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Entry
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- #608898 - HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 3; FHL3
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- OMIM
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<p>
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<span class="h4">#608898</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/608898"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS267700"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</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 class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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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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<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 class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL" 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=282&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/NBK1444/" 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/3308" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608898[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=540" 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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<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:0110923" 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/608898" 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:0110923" 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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<a id="title" class="mim-anchor"></a>
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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>ORPHA:</strong> 540<br />
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<strong>DO:</strong> 0110923<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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608898
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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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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 3; FHL3
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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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HPLH3<br />
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HLH3
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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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<a id="phenotypeMap" class="mim-anchor"></a>
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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 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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</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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<a href="/geneMap/17/954?start=-3&limit=10&highlight=954">
|
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17q25.1
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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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Hemophagocytic lymphohistiocytosis, familial, 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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<a href="/entry/608898"> 608898 </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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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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UNC13D
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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/608897"> 608897 </a>
|
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</span>
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</td>
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</tr>
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|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
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|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/608898" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS267700" 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>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<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/608898" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/608898" 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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|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
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|
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|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Liver </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hepatosplenomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36760000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36760000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019214&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019214</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001433" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001433</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001433" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001433</a>]</span><br /> -
|
|
Liver dysfunction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/75183008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">75183008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0086565&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0086565</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001410" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001410</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002910" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002910</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001410" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001410</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Spleen </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hepatosplenomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36760000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36760000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019214&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019214</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001433" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001433</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001433" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001433</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEMATOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Pancytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/127034005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">127034005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D61.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D61.81</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/284.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">284.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0030312&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030312</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001876" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001876</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001876" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001876</a>]</span><br /> -
