., Egberg, N., Anvret, M.
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<strong>Identification of a new nonsense mutation in the von Willebrand factor gene in patients with von Willebrand disease type III.</strong>
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Hum. Molec. Genet. 1: 61-62, 1992.
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[PubMed: 1301136]
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</li>
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<li>
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<p class="mim-text-font">
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Zhang, Z. P., Lindstedt, M., Falk, G., Blomback, M., Egberg, N., Anvret, M.
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<strong>Nonsense mutations of the von Willebrand factor gene in patients with von Willebrand disease type III and type I.</strong>
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Am. J. Hum. Genet. 51: 850-858, 1992.
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[PubMed: 1415226]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Zimmerman, T. S., Abildgaard, C. F., Meyer, D.
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<strong>The factor VIII abnormality in severe von Willebrand's disease.</strong>
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New Eng. J. Med. 301: 1307-1310, 1979.
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[PubMed: 315519]
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[Full Text: https://doi.org/10.1056/NEJM197912133012402]
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Contributors:
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Cassandra L. Kniffin - updated : 12/27/2010<br>Cassandra L. Kniffin - reorganized : 10/4/2010<br>Cassandra L. Kniffin - updated : 9/29/2010<br>Victor A. McKusick - updated : 7/10/1998
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Victor A. McKusick : 6/4/1986
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Edit History:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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alopez : 09/19/2016<br>terry : 07/31/2012<br>carol : 4/7/2011<br>wwang : 1/5/2011<br>ckniffin : 12/27/2010<br>terry : 10/8/2010<br>carol : 10/4/2010<br>ckniffin : 9/29/2010<br>terry : 3/25/2009<br>terry : 2/12/2009<br>carol : 7/15/1998<br>terry : 7/10/1998<br>warfield : 4/4/1994<br>mimadm : 3/12/1994<br>carol : 9/8/1992<br>supermim : 3/17/1992<br>carol : 3/2/1992<br>supermim : 3/20/1990
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