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Entry
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- #153100 - LYMPHATIC MALFORMATION 1; LMPHM1
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- OMIM
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<p>
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<span class="h4">#153100</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/153100"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS153100"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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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 class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=LYMPHATIC MALFORMATION" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=11478&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1239/" 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/5256" 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://medlineplus.gov/genetics/condition/milroy-disease" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=153100[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79452" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0070210" 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/153100" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0070210" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<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>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 399889006<br />
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<strong>ORPHA:</strong> 79452<br />
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<strong>DO:</strong> 0070210<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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153100
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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LYMPHATIC MALFORMATION 1; LMPHM1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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NONNE-MILROY LYMPHEDEMA<br />
|
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MILROY DISEASE<br />
|
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LYMPHEDEMA, EARLY-ONSET<br />
|
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PRIMARY CONGENITAL LYMPHEDEMA; PCL<br />
|
|
LYMPHEDEMA, HEREDITARY, TYPE I, FORMERLY<br />
|
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LYMPHEDEMA, HEREDITARY, IA, FORMERLY; LMPH1A, FORMERLY
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<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">
|
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<thead>
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<tr class="active">
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<th>
|
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
|
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Phenotype <br /> MIM number
|
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/5/845?start=-3&limit=10&highlight=845">
|
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5q35.3
|
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Lymphatic malformation 1
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/153100"> 153100 </a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
FLT4
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/136352"> 136352 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
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|
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</tbody>
|
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</table>
|
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</div>
|
|
</div>
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<div>
|
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|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/153100" 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>
|
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|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS153100" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
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|
|
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|
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|
|
<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/153100" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/153100" 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>
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|
|
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<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
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|
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|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hemangioma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253053003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253053003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/400210000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">400210000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D18.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D18.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D18.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D18.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/228.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">228.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/228.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">228.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018916&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018916</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001028</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001028</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GENITOURINARY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> External Genitalia (Male) </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hydrocele <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386152007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386152007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26614003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26614003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N43.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N43.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/603.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">603.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/603" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">603</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1720771&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1720771</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100673" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100673</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000034" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000034</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000034" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000034</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hyperkeratosis over edematous areas <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1835253&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1835253</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007448" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007448</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007448" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007448</a>]</span><br /> -
|
|
Papillomatosis over edematous areas <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1835254&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1835254</a>]</span><br /> -
|
|
Hemangioma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253053003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253053003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/400210000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">400210000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D18.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D18.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D18.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D18.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/228.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">228.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/228.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">228.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018916&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018916</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001028</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001028</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Nails </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Upturned toenails <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1835255&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1835255</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0032344" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0032344</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Lymphedema, predominantly in the lower limbs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1835228&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1835228</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003550" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003550</a>]</span><br /> -
|
|
Lymphography shows hypoplasia of lymphatic vessels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1835249&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1835249</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> PRENATAL MANIFESTATIONS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Amniotic Fluid </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Non-immune fetal hydrops (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/276509008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">276509008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/206538000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">206538000</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/778.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">778.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0455988&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0455988</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001790" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001790</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001790" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001790</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
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<div>
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<div>
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<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
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</span>
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</div>
|
|
<div style="margin-left: 2em;">
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<div>
|
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<span class="mim-font">
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- Onset usually at birth<br /> -
|
|
Later onset may occur<br /> -
|
|
