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<title>
Entry
- #613101 - HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5, WITH OR WITHOUT MICROVILLUS INCLUSION DISEASE; FHL5
- OMIM
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<span class="h4">#613101</span>
<br />
<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/613101"><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="#mapping">Mapping</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#references"><strong>References</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5, WITH OR WITHOUT MICROVILLUS INCLUSION DISEASE" 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 id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0110925" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/613101" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0110925" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>ORPHA:</strong> 540<br />
<strong>DO:</strong> 0110925<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
613101
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5, WITH OR WITHOUT MICROVILLUS INCLUSION DISEASE; FHL5
</span>
</h3>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/211?start=-3&limit=10&highlight=211">
19p13.2
</a>
</span>
</td>
<td>
<span class="mim-font">
Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613101"> 613101 </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">
STXBP2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601717"> 601717 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/613101" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/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>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/613101" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/613101" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Sensorineural hearing loss (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/60700002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">60700002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H90.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H90.5</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018784&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018784</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000407" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000407</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000407" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000407</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Nystagmus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/563001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">563001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H55.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H55.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/379.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">379.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0028738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0028738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000639</a>]</span><br /> -
Strabismus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22066006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22066006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H50.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H50.40</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038379&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038379</a>, <a href="https://bioportal.bioontology.org/search?q=C2020541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2020541</a>, <a href="https://bioportal.bioontology.org/search?q=C1423541&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1423541</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000486" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000486</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000486" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000486</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Liver </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hepatomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80515008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80515008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019209&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019209</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</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 /> -
Liver failure (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/59927004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">59927004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K72.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K72.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085605</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001399" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001399</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001399" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001399</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">
- Splenomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16294009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16294009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038002&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038002</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Chronic watery diarrhea (in patients with early-onset severe disease) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3808302&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3808302</a>]</span><br /> -
Tube feeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/61420007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">61420007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0041281&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0041281</a>, <a href="https://bioportal.bioontology.org/search?q=C0014327&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014327</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033454" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033454</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0040288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0040288</a>]</span><br /> -
Parenteral nutrition <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25156005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25156005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0030547&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030547</a>]</span><br /> -
Villous atrophy of the intestine seen on biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5775333&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5775333</a>]</span><br /> -
Decreased crypt depth <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5775334&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5775334</a>]</span><br /> -
Cytoplasmic vacuoles filled with amorphous material in surface enterocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5775335&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5775335</a>]</span><br /> -
Accumulation of PAS-positive material at the apical brush border membrane <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5775336&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5775336</a>]</span><br /> -
Colitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64226004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64226004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K52.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K52.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009319&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009319</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002583" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002583</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002583" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002583</a>]</span><br /> -
Abdominal pain <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/21522001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">21522001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R10.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R10.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/789.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0000737&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0000737</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002027</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002027</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> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Renal tubule dysfunction (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5775331&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5775331</a>]</span><br /> -
Cytoplasmic inclusions and PAS-positive material at the basal lamina and apical brush border in kidney epithelial cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5775332&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5775332</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">
- Petechiae <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271813007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271813007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/50091001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">50091001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/423716004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">423716004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R23.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R23.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241144&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241144</a>, <a href="https://bioportal.bioontology.org/search?q=C0031256&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0031256</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000967" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000967</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000967" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000967</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Neurologic involvement (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275580&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275580</a>]</span><br /> -
Irritability <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55929007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55929007</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.22</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0022107&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022107</a>, <a href="https://bioportal.bioontology.org/search?q=C2700617&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2700617</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000737" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000737</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000737" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000737</a>]</span><br /> -
Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br /> -
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Ataxia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20262006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20262006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39384006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39384006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85102008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85102008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R27.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R27.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.84</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004134</a>, <a href="https://bioportal.bioontology.org/search?q=C1135207&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1135207</a>, <a href="https://bioportal.bioontology.org/search?q=C0007758&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007758</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0010867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010867</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001251</a>]</span><br /> -
White matter abnormalities on brain imaging <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393814&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393814</a>]</span><br /> -
Myelination defects <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014372&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014372</a>]</span><br /> -
Increased cells in the CSF <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5775330&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5775330</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> METABOLIC FEATURES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Fever <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386661006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386661006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/50177009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">50177009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R50.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.60</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015967&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015967</a>, <a href="https://bioportal.bioontology.org/search?q=C0424755&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424755</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001945" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001945</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001945" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001945</a>]</span><br /> -
Metabolic acidosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/59455009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">59455009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0220981&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220981</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001942" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001942</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001942" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001942</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- 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 /> -
Thrombocytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/415116008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">415116008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302215000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302215000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D69.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D69.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/287.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">287.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0392386&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0392386</a>, <a href="https://bioportal.bioontology.org/search?q=C0040034&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040034</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001873" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001873</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001873" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001873</a>]</span><br /> -