|
|
Hemophagocytosis (in bone marrow or cerebrospinal fluid) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5232682&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5232682</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/61070002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">61070002</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012156" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012156</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> IMMUNOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Overwhelming activation of T lymphocytes and macrophages associated with fever <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5232679&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5232679</a>]</span><br /> -
|
|
Activated (HLA DR+) CD8+ T lymphocytes in peripheral blood <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5232680&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5232680</a>]</span><br /> -
|
|
Defective anti CD3-driven cytotoxic T-cell activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5232681&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5232681</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Low fibrinogen levels <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/131177005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">131177005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1295715&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1295715</a>]</span><br /> -
|
|
Hypertriglyceridemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302870006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302870006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/166848004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">166848004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020557&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020557</a>, <a href="https://bioportal.bioontology.org/search?q=C1522137&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1522137</a>, <a href="https://bioportal.bioontology.org/search?q=C0813230&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0813230</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002155" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002155</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002155" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002155</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Onset in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848924</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the unc-13 homolog D gene (UNC13D, <a href="/entry/608897#0001">608897.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Hemophagocytic lymphohistiocytosis, familial
|
|
- <a href="/phenotypicSeries/PS267700">PS267700</a>
|
|
- 5 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>
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<strong>Inheritance</strong>
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<strong>Phenotype<br />mapping key</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />MIM number</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus<br />MIM number</strong>
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<span class="mim-font">
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<a href="/geneMap/6/923?start=-3&limit=10&highlight=923"> 6q24.2 </a>
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<span class="mim-font">
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<a href="/entry/603552"> Hemophagocytic lymphohistiocytosis, familial, 4 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/603552"> 603552 </a>
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<span class="mim-font">
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<a href="/entry/605014"> STX11 </a>
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<span class="mim-font">
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<a href="/entry/605014"> 605014 </a>
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<span class="mim-font">
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<a href="/geneMap/9/262?start=-3&limit=10&highlight=262"> 9q21.3-q22 </a>
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<span class="mim-font">
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<a href="/entry/267700"> Hemophagocytic lymphohistiocytosis, familial, 1 </a>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
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<span class="mim-font">
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<a href="/entry/267700"> 267700 </a>
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<span class="mim-font">
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<a href="/entry/267700"> FHL1 </a>
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<span class="mim-font">
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<a href="/entry/267700"> 267700 </a>
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<span class="mim-font">
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<a href="/geneMap/10/274?start=-3&limit=10&highlight=274"> 10q22.1 </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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<a href="/entry/603553"> Hemophagocytic lymphohistiocytosis, familial, 2 </a>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/603553"> 603553 </a>
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<span class="mim-font">
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<a href="/entry/170280"> PRF1 </a>
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<span class="mim-font">
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<a href="/entry/170280"> 170280 </a>
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<span class="mim-font">
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<a href="/geneMap/17/954?start=-3&limit=10&highlight=954"> 17q25.1 </a>
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</span>
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</td>
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<span class="mim-font">
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<a href="/entry/608898"> Hemophagocytic lymphohistiocytosis, familial, 3 </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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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/608898"> 608898 </a>
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<span class="mim-font">