Variable expression and severity<br /> -
|
|
More prevalent in females<br /> -
|
|
Spontaneous resorption (rare)<br /> -
|
|
Lymphedema that presents at puberty is called Meige disease (<a href="/entry/153200">153200</a>)<br />
|
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|
|
</span>
|
|
</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
|
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<div style="margin-left: 2em;">
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<div>
|
|
<span class="mim-font">
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|
|
- Caused by mutation in the FMS-like tyrosine kinase-4 gene (FLT4, <a href="/entry/136352#0005">136352.0005</a>)<br />
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</span>
|
|
</div>
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</div>
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|
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</div>
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<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
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|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small">
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<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Lymphatic malformation
|
|
- <a href="/phenotypicSeries/PS153100">PS153100</a>
|
|
- 14 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/518?start=-3&limit=10&highlight=518"> 1p34.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619401"> Lymphatic malformation 11 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619401"> 619401 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600222"> TIE </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600222"> 600222 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1773?start=-3&limit=10&highlight=1773"> 1q42.13 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613480"> Lymphatic malformation 3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613480"> 613480 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608803"> GJC2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608803"> 608803 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/850?start=-3&limit=10&highlight=850"> 2q32.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618773"> ?Lymphatic malformation 8 </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">
|
|
<a href="/entry/618773"> 618773 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114190"> CALCRL </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114190"> 114190 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/4/692?start=-3&limit=10&highlight=692"> 4q34.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615907"> Lymphatic malformation 4 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615907"> 615907 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601528"> VEGFC </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601528"> 601528 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/5/845?start=-3&limit=10&highlight=845"> 5q35.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/153100"> Lymphatic malformation 1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/153100"> 153100 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/136352"> FLT4 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/136352"> 136352 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/6/723?start=-3&limit=10&highlight=723"> 6q16.2-q22.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611944"> Lymphatic malformation 2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611944"> 611944 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611944"> LMPHM2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611944"> 611944 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/517?start=-3&limit=10&highlight=517"> 7q22.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617300"> Lymphatic malformation 7 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617300"> 617300 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600011"> EPHB4 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600011"> 600011 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/599?start=-3&limit=10&highlight=599"> 7q31.1-q31.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620014"> Lymphatic malformation 12 </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">
|
|
<a href="/entry/620014"> 620014 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614511"> MDFIC </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614511"> 614511 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/8/17?start=-3&limit=10&highlight=17"> 8p23.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619369"> Lymphatic malformation 10 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619369"> 619369 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601922"> ANGPT2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601922"> 601922 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/13/197?start=-3&limit=10&highlight=197"> 13q14.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620244"> Lymphatic malformation 13 </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">
|
|
<a href="/entry/620244"> 620244 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616821"> THSD1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616821"> 616821 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/16/736?start=-3&limit=10&highlight=736"> 16q24.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616843"> Lymphatic malformation 6 </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>
|
|
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<p>A number sign (#) is used with this entry because of evidence that lymphatic malformation-1 (LMPHM1) is caused by heterozygous mutation in the FLT4 gene (<a href="/entry/136352">136352</a>) on chromosome 5q35. One patient with homozygous mutation in the FLT4 gene has been reported.</p>
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<p>Primary lymphedema is caused by anatomic or functional defects in the lymphatic system, resulting in chronic swelling of body parts. There may be accompanying nail and skin changes, such as nail dysplasia or papillomatosis. Onset is usually at birth or in early childhood but can occur later, and the severity is variable (summary by <a href="#10" class="mim-tip-reference" title="Gordon, K., Schulte, D., Brice, G., Simpson, M. A., Roukens, M. G., van Impel, A., Connell, F., Kalidas, K., Jeffery, S., Mortimer, P. S., Mansour, S., Schulte-Merker, S., Ostergaard, P. <strong>Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant Milroy-like primary lymphedema.</strong> Circ. Res. 112: 956-960, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23410910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23410910</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.113.300350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23410910">Gordon et al., 2013</a> and <a href="#1" class="mim-tip-reference" title="Balboa-Beltran, E., Fernandez-Seara, M. J., Perez-Munuzuri, A., Lago, R., Garcia-Magan, C., Couce, M. L., Sobrino, B., Amigo, J., Carracedo, A., Barros, F. <strong>A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease.</strong> J. Med. Genet. 51: 475-478, 2014. Note: Erratum: J. Med. Genet. 52: 216 only, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24744435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24744435</a>] [<a href="https://doi.org/10.1136/jmedgenet-2013-102020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24744435">Balboa-Beltran et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23410910+24744435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Lymphatic Malformation</em></strong></p><p>
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Primary lymphedema is genetically heterogeneous: see also LMPHM2 (<a href="/entry/611944">611944</a>), which maps to chromosome 6q16.2-q22.1; LMPHM3 (<a href="/entry/613480">613480</a>), caused by mutation in the GJC2 gene (<a href="/entry/608803">608803</a>) on chromosome 1q42; LMPHM4 (<a href="/entry/615907">615907</a>), caused by mutation in the VEGFC gene (<a href="/entry/601528">601528</a>) on chromosome 4q34; LMPHM5 (<a href="/entry/153200">153200</a>); LMPHM6 (<a href="/entry/616843">616843</a>), caused by mutation in the PIEZO1 gene (<a href="/entry/611184">611184</a>) on chromosome 16q24; LMPHM7 (<a href="/entry/617300">617300</a>), caused by mutation in the EPHB4 gene (<a href="/entry/600011">600011</a>) on chromosome 7q22; LMPHM8 (<a href="/entry/618773">618773</a>), caused by mutation in the CALCRL gene (<a href="/entry/114190">114190</a>) on chromosome 2q31; LMPHM9 (<a href="/entry/619319">619319</a>), caused by mutation in the CELSR1 gene (<a href="/entry/604523">604523</a>) on chromosome 22q13; LMPHM10 (<a href="/entry/610369">610369</a>), caused by mutation in the ANGPT2 gene (<a href="/entry/601922">601922</a>) on chromosome 8p23; LMPHM11 (<a href="/entry/619401">619401</a>), caused by mutation in the TIE1 gene (<a href="/entry/600222">600222</a>) on chromosome 1p34; LMPHM12 (<a href="/entry/620014">620014</a>), caused by mutation in the MDFIC gene (<a href="/entry/614511">614511</a>) on chromosome 7q31; LMPHM13 (<a href="/entry/620244">620244</a>), caused by mutation in the THSD1 gene (<a href="/entry/616821">616821</a>) on chromosome 13q14; and LMPHM14 (<a href="/entry/620602">620602</a>), caused by mutation in the ERG gene (<a href="/entry/165080">165080</a>) on chromosome 21q22.</p><p>Lymphedema can also be a feature of syndromic disorders such as lymphedema-distichiasis syndrome (<a href="/entry/153400">153400</a>), which is caused by mutation in the FOXC2 gene (<a href="/entry/602402">602402</a>), and various forms of nonimmune hydrops fetalis (NIHF; see <a href="/entry/236750">236750</a>).</p>
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<p>An early classification of primary lymphedema was based on age of onset. The first descriptions of familial lymphedema were published by <a href="#18" class="mim-tip-reference" title="Milroy, W. F. <strong>An undescribed variety of hereditary oedema.</strong> N.Y. Med. J. 56: 505-508, 1892."None>Milroy (1892)</a>, who described early onset of the disorder, and <a href="#17" class="mim-tip-reference" title="Meige, H. <strong>Dystrophie oedemateuse hereditaire.</strong> Presse Med. 6: 341-343, 1898."None>Meige (1898)</a>, who described onset around the time of puberty. Lymphedema of early onset became classified as Milroy disease (type I), and lymphedema after puberty as Meige disease or lymphedema praecox (type II; see <a href="/entry/153200">153200</a>). However, later reports showed that lymphedema could occur with early and late onset within the same family and that the features of the disorder could vary within a family. Primary lymphedema is here classified by molecular defect and mode of inheritance.</p>
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<p><a href="#18" class="mim-tip-reference" title="Milroy, W. F. <strong>An undescribed variety of hereditary oedema.</strong> N.Y. Med. J. 56: 505-508, 1892."None>Milroy (1892)</a>, a physician in Omaha, Nebraska, described the lymphedema in 6 generations of a family. Also see <a href="#19" class="mim-tip-reference" title="Milroy, W. F. <strong>Chronic hereditary edema: Milroy's disease.</strong> JAMA 91: 1172-1175, 1928."None>Milroy (1928)</a>.</p><p><a href="#20" class="mim-tip-reference" title="Rosen, F. S., Smith, D. H., Earle, R., Jr., Janeway, C. A., Gitlin, D. <strong>The etiology of hypoproteinemia in a patient with congenital chylous ascites.</strong> Pediatrics 30: 696-706, 1962."None>Rosen et al. (1962)</a> observed congenital chylous ascites in an affected infant whose father had recurrent swelling of the scrotum beginning at the age of 20 years. Marked loss of albumin into the intestinal tract with consequent hypoproteinemia was demonstrated.</p><p>In 2 patients, <a href="#12" class="mim-tip-reference" title="Hurwitz, P. A., Pinals, D. J. <strong>Pleural effusion in chronic hereditary lymphedema (Nonne, Milroy, Meige's disease): report of two cases.</strong> Radiology 82: 246-248, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14115303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14115303</a>] [<a href="https://doi.org/10.1148/82.2.246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14115303">Hurwitz and Pinals (1964)</a> observed persistent bilateral pleural effusion in which the protein content of the pleural fluid was high. <a href="#4" class="mim-tip-reference" title="Esterly, J. R. <strong>Congenital hereditary lymphoedema.</strong> J. Med. Genet. 2: 93-98, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14295660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14295660</a>] [<a href="https://doi.org/10.1136/jmg.2.2.93" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14295660">Esterly (1965)</a> described a family with 15 affected members of 3 generations. One child had striking congenital edema of the hands as a main feature and a second had similar swelling of the hands, as well as bilateral involvement of the legs and feet. A sib of the proposita had no apparent lymphedema, although 2 of his 4 children had bilateral swelling of the legs and feet. He was regarded at first as a 'skipped' generation similar to those noted in previous pedigrees of Milroy disease. Closer examination, however, demonstrated a definite 3 x 5 cm area of slight edema on the medial aspect of the left lower leg. This area was warm to the touch and could be pitted against the underlying tibia. High blood flow in the leg affected by congenital lymphedema has been thought to be due to accumulation of vasodilatory metabolites. Lymphedematous legs generally feel warm and the patients have warm feet. The proposita in the family reported by <a href="#4" class="mim-tip-reference" title="Esterly, J. R. <strong>Congenital hereditary lymphoedema.</strong> J. Med. Genet. 2: 93-98, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14295660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14295660</a>] [<a href="https://doi.org/10.1136/jmg.2.2.93" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14295660">Esterly (1965)</a> could recover the newspaper from her front walk in her bare feet in winter without discomfort. <a href="#4" class="mim-tip-reference" title="Esterly, J. R. <strong>Congenital hereditary lymphoedema.</strong> J. Med. Genet. 2: 93-98, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14295660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14295660</a>] [<a href="https://doi.org/10.1136/jmg.2.2.93" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14295660">Esterly (1965)</a> reviewed 22 previously documented pedigrees which, with his own family, gave a total of 152 affected persons. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14115303+14295660" 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="#7" class="mim-tip-reference" title="Ferrell, R. E., Levinson, K. L., Esman, J. H., Kimak, M. A., Lawrence, E. C., Barmada, M. M., Finegold, D. N. <strong>Hereditary lymphedema: evidence for linkage and genetic heterogeneity.</strong> Hum. Molec. Genet. 7: 2073-2078, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817924</a>] [<a href="https://doi.org/10.1093/hmg/7.13.2073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9817924">Ferrell et al. (1998)</a> studied 13 lymphedema families from the U.S. and Canada. All members of these families were of western European ancestry. In the 13 families, 105 individuals were classified as affected, with a male:female ratio of 1:2.3. The age of onset of lymphedema ranged from prenatal (diagnosed by ultrasound) to age 55 years. When affected x normal matings were analyzed, 76 of 191 children were affected, yielding a penetrance of 80%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9817924" 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="Brice, G., Child, A. H., Evans, A., Bell, R., Mansour, S., Burnand, K., Sarfarazi, M., Jeffery, S., Mortimer, P. <strong>Milroy disease and the VEGFR-3 mutation phenotype.</strong> J. Med. Genet. 42: 98-102, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689446</a>] [<a href="https://doi.org/10.1136/jmg.2004.024802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689446">Brice et al. (2005)</a> examined 211 individuals from 10 families with a history of congenital lymphedema and mutations in FLT4. Mutations were confirmed in 64 clinically affected individuals, and 7 clinically unaffected individuals were also found to have mutations. In all but 2 patients onset of swelling was from birth. Lymphedema was confined to the lower extremities in all patients and was associated with secondary changes including deep creases over the toes, small dysplastic ('ski jump') toenails, and papillomas. <a href="#2" class="mim-tip-reference" title="Brice, G., Child, A. H., Evans, A., Bell, R., Mansour, S., Burnand, K., Sarfarazi, M., Jeffery, S., Mortimer, P. <strong>Milroy disease and the VEGFR-3 mutation phenotype.</strong> J. Med. Genet. 42: 98-102, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689446</a>] [<a href="https://doi.org/10.1136/jmg.2004.024802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689446">Brice et al. (2005)</a> noted that these patients also had prominent, wide-caliber leg and foot veins not seen in other forms of congenital lymphedema. Apart from hydroceles and some urethral abnormalities, there were no major structural abnormalities or consistent dysmorphic features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689446" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Ghalamkarpour, A., Morlot, S., Raas-Rothschild, A., Utkus, A., Mulliken, J. B., Boon, L. M., Vikkula, M. <strong>Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations.</strong> Clin. Genet. 70: 330-335, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16965327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16965327</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00687.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16965327">Ghalamkarpour et al. (2006)</a> reported 3 unrelated families with autosomal dominant lymphedema confirmed by genetic analysis (see, e.g., <a href="/entry/136352#0008">136352.0008</a>-<a href="/entry/136352#0009">136352.0009</a>). In 1 family, the proband had severe elephantiasis up to the inguinal ligaments bilaterally associated with chronic venous ulcerations, cellulitis, and papillomatosis. In another family, a 22-week-old fetus was found to have fetal hydrops with bilateral leg edema, pleural effusions, hydrothorax, and pulmonary hypoplasia on ultrasound. The pregnancy was terminated. Other affected family members had congenital lymphedema of the legs with variable severity. One affected member from a third family had spontaneous resolution of the edema. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16965327" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Liu, N. F., Yan, Z. X., Wu, X. F. <strong>Classification of lymphatic-system malformations in primary lymphoedema based on MR lymphangiography.</strong> Europ. J. Vasc. Endovasc. Surg. 44: 345-349, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22831870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22831870</a>] [<a href="https://doi.org/10.1016/j.ejvs.2012.06.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22831870">Liu et al. (2012)</a> examined 378 patients with primary lymphedema of the lower extremities using magnetic resonance lymphangiography. Defects of the inguinal lymph nodes were detected in 63 (17%) of the patients, with mild or moderate dilation of the afferent lymph vessels. Lymphatic abnormalities were present in 123 (32%) of the patients, including aplasia, hypoplasia, or hyperplasia, with no obvious defects of the drainage lymph nodes. Abnormalities of both lymph vessels and lymph nodes were observed in 192 (51%) of the patients. There was no significant difference in age at onset or severity of disease between the groups, including between patients exhibiting hypoplasia or hyperplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22831870" 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="#11" class="mim-tip-reference" title="Holberg, C. J., Erickson, R. P., Bernas, M. J., Witte, M. H., Fultz, K. E., Andrade, M., Witte, C. L. <strong>Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families.</strong> Am. J. Med. Genet. 98: 303-312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170072</a>] [<a href="https://doi.org/10.1002/1096-8628(20010201)98:4<303::aid-ajmg1113>3.0.co;2-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170072">Holberg et al. (2001)</a> performed a complex segregation analysis and a genomewide search for linkage in 6 previously described families with Milroy congenital lymphedema. Results confirmed that Milroy lymphedema is generally inherited as a dominant condition, but this mode of inheritance did not account for all observed familial correlations. The authors suggested that shared environmental or additional genetic factors may also be important in explaining the observed familial aggregation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The possibility of an autosomal recessive form of congenital lymphedema was raised by <a href="#13" class="mim-tip-reference" title="Kajii, T., Tsukahara, M. <strong>Congenital lymphedema in two siblings.</strong> Jpn. J. Hum. Genet. 30: 31-34, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4010046/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4010046</a>] [<a href="https://doi.org/10.1007/BF01883671" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4010046">Kajii and Tsukahara (1985)</a>, who described brother and sister. The parents were not known to be related but came from an island with a population of 1,500 in the Sea of Japan. <a href="#14" class="mim-tip-reference" title="Kajii, T., Tsukahara, M. <strong>Autosomal recessive lymphedema? (Letter)</strong> Jpn. J. Hum. Genet. 