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<a href="/entry/608897"> UNC13D </a>
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<span class="mim-font">
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<a href="/entry/608897"> 608897 </a>
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<a href="/geneMap/19/211?start=-3&limit=10&highlight=211"> 19p13.2 </a>
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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/613101"> Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease </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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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/613101"> 613101 </a>
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<span class="mim-font">
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<a href="/entry/601717"> STXBP2 </a>
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<span class="mim-font">
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<a href="/entry/601717"> 601717 </a>
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because hemophagocytic lymphohistiocytosis-3 (FHL3) is caused by homozygous or compound heterozygous mutation in the UNC13D gene (<a href="/entry/608897">608897</a>) on chromosome 17q25.</p>
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<br />
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Secretion of the contents of cytolytic granules at the immunologic synapse is a highly regulated process essential for lymphocyte cytotoxicity. This process requires the rapid transfer of perforin (<a href="/entry/170280">170280</a>)-containing lytic granules to the target cell interface, followed by their docking and fusion with the plasma membrane. Familial hemophagocytic lymphohistiocytosis is a genetically heterogeneous condition characterized by defective cytotoxicity. For a more detailed description of FHL, see <a href="/entry/267700">267700</a>.</p>
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<br />
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Clinical Features</strong>
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<p><a href="#2" class="mim-tip-reference" title="Feldmann, J., Callebaut, I., Raposo, G., Certain, S., Bacq, D., Dumont, C., Lambert, N., Ouachee-Chardin, M., Chedeville, G., Tamary, H., Minard-Colin, V., Vilmer, E., Blanche, S., Le Deist, F., Fischer, A., de Saint Basile, G. <strong>Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3).</strong> Cell 115: 461-473, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14622600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14622600</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00855-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14622600">Feldmann et al. (2003)</a> identified a novel FHL subtype, FHL3, in 10 patients from 7 unrelated families. These patients presented with typical features of FHL, defined by early onset of overwhelming activation of T lymphocytes and macrophages and detection of activated CD8 (see <a href="/entry/186910">186910</a>)-positive T lymphocytes in peripheral blood, in association with fever, hepatosplenomegaly, pancytopenia, coagulation abnormality, liver dysfunction, and features of hemophagocytosis in the bone marrow or cerebrospinal fluid. All 10 patients had defective anti-CD3 (see <a href="/entry/186790">186790</a>)-driven cytotoxic T-cell activity, and intracellular perforin could be detected normally. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14622600" 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="Santoro, A., Cannella, S., Bossi, G., Gallo, F., Trizzino, A., Pende, D., Dieli, F., Bruno, G., Stinchcombe, J. C., Micalizzi, C., De Fusco, C., Danesino, C., Moretta, L., Notarangelo, L. D., Griffiths, G. M., Arico, M. <strong>Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. (Letter)</strong> J. Med. Genet. 43: 953-960, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825436</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825436[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2006.041863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16825436">Santoro et al. (2006)</a> reported 15 patients with FHL3 due to UNC13D mutation (see, e.g., <a href="/entry/608897#0001">608897.0001</a>, <a href="/entry/608897#0006">608897.0006</a>, and <a href="/entry/608897#0009">608897.0009</a>). Median age at diagnosis was 4 months, but 6 patients developed the disease after 5 years of age and 1 as a young adult of 18 years. Involvement of the central nervous system was present in 9 of 15 patients. Activity of natural killer cells was markedly reduced or absent in 13 patients who were tested. Chemoimmunotherapy was effective in all patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16825436" 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="#4" class="mim-tip-reference" title="Rudd, E., Bryceson, Y. T., Zheng, C., Edner, J., Wood, S. M., Ramme, K., Gavhed, S., Gurgey, A., Hellebostad, M., Bechensteen, A. G., Ljunggren, H.-G., Fadeel, B., Nordenskjold, M., Henter, J.-I. <strong>Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis.</strong> J. Med. Genet. 45: 134-141, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17993578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17993578</a>] [<a href="https://doi.org/10.1136/jmg.2007.054288" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17993578">Rudd et al. (2008)</a> reported 9 patients from 6 families with genetically confirmed FHL3. There was considerable variation in age at diagnosis, ranging from birth to 14 years, and 3 of the 9 mutation-positive patients developed central nervous system symptoms. Natural killer cell activity was impaired in all 4 patients studied. Defective cytotoxic lymphocyte degranulation was evident in the 2 patients investigated, and was more pronounced in the patient with onset during infancy than in the patient with adolescent onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17993578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Bogaert, D., De Bruyne, R., Vanlander, A. V., Garabedian, L., Louis, Y., Haerynck, F., Bordon, V., De Moerloose, B. <strong>Familial hemophagocytic lymphohistiocytosis type 3 presenting as neonatal cholestasis and splenomegaly. (Letter)</strong> Pediat. Allergy Immun. 