31: 57 only, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3735758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3735758</a>] [<a href="https://doi.org/10.1007/BF01876803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3735758">Kajii and Tsukahara (1986)</a> cited a similar experience of brother and sister with congenital lymphedema of the lower extremities and no associated malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3735758+4010046" 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 linkage studies of 3 multigeneration families demonstrating hereditary lymphedema segregating as an autosomal dominant with incomplete penetrance, <a href="#7" class="mim-tip-reference" title="Ferrell, R. E., Levinson, K. L., Esman, J. H., Kimak, M. A., Lawrence, E. C., Barmada, M. M., Finegold, D. N. <strong>Hereditary lymphedema: evidence for linkage and genetic heterogeneity.</strong> Hum. Molec. Genet. 7: 2073-2078, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817924</a>] [<a href="https://doi.org/10.1093/hmg/7.13.2073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9817924">Ferrell et al. (1998)</a> demonstrated a 2-point lod score of 6.1 at theta = 0.0 for marker D5S1354 and a maximum multipoint lod score of 8.8 at marker D5S1354 located at 5q34-q35. Linkage analysis in 2 additional families using markers from the linked region showed 1 family consistent with linkage to distal chromosome 5; in the second family, linkage to 5q was excluded for all markers in the region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9817924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Evans, A. L., Brice, G., Sotirova, V., Mortimer, P., Beninson, J., Burnand, K., Rosbotham, J., Child, A., Sarfarazi, M. <strong>Mapping of primary congenital lymphedema to the 5q35.3 region.</strong> Am. J. Hum. Genet. 64: 547-555, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973292</a>] [<a href="https://doi.org/10.1086/302248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9973292">Evans et al. (1999)</a> carried out a genomewide search in a 4-generation North American family with what they termed 'dominantly inherited primary congenital lymphedema.' They established linkage to markers from the 5q35.3 region in this family and in 4 additional British families. The locus appeared to be situated in the most telomeric region of 5q35.3. No recombination was observed with D5S408 (lod = 10.03) and D5S2006 (lod = 8.46), with a combined multipoint score of 16.55. Four unaffected subjects were identified as gene carriers and provided an estimated penetrance ratio of 0.84 for this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9973292" 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 family with hereditary lymphedema, <a href="#7" class="mim-tip-reference" title="Ferrell, R. E., Levinson, K. L., Esman, J. H., Kimak, M. A., Lawrence, E. C., Barmada, M. M., Finegold, D. N. <strong>Hereditary lymphedema: evidence for linkage and genetic heterogeneity.</strong> Hum. Molec. Genet. 7: 2073-2078, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817924</a>] [<a href="https://doi.org/10.1093/hmg/7.13.2073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9817924">Ferrell et al. (1998)</a> identified a mutation in the FLT4 gene (<a href="/entry/136352#0005">136352.0005</a>). In several families with autosomal dominant hereditary lymphedema, <a href="#15" class="mim-tip-reference" title="Karkkainen, M. J., Ferrell, R. E., Lawrence, E. C., Kimak, M. A., Levinson, K. L., McTigue, M. A., Alitalo, K., Finegold, D. N. <strong>Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.</strong> Nature Genet. 25: 153-159, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835628</a>] [<a href="https://doi.org/10.1038/75997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835628">Karkkainen et al. (2000)</a> identified different mutations in the FLT4 gene (see, e.g., <a href="/entry/136352#0002">136352.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10835628+9817924" 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="#5" class="mim-tip-reference" title="Evans, A. L., Bell, R., Brice, G., Comeglio, P., Lipede, C., Jeffery, S., Mortimer, P., Sarfarazi, M., Child, A. H. <strong>Identification of eight novel VEGFR-3 mutations in families with primary lymphoedema.</strong> J. Med. Genet. 40: 697-703, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960217</a>] [<a href="https://doi.org/10.1136/jmg.40.9.697" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12960217">Evans et al. (2003)</a> identified 8 different heterozygous mutations in the FLT4 gene (see, e.g., <a href="/entry/136352#0011">136352.0011</a>) in affected members of 12 different Caucasian families with hereditary lymphedema. All the mutations occurred in the tyrosine kinase domains. Several families showed incomplete penetrance of the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12960217" 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 14 affected and 2 unaffected members of a 3-generation consanguineous Israeli family of Muslim Arab origin with hereditary lymphedema, <a href="#21" class="mim-tip-reference" title="Spiegel, R., Ghalamkarpour, A., Daniel-Spiegel, E., Vikkula, M., Shalev, S. A. <strong>Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3.</strong> J. Hum. Genet. 51: 846-850, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16924388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16924388</a>] [<a href="https://doi.org/10.1007/s10038-006-0031-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16924388">Spiegel et al. (2006)</a> identified heterozygosity for a missense mutation in the FLT4 gene (<a href="/entry/136352#0010">136352.0010</a>). The mutation was not found in 110 control individuals. There was wide intrafamilial phenotypic variability including 2 asymptomatic individuals, a case of prenatal hydrothorax evolving to hydrops fetalis, and a late-onset complication of chronic degenerative joint disease of the knees. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16924388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Connell, F. C., Ostergaard, P., Carver, C., Brice, G., Williams, N., Mansour, S., Mortimer, P. S., Jeffery, S., Lymphoedema Consortium. <strong>Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas.</strong> Hum. Genet. 124: 625-631, 2009. Note: Erratum: Hum. Genet. 125: 237 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19002718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19002718</a>] [<a href="https://doi.org/10.1007/s00439-008-0586-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19002718">Connell et al. (2009)</a> identified mutations in the FLT4 gene, including 14 novel mutations, in 22 (42%) of 52 patients with primary lymphedema. Mutation prevalence was 75% in patients with a typical Milroy phenotype and a positive family history, and 68% if positive family history was not a diagnostic criterion. No mutations were found outside the kinase domains, showing that analysis of nonkinase domains of FLT4 is not useful for Milroy disease patients. No mutations were identified in the VEGFC gene (<a href="/entry/601528">601528</a>), which encodes the FLT4 ligand. The findings indicated that a positive family history is not essential in Milroy disease, and that the likelihood of detecting FLT4 mutations in patients with a phenotype not typical for Milroy disease is less than 5%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19002718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Recessive Inheritance</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Ghalamkarpour, A., Holnthoner, W., Saharinen, P., Boon, L. M., Mulliken, J. B., Alitalo, K., Vikkula, M. <strong>Recessive primary congenital lymphoedema caused by a VEGFR3 mutation.</strong> J. Med. Genet. 46: 399-404, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19289394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19289394</a>] [<a href="https://doi.org/10.1136/jmg.2008.064469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19289394">Ghalamkarpour et al. (2009)</a> studied a Hispanic female, born of first-cousin parents, who had lymphedema at birth that extended below the knees bilaterally and was accompanied by a hypoplastic fourth toe. Her parents were unaffected, and there was no family history of lymphedema. The authors identified homozygosity for a missense mutation in the ATP-binding domain of the FLT4 gene (<a href="/entry/136352#0012">136352.0012</a>) in the proband; her parents were heterozygous for the hypomorphic mutation, which was not found in 110 controls. <a href="#8" class="mim-tip-reference" title="Ghalamkarpour, A., Holnthoner, W., Saharinen, P., Boon, L. M., Mulliken, J. B., Alitalo, K., Vikkula, M. <strong>Recessive primary congenital lymphoedema caused by a VEGFR3 mutation.</strong> J. Med. Genet. 46: 399-404, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19289394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19289394</a>] [<a href="https://doi.org/10.1136/jmg.2008.064469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19289394">Ghalamkarpour et al. (2009)</a> suggested that there should be large-scale screening of the FLT4 gene in all primary lymphedema patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19289394" 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>Congenital lymphedema is autosomal dominant in the pig (Van der Putte (<a href="#22" class="mim-tip-reference" title="Van der Putte, S. C. J. <strong>Congenital hereditary lymphedema in the pig.</strong> Lymphology 11: 1-9, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/642582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">642582</a>]" pmid="642582">1978</a>, <a href="#23" class="mim-tip-reference" title="Van der Putte, S. C. J. <strong>The pathogenesis of congenital hereditary lymphedema in the pig.</strong> Lymphology 11: 10-21, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/642583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">642583</a>]" pmid="642583">1978</a>)). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=642583+642582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1136/jmedgenet-2013-102020" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.024802" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-008-0586-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2.2.93" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960217</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12960217" 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/10.1136/jmg.40.9.697" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302248" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/7.13.2073" target="_blank">Full Text</a>]
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<a id="Ghalamkarpour2009" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19289394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19289394</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19289394" 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/10.1136/jmg.2008.064469" target="_blank">Full Text</a>]
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<a id="Ghalamkarpour2006" class="mim-anchor"></a>
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Ghalamkarpour, A., Morlot, S., Raas-Rothschild, A., Utkus, A., Mulliken, J. B., Boon, L. M., Vikkula, M.
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[<a href="https://doi.org/10.1111/j.1399-0004.2006.00687.x" target="_blank">Full Text</a>]
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<a id="Gordon2013" class="mim-anchor"></a>
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Gordon, K., Schulte, D., Brice, G., Simpson, M. A., Roukens, M. G., van Impel, A., Connell, F., Kalidas, K., Jeffery, S., Mortimer, P. S., Mansour, S., Schulte-Merker, S., Ostergaard, P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23410910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23410910</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23410910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/CIRCRESAHA.113.300350" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170072</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/1096-8628(20010201)98:4<303::aid-ajmg1113>3.0.co;2-9" target="_blank">Full Text</a>]
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<a id="Hurwitz1964" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1148/82.2.246" target="_blank">Full Text</a>]
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<a id="Kajii1985" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1007/BF01883671" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF01876803" target="_blank">Full Text</a>]
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<a id="Karkkainen2000" class="mim-anchor"></a>
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<div class="">
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Karkkainen, M. J., Ferrell, R. E., Lawrence, E. C., Kimak, M. A., Levinson, K. L., McTigue, M. A., Alitalo, K., Finegold, D. N.
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<strong>Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835628</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835628" 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/10.1038/75997" target="_blank">Full Text</a>]
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<a id="Liu2012" class="mim-anchor"></a>
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<p class="mim-text-font">
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Liu, N. F., Yan, Z. X., Wu, X. F.
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<strong>Classification of lymphatic-system malformations in primary lymphoedema based on MR lymphangiography.</strong>
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Europ. J. Vasc. Endovasc. Surg. 44: 345-349, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22831870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22831870</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22831870" 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/10.1016/j.ejvs.2012.06.019" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Meige1898" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Meige, H.
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<strong>Dystrophie oedemateuse hereditaire.</strong>
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Presse Med. 6: 341-343, 1898.
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</p>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Milroy1892" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Milroy, W. F.
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<strong>An undescribed variety of hereditary oedema.</strong>
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N.Y. Med. J. 56: 505-508, 1892.
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</p>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Milroy1928" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Milroy, W. F.
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<strong>Chronic hereditary edema: Milroy's disease.</strong>
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JAMA 91: 1172-1175, 1928.
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</p>
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</div>
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</li>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Rosen1962" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rosen, F. S., Smith, D. H., Earle, R., Jr., Janeway, C. A., Gitlin, D.
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<strong>The etiology of hypoproteinemia in a patient with congenital chylous ascites.</strong>
|
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Pediatrics 30: 696-706, 1962.
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</p>
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</div>
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</li>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Spiegel2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Spiegel, R., Ghalamkarpour, A., Daniel-Spiegel, E., Vikkula, M., Shalev, S. A.
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<strong>Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3.</strong>
|
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J. Hum. Genet. 51: 846-850, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16924388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16924388</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16924388" 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/10.1007/s10038-006-0031-3" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Van der Putte1978" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Van der Putte, S. C. J.
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<strong>Congenital hereditary lymphedema in the pig.</strong>
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Lymphology 11: 1-9, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/642582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">642582</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=642582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Van der Putte1978" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Van der Putte, S. C. J.