33: e13774, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35470934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35470934</a>] [<a href="https://doi.org/10.1111/pai.13774" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35470934">Bogaert et al. (2022)</a> reported a girl with FHL3 who presented with cholestasis, splenomegaly, and marked thrombocytopenia 4 days after birth. Thrombocytopenia spontaneously normalized by day 15 of life, and cholestasis resolved by the end of the first month. At the age of 2 months, the patient had her first hemophagocytic lymphohistiocytosis (HLH) episode with high fever, marked hepatosplenomegaly, pancytopenia, hyperferritinemia, and hemophagocytosis in the bone marrow. The fever and neutropenia rapidly resolved without corticosteroid treatment. At age 4 months she had a second HLH episode with neutropenic fever and cardiorespiratory and neurologic symptoms. Despite treatment with dexamethasone, cyclosporine A, and antithymocyte globulin, she developed severe central nervous system findings, including refractory seizures and encephalopathy, and died at age 8 months. A molecular diagnosis of FHL3 was not made until she was 7 months of age. The authors emphasized that FHL3 can present with neonatal cholestasis and recommended that clinicians maintain a high index of suspicion of FHL3 when neonatal cholestasis is seen, especially when accompanied by persisting cytopenia and splenomegaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35470934" 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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<span class="mim-font">
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<strong>Inheritance</strong>
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</h4>
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<p>An equal sex ratio among patients and a high frequency of consanguinity in the families with FHL3 reported by <a href="#2" class="mim-tip-reference" title="Feldmann, J., Callebaut, I., Raposo, G., Certain, S., Bacq, D., Dumont, C., Lambert, N., Ouachee-Chardin, M., Chedeville, G., Tamary, H., Minard-Colin, V., Vilmer, E., Blanche, S., Le Deist, F., Fischer, A., de Saint Basile, G. <strong>Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3).</strong> Cell 115: 461-473, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14622600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14622600</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00855-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14622600">Feldmann et al. (2003)</a> suggested autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14622600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Locatelli, F., Jordan, M. B., Allen, C., Cesaro, S., Rizzari, C., Rao, A., Degar, B., Garrington, T. P., Sevilla, J., Putti, M. C., Fagioli, F., Ahlmann, M., Dapena Diaz, J.-L., Henry, M., De Benedetti, F., Grom, A., Lapeyre, G., Jacqmin, P., Ballabio, M., de Min, C. <strong>Emapalumab in children with primary hemophagocytic lymphohistiocytosis.</strong> New Eng. J. Med. 382: 1811-1822, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32374962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32374962</a>] [<a href="https://doi.org/10.1056/NEJMoa1911326" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32374962">Locatelli et al. (2020)</a> investigated the efficacy and safety of emapalumab, a human anti-interferon-gamma (<a href="/entry/147570">147570</a>) antibody, administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving previously treated and untreated patients with primary hemophagocytic lymphohistiocytosis 18 years of age or younger. A total of 34 patients, 27 previously treated and 7 previously untreated, received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40%. In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. The authors concluded that emapalumab is an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32374962" 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>By genetic mapping and linkage analysis, <a href="#2" class="mim-tip-reference" title="Feldmann, J., Callebaut, I., Raposo, G., Certain, S., Bacq, D., Dumont, C., Lambert, N., Ouachee-Chardin, M., Chedeville, G., Tamary, H., Minard-Colin, V., Vilmer, E., Blanche, S., Le Deist, F., Fischer, A., de Saint Basile, G. <strong>Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3).</strong> Cell 115: 461-473, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14622600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14622600</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00855-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14622600">Feldmann et al. (2003)</a> mapped the FHL3 locus to a 17-cM region on chromosome 17q25.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14622600" 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="#2" class="mim-tip-reference" title="Feldmann, J., Callebaut, I., Raposo, G., Certain, S., Bacq, D., Dumont, C., Lambert, N., Ouachee-Chardin, M., Chedeville, G., Tamary, H., Minard-Colin, V., Vilmer, E., Blanche, S., Le Deist, F., Fischer, A., de Saint Basile, G. <strong>Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3).</strong> Cell 115: 461-473, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14622600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14622600</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00855-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14622600">Feldmann et al. (2003)</a> identified 6 different mutations in the UNC13D gene in 10 patients from 7 unrelated families with FHL3 (see <a href="/entry/608897#0001">608897.0001</a>-<a href="/entry/608897#0006">608897.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14622600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Turkish patient from a consanguineous family with primary hemophagocytic lymphohistiocytosis, <a href="#6" class="mim-tip-reference" title="Zur Stadt, U., Beutel, K., Kolberg, S., Schneppenheim, R., Kabisch, H., Janka, G., Hennies, H. C. <strong>Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A.</strong> Hum. Mutat. 27: 62-68, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278825</a>] [<a href="https://doi.org/10.1002/humu.20274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16278825">Zur Stadt et al. (2006)</a> identified homozygosity for a missense mutation in the UNC13D gene (<a href="/entry/608897#0007">608897.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16278825" 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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Bogaert, D., De Bruyne, R., Vanlander, A. V., Garabedian, L., Louis, Y., Haerynck, F., Bordon, V., De Moerloose, B.
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<strong>Familial hemophagocytic lymphohistiocytosis type 3 presenting as neonatal cholestasis and splenomegaly. (Letter)</strong>
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Pediat. Allergy Immun. 33: e13774, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35470934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35470934</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35470934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/pai.13774" target="_blank">Full Text</a>]
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Feldmann, J., Callebaut, I., Raposo, G., Certain, S., Bacq, D., Dumont, C., Lambert, N., Ouachee-Chardin, M., Chedeville, G., Tamary, H., Minard-Colin, V., Vilmer, E., Blanche, S., Le Deist, F., Fischer, A., de Saint Basile, G.
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<strong>Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3).</strong>
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Cell 115: 461-473, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14622600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14622600</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14622600" 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/s0092-8674(03)00855-9" target="_blank">Full Text</a>]
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<a id="Locatelli2020" class="mim-anchor"></a>
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Locatelli, F., Jordan, M. B., Allen, C., Cesaro, S., Rizzari, C., Rao, A., Degar, B., Garrington, T. P., Sevilla, J., Putti, M. C., Fagioli, F., Ahlmann, M., Dapena Diaz, J.-L., Henry, M., De Benedetti, F., Grom, A., Lapeyre, G., Jacqmin, P., Ballabio, M., de Min, C.
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<strong>Emapalumab in children with primary hemophagocytic lymphohistiocytosis.</strong>
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New Eng. J. Med. 382: 1811-1822, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32374962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32374962</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32374962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1911326" target="_blank">Full Text</a>]
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Rudd, E., Bryceson, Y. T., Zheng, C., Edner, J., Wood, S. M., Ramme, K., Gavhed, S., Gurgey, A., Hellebostad, M., Bechensteen, A. G., Ljunggren, H.-G., Fadeel, B., Nordenskjold, M., Henter, J.-I.
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<strong>Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis.</strong>
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J. Med. Genet. 45: 134-141, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17993578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17993578</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17993578" 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.2007.054288" target="_blank">Full Text</a>]
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Santoro, A., Cannella, S., Bossi, G., Gallo, F., Trizzino, A., Pende, D., Dieli, F., Bruno, G., Stinchcombe, J. C., Micalizzi, C., De Fusco, C., Danesino, C., Moretta, L., Notarangelo, L. D., Griffiths, G. M., Arico, M.
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<strong>Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. (Letter)</strong>
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J. Med. Genet. 43: 953-960, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825436</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825436[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16825436" 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.2006.041863" target="_blank">Full Text</a>]
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Zur Stadt, U., Beutel, K., Kolberg, S., Schneppenheim, R., Kabisch, H., Janka, G., Hennies, H. C.
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<strong>Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A.</strong>
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Hum. Mutat. 27: 62-68, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16278825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16278825</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16278825" 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/humu.20274" target="_blank">Full Text</a>]
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Sonja A. Rasmussen - updated : 07/19/2022
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Ada Hamosh - updated : 12/01/2020<br>Marla J. F. O'Neill - updated : 11/12/2008<br>Victor A. McKusick - updated : 5/31/2007
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Stylianos E. Antonarakis : 9/3/2004
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carol : 06/05/2024
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carol : 06/04/2024<br>carol : 07/20/2022<br>carol : 07/19/2022<br>alopez : 12/01/2020<br>carol : 05/23/2017<br>wwang : 11/13/2008<br>terry : 11/12/2008<br>terry : 11/12/2008<br>alopez : 6/5/2007<br>terry : 5/31/2007<br>alopez : 3/13/2006<br>tkritzer : 9/24/2004<br>mgross : 9/3/2004
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<strong>#</strong> 608898
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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 3; FHL3
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<em>Alternative titles; symbols</em>
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HPLH3<br />
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HLH3
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<strong>ORPHA:</strong> 540;
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<strong>DO:</strong> 0110923;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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17q25.1
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Hemophagocytic lymphohistiocytosis, familial, 3
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608898
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Autosomal recessive
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<span class="mim-font">
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3
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UNC13D
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608897
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<p>A number sign (#) is used with this entry because hemophagocytic lymphohistiocytosis-3 (FHL3) is caused by homozygous or compound heterozygous mutation in the UNC13D gene (608897) on chromosome 17q25.</p>