|
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<strong>The pathogenesis of congenital hereditary lymphedema in the pig.</strong>
|
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Lymphology 11: 10-21, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/642583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">642583</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=642583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 06/04/2021
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 02/10/2020<br>Marla J. F. O'Neill - updated : 12/19/2018<br>Cassandra L. Kniffin - updated : 6/10/2009<br>Cassandra L. Kniffin - updated : 2/25/2009<br>Marla J. F. O'Neill - updated : 12/29/2006<br>Cassandra L. Kniffin - updated : 11/1/2006<br>Marla J. F. O'Neill - updated : 3/2/2005<br>Cassandra L. Kniffin - reorganized : 11/19/2003<br>Sonja A. Rasmussen - updated : 3/12/2001<br>Victor A. McKusick - updated : 2/10/1999<br>Victor A. McKusick - updated : 1/6/1999
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</span>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/2/1986
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</span>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 11/14/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 02/10/2023<br>alopez : 08/23/2022<br>alopez : 06/24/2021<br>carol : 06/04/2021<br>alopez : 05/14/2021<br>ckniffin : 05/10/2021<br>carol : 02/12/2020<br>ckniffin : 02/10/2020<br>alopez : 08/06/2019<br>carol : 01/10/2019<br>carol : 12/19/2018<br>carol : 12/18/2018<br>carol : 11/26/2018<br>carol : 03/30/2018<br>carol : 08/12/2016<br>carol : 08/11/2016<br>carol : 08/04/2014<br>alopez : 7/29/2014<br>mcolton : 7/28/2014<br>ckniffin : 7/25/2014<br>wwang : 7/13/2010<br>ckniffin : 7/13/2010<br>wwang : 9/28/2009<br>wwang : 7/1/2009<br>ckniffin : 6/10/2009<br>terry : 6/3/2009<br>wwang : 6/1/2009<br>ckniffin : 5/20/2009<br>wwang : 3/5/2009<br>ckniffin : 2/25/2009<br>wwang : 4/18/2008<br>ckniffin : 4/14/2008<br>wwang : 12/29/2006<br>ckniffin : 11/6/2006<br>carol : 11/6/2006<br>ckniffin : 11/1/2006<br>carol : 9/29/2006<br>carol : 9/26/2006<br>wwang : 3/11/2005<br>wwang : 3/8/2005<br>terry : 3/2/2005<br>carol : 11/19/2003<br>ckniffin : 11/12/2003<br>mcapotos : 3/12/2001<br>terry : 3/9/1999<br>carol : 3/3/1999<br>carol : 2/10/1999<br>terry : 2/10/1999<br>carol : 1/18/1999<br>terry : 1/6/1999<br>mimadm : 11/6/1994<br>carol : 5/16/1994<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988
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</span>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 153100
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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LYMPHATIC MALFORMATION 1; LMPHM1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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NONNE-MILROY LYMPHEDEMA<br />
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MILROY DISEASE<br />
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LYMPHEDEMA, EARLY-ONSET<br />
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PRIMARY CONGENITAL LYMPHEDEMA; PCL<br />
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LYMPHEDEMA, HEREDITARY, TYPE I, FORMERLY<br />
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LYMPHEDEMA, HEREDITARY, IA, FORMERLY; LMPH1A, FORMERLY
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 399889006;
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<strong>ORPHA:</strong> 79452;
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<strong>DO:</strong> 0070210;
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</span>
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</p>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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5q35.3
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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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Lymphatic malformation 1
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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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153100
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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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Autosomal dominant
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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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</span>
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</td>
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<td>
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<span class="mim-font">
|
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FLT4
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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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136352
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that lymphatic malformation-1 (LMPHM1) is caused by heterozygous mutation in the FLT4 gene (136352) on chromosome 5q35. One patient with homozygous mutation in the FLT4 gene has been reported.</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>Description</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>Primary lymphedema is caused by anatomic or functional defects in the lymphatic system, resulting in chronic swelling of body parts. There may be accompanying nail and skin changes, such as nail dysplasia or papillomatosis. Onset is usually at birth or in early childhood but can occur later, and the severity is variable (summary by Gordon et al., 2013 and Balboa-Beltran et al., 2014). </p><p><strong><em>Genetic Heterogeneity of Lymphatic Malformation</em></strong></p><p>
|
|
Primary lymphedema is genetically heterogeneous: see also LMPHM2 (611944), which maps to chromosome 6q16.2-q22.1; LMPHM3 (613480), caused by mutation in the GJC2 gene (608803) on chromosome 1q42; LMPHM4 (615907), caused by mutation in the VEGFC gene (601528) on chromosome 4q34; LMPHM5 (153200); LMPHM6 (616843), caused by mutation in the PIEZO1 gene (611184) on chromosome 16q24; LMPHM7 (617300), caused by mutation in the EPHB4 gene (600011) on chromosome 7q22; LMPHM8 (618773), caused by mutation in the CALCRL gene (114190) on chromosome 2q31; LMPHM9 (619319), caused by mutation in the CELSR1 gene (604523) on chromosome 22q13; LMPHM10 (610369), caused by mutation in the ANGPT2 gene (601922) on chromosome 8p23; LMPHM11 (619401), caused by mutation in the TIE1 gene (600222) on chromosome 1p34; LMPHM12 (620014), caused by mutation in the MDFIC gene (614511) on chromosome 7q31; LMPHM13 (620244), caused by mutation in the THSD1 gene (616821) on chromosome 13q14; and LMPHM14 (620602), caused by mutation in the ERG gene (165080) on chromosome 21q22.</p><p>Lymphedema can also be a feature of syndromic disorders such as lymphedema-distichiasis syndrome (153400), which is caused by mutation in the FOXC2 gene (602402), and various forms of nonimmune hydrops fetalis (NIHF; see 236750).</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">
|
|
<strong>Nomenclature</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">
|
|
<p>An early classification of primary lymphedema was based on age of onset. The first descriptions of familial lymphedema were published by Milroy (1892), who described early onset of the disorder, and Meige (1898), who described onset around the time of puberty. Lymphedema of early onset became classified as Milroy disease (type I), and lymphedema after puberty as Meige disease or lymphedema praecox (type II; see 153200). However, later reports showed that lymphedema could occur with early and late onset within the same family and that the features of the disorder could vary within a family. Primary lymphedema is here classified by molecular defect and mode of inheritance.</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>Clinical Features</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>Milroy (1892), a physician in Omaha, Nebraska, described the lymphedema in 6 generations of a family. Also see Milroy (1928).</p><p>Rosen et al. (1962) observed congenital chylous ascites in an affected infant whose father had recurrent swelling of the scrotum beginning at the age of 20 years. Marked loss of albumin into the intestinal tract with consequent hypoproteinemia was demonstrated.</p><p>In 2 patients, Hurwitz and Pinals (1964) observed persistent bilateral pleural effusion in which the protein content of the pleural fluid was high. Esterly (1965) described a family with 15 affected members of 3 generations. One child had striking congenital edema of the hands as a main feature and a second had similar swelling of the hands, as well as bilateral involvement of the legs and feet. A sib of the proposita had no apparent lymphedema, although 2 of his 4 children had bilateral swelling of the legs and feet. He was regarded at first as a 'skipped' generation similar to those noted in previous pedigrees of Milroy disease. Closer examination, however, demonstrated a definite 3 x 5 cm area of slight edema on the medial aspect of the left lower leg. This area was warm to the touch and could be pitted against the underlying tibia. High blood flow in the leg affected by congenital lymphedema has been thought to be due to accumulation of vasodilatory metabolites. Lymphedematous legs generally feel warm and the patients have warm feet. The proposita in the family reported by Esterly (1965) could recover the newspaper from her front walk in her bare feet in winter without discomfort. Esterly (1965) reviewed 22 previously documented pedigrees which, with his own family, gave a total of 152 affected persons. </p><p>Ferrell et al. (1998) studied 13 lymphedema families from the U.S. and Canada. All members of these families were of western European ancestry. In the 13 families, 105 individuals were classified as affected, with a male:female ratio of 1:2.3. The age of onset of lymphedema ranged from prenatal (diagnosed by ultrasound) to age 55 years. When affected x normal matings were analyzed, 76 of 191 children were affected, yielding a penetrance of 80%. </p><p>Brice et al. (2005) examined 211 individuals from 10 families with a history of congenital lymphedema and mutations in FLT4. Mutations were confirmed in 64 clinically affected individuals, and 7 clinically unaffected individuals were also found to have mutations. In all but 2 patients onset of swelling was from birth. Lymphedema was confined to the lower extremities in all patients and was associated with secondary changes including deep creases over the toes, small dysplastic ('ski jump') toenails, and papillomas. Brice et al. (2005) noted that these patients also had prominent, wide-caliber leg and foot veins not seen in other forms of congenital lymphedema. Apart from hydroceles and some urethral abnormalities, there were no major structural abnormalities or consistent dysmorphic features. </p><p>Ghalamkarpour et al. (2006) reported 3 unrelated families with autosomal dominant lymphedema confirmed by genetic analysis (see, e.g., 136352.0008-136352.0009). In 1 family, the proband had severe elephantiasis up to the inguinal ligaments bilaterally associated with chronic venous ulcerations, cellulitis, and papillomatosis. In another family, a 22-week-old fetus was found to have fetal hydrops with bilateral leg edema, pleural effusions, hydrothorax, and pulmonary hypoplasia on ultrasound. The pregnancy was terminated. Other affected family members had congenital lymphedema of the legs with variable severity. One affected member from a third family had spontaneous resolution of the edema. </p><p>Liu et al. (2012) examined 378 patients with primary lymphedema of the lower extremities using magnetic resonance lymphangiography. Defects of the inguinal lymph nodes were detected in 63 (17%) of the patients, with mild or moderate dilation of the afferent lymph vessels. Lymphatic abnormalities were present in 123 (32%) of the patients, including aplasia, hypoplasia, or hyperplasia, with no obvious defects of the drainage lymph nodes. Abnormalities of both lymph vessels and lymph nodes were observed in 192 (51%) of the patients. There was no significant difference in age at onset or severity of disease between the groups, including between patients exhibiting hypoplasia or hyperplasia. </p>
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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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<span class="mim-text-font">
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<p>Holberg et al. (2001) performed a complex segregation analysis and a genomewide search for linkage in 6 previously described families with Milroy congenital lymphedema. Results confirmed that Milroy lymphedema is generally inherited as a dominant condition, but this mode of inheritance did not account for all observed familial correlations. The authors suggested that shared environmental or additional genetic factors may also be important in explaining the observed familial aggregation. </p><p>The possibility of an autosomal recessive form of congenital lymphedema was raised by Kajii and Tsukahara (1985), who described brother and sister. The parents were not known to be related but came from an island with a population of 1,500 in the Sea of Japan. Kajii and Tsukahara (1986) cited a similar experience of brother and sister with congenital lymphedema of the lower extremities and no associated malformations. </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>Mapping</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 linkage studies of 3 multigeneration families demonstrating hereditary lymphedema segregating as an autosomal dominant with incomplete penetrance, Ferrell et al. (1998) demonstrated a 2-point lod score of 6.1 at theta = 0.0 for marker D5S1354 and a maximum multipoint lod score of 8.8 at marker D5S1354 located at 5q34-q35. Linkage analysis in 2 additional families using markers from the linked region showed 1 family consistent with linkage to distal chromosome 5; in the second family, linkage to 5q was excluded for all markers in the region. </p><p>Evans et al. (1999) carried out a genomewide search in a 4-generation North American family with what they termed 'dominantly inherited primary congenital lymphedema.' They established linkage to markers from the 5q35.3 region in this family and in 4 additional British families. The locus appeared to be situated in the most telomeric region of 5q35.3. No recombination was observed with D5S408 (lod = 10.03) and D5S2006 (lod = 8.46), with a combined multipoint score of 16.55. Four unaffected subjects were identified as gene carriers and provided an estimated penetrance ratio of 0.84 for this disorder. </p>
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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>In a family with hereditary lymphedema, Ferrell et al. (1998) identified a mutation in the FLT4 gene (136352.0005). In several families with autosomal dominant hereditary lymphedema, Karkkainen et al. (2000) identified different mutations in the FLT4 gene (see, e.g., 136352.0002). </p><p>Evans et al. (2003) identified 8 different heterozygous mutations in the FLT4 gene (see, e.g., 136352.0011) in affected members of 12 different Caucasian families with hereditary lymphedema. All the mutations occurred in the tyrosine kinase domains. Several families showed incomplete penetrance of the phenotype. </p><p>In 14 affected and 2 unaffected members of a 3-generation consanguineous Israeli family of Muslim Arab origin with hereditary lymphedema, Spiegel et al. (2006) identified heterozygosity for a missense mutation in the FLT4 gene (136352.0010). The mutation was not found in 110 control individuals. There was wide intrafamilial phenotypic variability including 2 asymptomatic individuals, a case of prenatal hydrothorax evolving to hydrops fetalis, and a late-onset complication of chronic degenerative joint disease of the knees. </p><p>Connell et al. (2009) identified mutations in the FLT4 gene, including 14 novel mutations, in 22 (42%) of 52 patients with primary lymphedema. Mutation prevalence was 75% in patients with a typical Milroy phenotype and a positive family history, and 68% if positive family history was not a diagnostic criterion. No mutations were found outside the kinase domains, showing that analysis of nonkinase domains of FLT4 is not useful for Milroy disease patients. No mutations were identified in the VEGFC gene (601528), which encodes the FLT4 ligand. The findings indicated that a positive family history is not essential in Milroy disease, and that the likelihood of detecting FLT4 mutations in patients with a phenotype not typical for Milroy disease is less than 5%. </p><p><strong><em>Recessive Inheritance</em></strong></p><p>
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Ghalamkarpour et al. (2009) studied a Hispanic female, born of first-cousin parents, who had lymphedema at birth that extended below the knees bilaterally and was accompanied by a hypoplastic fourth toe. Her parents were unaffected, and there was no family history of lymphedema. The authors identified homozygosity for a missense mutation in the ATP-binding domain of the FLT4 gene (136352.0012) in the proband; her parents were heterozygous for the hypomorphic mutation, which was not found in 110 controls. Ghalamkarpour et al. (2009) suggested that there should be large-scale screening of the FLT4 gene in all primary lymphedema patients. </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>Animal Model</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>Congenital lymphedema is autosomal dominant in the pig (Van der Putte (1978, 1978)). </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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<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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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Balboa-Beltran, E., Fernandez-Seara, M. J., Perez-Munuzuri, A., Lago, R., Garcia-Magan, C., Couce, M. L., Sobrino, B., Amigo, J., Carracedo, A., Barros, F.
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<strong>A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease.</strong>
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J. Med. Genet. 51: 475-478, 2014. Note: Erratum: J. Med. Genet. 52: 216 only, 2015.
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Brice, G., Child, A. H., Evans, A., Bell, R., Mansour, S., Burnand, K., Sarfarazi, M., Jeffery, S., Mortimer, P.
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<strong>Milroy disease and the VEGFR-3 mutation phenotype.</strong>
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J. Med. Genet. 42: 98-102, 2005.
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<p class="mim-text-font">
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Connell, F. C., Ostergaard, P., Carver, C., Brice, G., Williams, N., Mansour, S., Mortimer, P. S., Jeffery, S., Lymphoedema Consortium.