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<strong>Description</strong>
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<p>Secretion of the contents of cytolytic granules at the immunologic synapse is a highly regulated process essential for lymphocyte cytotoxicity. This process requires the rapid transfer of perforin (170280)-containing lytic granules to the target cell interface, followed by their docking and fusion with the plasma membrane. Familial hemophagocytic lymphohistiocytosis is a genetically heterogeneous condition characterized by defective cytotoxicity. For a more detailed description of FHL, see 267700.</p>
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<strong>Clinical Features</strong>
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<p>Feldmann et al. (2003) identified a novel FHL subtype, FHL3, in 10 patients from 7 unrelated families. These patients presented with typical features of FHL, defined by early onset of overwhelming activation of T lymphocytes and macrophages and detection of activated CD8 (see 186910)-positive T lymphocytes in peripheral blood, in association with fever, hepatosplenomegaly, pancytopenia, coagulation abnormality, liver dysfunction, and features of hemophagocytosis in the bone marrow or cerebrospinal fluid. All 10 patients had defective anti-CD3 (see 186790)-driven cytotoxic T-cell activity, and intracellular perforin could be detected normally. </p><p>Santoro et al. (2006) reported 15 patients with FHL3 due to UNC13D mutation (see, e.g., 608897.0001, 608897.0006, and 608897.0009). Median age at diagnosis was 4 months, but 6 patients developed the disease after 5 years of age and 1 as a young adult of 18 years. Involvement of the central nervous system was present in 9 of 15 patients. Activity of natural killer cells was markedly reduced or absent in 13 patients who were tested. Chemoimmunotherapy was effective in all patients. </p><p>Rudd et al. (2008) reported 9 patients from 6 families with genetically confirmed FHL3. There was considerable variation in age at diagnosis, ranging from birth to 14 years, and 3 of the 9 mutation-positive patients developed central nervous system symptoms. Natural killer cell activity was impaired in all 4 patients studied. Defective cytotoxic lymphocyte degranulation was evident in the 2 patients investigated, and was more pronounced in the patient with onset during infancy than in the patient with adolescent onset. </p><p>Bogaert et al. (2022) reported a girl with FHL3 who presented with cholestasis, splenomegaly, and marked thrombocytopenia 4 days after birth. Thrombocytopenia spontaneously normalized by day 15 of life, and cholestasis resolved by the end of the first month. At the age of 2 months, the patient had her first hemophagocytic lymphohistiocytosis (HLH) episode with high fever, marked hepatosplenomegaly, pancytopenia, hyperferritinemia, and hemophagocytosis in the bone marrow. The fever and neutropenia rapidly resolved without corticosteroid treatment. At age 4 months she had a second HLH episode with neutropenic fever and cardiorespiratory and neurologic symptoms. Despite treatment with dexamethasone, cyclosporine A, and antithymocyte globulin, she developed severe central nervous system findings, including refractory seizures and encephalopathy, and died at age 8 months. A molecular diagnosis of FHL3 was not made until she was 7 months of age. The authors emphasized that FHL3 can present with neonatal cholestasis and recommended that clinicians maintain a high index of suspicion of FHL3 when neonatal cholestasis is seen, especially when accompanied by persisting cytopenia and splenomegaly. </p>
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<strong>Inheritance</strong>
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<p>An equal sex ratio among patients and a high frequency of consanguinity in the families with FHL3 reported by Feldmann et al. (2003) suggested autosomal recessive inheritance. </p>
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<strong>Clinical Management</strong>
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<p>Locatelli et al. (2020) investigated the efficacy and safety of emapalumab, a human anti-interferon-gamma (147570) antibody, administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving previously treated and untreated patients with primary hemophagocytic lymphohistiocytosis 18 years of age or younger. A total of 34 patients, 27 previously treated and 7 previously untreated, received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40%. In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. The authors concluded that emapalumab is an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. </p>
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<strong>Mapping</strong>
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<p>By genetic mapping and linkage analysis, Feldmann et al. (2003) mapped the FHL3 locus to a 17-cM region on chromosome 17q25.1. </p>
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<strong>Molecular Genetics</strong>
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<p>Feldmann et al. (2003) identified 6 different mutations in the UNC13D gene in 10 patients from 7 unrelated families with FHL3 (see 608897.0001-608897.0006). </p><p>In a Turkish patient from a consanguineous family with primary hemophagocytic lymphohistiocytosis, Zur Stadt et al. (2006) identified homozygosity for a missense mutation in the UNC13D gene (608897.0007). </p>
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<strong>REFERENCES</strong>
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Bogaert, D., De Bruyne, R., Vanlander, A. V., Garabedian, L., Louis, Y., Haerynck, F., Bordon, V., De Moerloose, B.
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<strong>Familial hemophagocytic lymphohistiocytosis type 3 presenting as neonatal cholestasis and splenomegaly. (Letter)</strong>
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Pediat. Allergy Immun. 33: e13774, 2022.
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[PubMed: 35470934]
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[Full Text: https://doi.org/10.1111/pai.13774]
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Feldmann, J., Callebaut, I., Raposo, G., Certain, S., Bacq, D., Dumont, C., Lambert, N., Ouachee-Chardin, M., Chedeville, G., Tamary, H., Minard-Colin, V., Vilmer, E., Blanche, S., Le Deist, F., Fischer, A., de Saint Basile, G.
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<strong>Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3).</strong>
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Cell 115: 461-473, 2003.
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[PubMed: 14622600]
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[Full Text: https://doi.org/10.1016/s0092-8674(03)00855-9]
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Locatelli, F., Jordan, M. B., Allen, C., Cesaro, S., Rizzari, C., Rao, A., Degar, B., Garrington, T. P., Sevilla, J., Putti, M. C., Fagioli, F., Ahlmann, M., Dapena Diaz, J.-L., Henry, M., De Benedetti, F., Grom, A., Lapeyre, G., Jacqmin, P., Ballabio, M., de Min, C.
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<strong>Emapalumab in children with primary hemophagocytic lymphohistiocytosis.</strong>
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New Eng. J. Med. 382: 1811-1822, 2020.
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[PubMed: 32374962]
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[Full Text: https://doi.org/10.1056/NEJMoa1911326]
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Rudd, E., Bryceson, Y. T., Zheng, C., Edner, J., Wood, S. M., Ramme, K., Gavhed, S., Gurgey, A., Hellebostad, M., Bechensteen, A. G., Ljunggren, H.-G., Fadeel, B., Nordenskjold, M., Henter, J.-I.
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<strong>Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis.</strong>
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J. Med. Genet. 45: 134-141, 2008.
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[PubMed: 17993578]
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[Full Text: https://doi.org/10.1136/jmg.2007.054288]
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Santoro, A., Cannella, S., Bossi, G., Gallo, F., Trizzino, A., Pende, D., Dieli, F., Bruno, G., Stinchcombe, J. C., Micalizzi, C., De Fusco, C., Danesino, C., Moretta, L., Notarangelo, L. D., Griffiths, G. M., Arico, M.
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<strong>Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. (Letter)</strong>
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J. Med. Genet. 43: 953-960, 2006.
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[PubMed: 16825436]
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[Full Text: https://doi.org/10.1136/jmg.2006.041863]
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Zur Stadt, U., Beutel, K., Kolberg, S., Schneppenheim, R., Kabisch, H., Janka, G., Hennies, H. C.
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<strong>Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A.</strong>
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Hum. Mutat. 27: 62-68, 2006.
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[PubMed: 16278825]
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[Full Text: https://doi.org/10.1002/humu.20274]
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Contributors:
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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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Sonja A. Rasmussen - updated : 07/19/2022<br>Ada Hamosh - updated : 12/01/2020<br>Marla J. F. O'Neill - updated : 11/12/2008<br>Victor A. McKusick - updated : 5/31/2007
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Creation Date:
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Stylianos E. Antonarakis : 9/3/2004
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Edit History:
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carol : 06/05/2024<br>carol : 06/04/2024<br>carol : 07/20/2022<br>carol : 07/19/2022<br>alopez : 12/01/2020<br>carol : 05/23/2017<br>wwang : 11/13/2008<br>terry : 11/12/2008<br>terry : 11/12/2008<br>alopez : 6/5/2007<br>terry : 5/31/2007<br>alopez : 3/13/2006<br>tkritzer : 9/24/2004<br>mgross : 9/3/2004
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