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<strong>Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas.</strong>
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Hum. Genet. 124: 625-631, 2009. Note: Erratum: Hum. Genet. 125: 237 only, 2009.
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<p class="mim-text-font">
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Esterly, J. R.
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<strong>Congenital hereditary lymphoedema.</strong>
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J. Med. Genet. 2: 93-98, 1965.
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[PubMed: 14295660]
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Evans, A. L., Bell, R., Brice, G., Comeglio, P., Lipede, C., Jeffery, S., Mortimer, P., Sarfarazi, M., Child, A. H.
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<strong>Identification of eight novel VEGFR-3 mutations in families with primary lymphoedema.</strong>
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J. Med. Genet. 40: 697-703, 2003.
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Evans, A. L., Brice, G., Sotirova, V., Mortimer, P., Beninson, J., Burnand, K., Rosbotham, J., Child, A., Sarfarazi, M.
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<strong>Mapping of primary congenital lymphedema to the 5q35.3 region.</strong>
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Am. J. Hum. Genet. 64: 547-555, 1999.
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Ferrell, R. E., Levinson, K. L., Esman, J. H., Kimak, M. A., Lawrence, E. C., Barmada, M. M., Finegold, D. N.
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<strong>Hereditary lymphedema: evidence for linkage and genetic heterogeneity.</strong>
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Hum. Molec. Genet. 7: 2073-2078, 1998.
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Ghalamkarpour, A., Holnthoner, W., Saharinen, P., Boon, L. M., Mulliken, J. B., Alitalo, K., Vikkula, M.
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<strong>Recessive primary congenital lymphoedema caused by a VEGFR3 mutation.</strong>
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<p class="mim-text-font">
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Ghalamkarpour, A., Morlot, S., Raas-Rothschild, A., Utkus, A., Mulliken, J. B., Boon, L. M., Vikkula, M.
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<strong>Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations.</strong>
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Clin. Genet. 70: 330-335, 2006.
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[Full Text: https://doi.org/10.1111/j.1399-0004.2006.00687.x]
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<li>
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<p class="mim-text-font">
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Gordon, K., Schulte, D., Brice, G., Simpson, M. A., Roukens, M. G., van Impel, A., Connell, F., Kalidas, K., Jeffery, S., Mortimer, P. S., Mansour, S., Schulte-Merker, S., Ostergaard, P.
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<strong>Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant Milroy-like primary lymphedema.</strong>
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Circ. Res. 112: 956-960, 2013.
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[PubMed: 23410910]
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</p>
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<li>
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<p class="mim-text-font">
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Holberg, C. J., Erickson, R. P., Bernas, M. J., Witte, M. H., Fultz, K. E., Andrade, M., Witte, C. L.
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<strong>Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families.</strong>
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Am. J. Med. Genet. 98: 303-312, 2001.
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[PubMed: 11170072]
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[Full Text: https://doi.org/10.1002/1096-8628(20010201)98:4<303::aid-ajmg1113>3.0.co;2-9]
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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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Hurwitz, P. A., Pinals, D. J.
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<strong>Pleural effusion in chronic hereditary lymphedema (Nonne, Milroy, Meige's disease): report of two cases.</strong>
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Radiology 82: 246-248, 1964.
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[PubMed: 14115303]
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[Full Text: https://doi.org/10.1148/82.2.246]
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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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Kajii, T., Tsukahara, M.
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<strong>Congenital lymphedema in two siblings.</strong>
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Jpn. J. Hum. Genet. 30: 31-34, 1985.
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[PubMed: 4010046]
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[Full Text: https://doi.org/10.1007/BF01883671]
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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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Kajii, T., Tsukahara, M.
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<strong>Autosomal recessive lymphedema? (Letter)</strong>
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Jpn. J. Hum. Genet. 31: 57 only, 1986.
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[PubMed: 3735758]
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[Full Text: https://doi.org/10.1007/BF01876803]
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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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Karkkainen, M. J., Ferrell, R. E., Lawrence, E. C., Kimak, M. A., Levinson, K. L., McTigue, M. A., Alitalo, K., Finegold, D. N.
|
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<strong>Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.</strong>
|
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Nature Genet. 25: 153-159, 2000.
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[PubMed: 10835628]
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[Full Text: https://doi.org/10.1038/75997]
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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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Liu, N. F., Yan, Z. X., Wu, X. F.
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<strong>Classification of lymphatic-system malformations in primary lymphoedema based on MR lymphangiography.</strong>
|
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Europ. J. Vasc. Endovasc. Surg. 44: 345-349, 2012.
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[PubMed: 22831870]
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[Full Text: https://doi.org/10.1016/j.ejvs.2012.06.019]
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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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Meige, H.
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<strong>Dystrophie oedemateuse hereditaire.</strong>
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Presse Med. 6: 341-343, 1898.
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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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Milroy, W. F.
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<strong>An undescribed variety of hereditary oedema.</strong>
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N.Y. Med. J. 56: 505-508, 1892.
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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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Milroy, W. F.
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<strong>Chronic hereditary edema: Milroy's disease.</strong>
|
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JAMA 91: 1172-1175, 1928.
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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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Rosen, F. S., Smith, D. H., Earle, R., Jr., Janeway, C. A., Gitlin, D.
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<strong>The etiology of hypoproteinemia in a patient with congenital chylous ascites.</strong>
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Pediatrics 30: 696-706, 1962.
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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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Spiegel, R., Ghalamkarpour, A., Daniel-Spiegel, E., Vikkula, M., Shalev, S. A.
|
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<strong>Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3.</strong>
|
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J. Hum. Genet. 51: 846-850, 2006.
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[PubMed: 16924388]
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[Full Text: https://doi.org/10.1007/s10038-006-0031-3]
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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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Van der Putte, S. C. J.
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<strong>Congenital hereditary lymphedema in the pig.</strong>
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Lymphology 11: 1-9, 1978.
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[PubMed: 642582]
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Van der Putte, S. C. J.
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<strong>The pathogenesis of congenital hereditary lymphedema in the pig.</strong>
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Lymphology 11: 10-21, 1978.
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[PubMed: 642583]
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Marla J. F. O'Neill - updated : 06/04/2021<br>Cassandra L. Kniffin - updated : 02/10/2020<br>Marla J. F. O'Neill - updated : 12/19/2018<br>Cassandra L. Kniffin - updated : 6/10/2009<br>Cassandra L. Kniffin - updated : 2/25/2009<br>Marla J. F. O'Neill - updated : 12/29/2006<br>Cassandra L. Kniffin - updated : 11/1/2006<br>Marla J. F. O'Neill - updated : 3/2/2005<br>Cassandra L. Kniffin - reorganized : 11/19/2003<br>Sonja A. Rasmussen - updated : 3/12/2001<br>Victor A. McKusick - updated : 2/10/1999<br>Victor A. McKusick - updated : 1/6/1999
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Victor A. McKusick : 6/2/1986
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