Coagulation defects <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64779008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64779008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/362970003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">362970003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D68.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D68.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">286</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0005779&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005779</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003256</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001928" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001928</a>]</span><br /> -
Bleeding tendency <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64779008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64779008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/362970003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">362970003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248250000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248250000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D68.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D68.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">286</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0005779&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005779</a>, <a href="https://bioportal.bioontology.org/search?q=C1458140&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1458140</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001892" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001892</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0003256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003256</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001928" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001928</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001892" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001892</a>]</span><br /> -
Anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271737000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271737000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D64.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D64.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/285.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">285.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002871&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002871</a>, <a href="https://bioportal.bioontology.org/search?q=C1000483&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1000483</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001903" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001903</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001903" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001903</a>]</span><br /> -
Neutropenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/303011007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">303011007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165517008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165517008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/84828003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">84828003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D70" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D70</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.819" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.819</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D70.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D70.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/288.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.50</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/288.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0853697&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0853697</a>, <a href="https://bioportal.bioontology.org/search?q=C0027947&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027947</a>, <a href="https://bioportal.bioontology.org/search?q=C0023530&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023530</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001875" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001875</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001882" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001882</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001875" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001875</a>]</span><br /> -
Thrombocytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/415116008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">415116008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302215000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302215000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D69.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D69.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/287.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">287.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0392386&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0392386</a>, <a href="https://bioportal.bioontology.org/search?q=C0040034&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040034</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001873" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001873</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001873" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001873</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">
- Hyperinflammatory disorder <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807248&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807248</a>]</span><br /> -
Lymphadenopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30746006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30746006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R59.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R59.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R59" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R59</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R59.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R59.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/785.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">785.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4282165&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4282165</a>, <a href="https://bioportal.bioontology.org/search?q=C0497156&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0497156</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002716</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002716</a>]</span><br /> -
Hemophagocytosis in bone marrow and lymph nodes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807249&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807249</a>]</span><br /> -
Defective NK cell activity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807251&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807251</a>]</span><br /> -
Defective NK cell degranulation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807252&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807252</a>]</span><br /> -
Defective cytotoxic T cell degranulation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5775337&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5775337</a>]</span><br /> -
Hypogammaglobulinemia (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/119250001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">119250001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D80.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D80.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/279.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">279.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0086438&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0086438</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004313" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004313</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004313" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004313</a>]</span><br />
</span>
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<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Increased triglycerides <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=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 /> -
Increased ferritin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0743912&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0743912</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003281" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003281</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003281" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003281</a>]</span><br /> -
Decreased fibrinogen <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 /> -
Increased soluble IL2 receptor <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3807250&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3807250</a>]</span><br /> -
Elevated liver enzymes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235996&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235996</a> HPO: <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:0002910" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002910</a>]</span><br />
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<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset in infancy (severe form) <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 /> -
Onset in first decade (milder form)<br /> -
Patients with earlier onset have a more severe and rapid disease course<br /> -
Patients with early-onset have diarrhea that may precede HLH features<br /> -
Patients with exon 15 splice site mutations do not have MVID<br /> -
Hematopoietic stem cell transplant can cure the HLH but not the MVID<br /> -
Early death may occur<br />
</span>
</div>
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<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the syntaxin-binding protein 2 gene (STXBP2, <a href="/entry/601717#0001">601717.0001</a>)<br />
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<h5>
Hemophagocytic lymphohistiocytosis, familial
- <a href="/phenotypicSeries/PS267700">PS267700</a>
- 5 Entries
</h5>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<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>
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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">
<strong>Gene/Locus</strong>
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<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/6/923?start=-3&limit=10&highlight=923"> 6q24.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603552"> Hemophagocytic lymphohistiocytosis, familial, 4 </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/603552"> 603552 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605014"> STX11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605014"> 605014 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/262?start=-3&limit=10&highlight=262"> 9q21.3-q22 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/267700"> Hemophagocytic lymphohistiocytosis, familial, 1 </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="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/267700"> 267700 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/267700"> FHL1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/267700"> 267700 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/274?start=-3&limit=10&highlight=274"> 10q22.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603553"> Hemophagocytic lymphohistiocytosis, familial, 2 </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/603553"> 603553 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/170280"> PRF1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/170280"> 170280 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/954?start=-3&limit=10&highlight=954"> 17q25.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608898"> Hemophagocytic lymphohistiocytosis, familial, 3 </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/608898"> 608898 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608897"> UNC13D </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608897"> 608897 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/211?start=-3&limit=10&highlight=211"> 19p13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613101"> Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease </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/613101"> 613101 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601717"> STXBP2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601717"> 601717 </a>
</span>
</td>
</tr>
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<p>A number sign (#) is used with this entry because familial hemophagocytic lymphohistiocytosis-5 with or without microvillus inclusion disease (FHL5) is caused by homozygous or compound heterozygous mutation in the syntaxin-binding protein-2 gene (STXBP2; <a href="/entry/601717">601717</a>) on chromosome 19p13.</p>
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<strong>Description</strong>
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<p>Familial hemophagocytic lymphohistiocytosis-5 with or without microvillus inclusion disease (FHL5) is an autosomal recessive hyperinflammatory disorder characterized clinically by fever, hepatosplenomegaly, pancytopenia, coagulation abnormalities, and other laboratory findings. Some patients have neurologic symptoms due to inflammatory CNS disease. There is uncontrolled and ineffective proliferation and activation of T lymphocytes, NK cells, and macrophages that infiltrate multiple organs, including liver, spleen, lymph nodes, and the CNS. The phenotype is variable: some patients may present in early infancy with severe diarrhea, prior to the onset of typical FHL features, whereas others present later in childhood and have a more protracted course without diarrhea. The early-onset diarrhea is due to enteropathy reminiscent of microvillus inclusion disease (see MVID, <a href="/entry/251850">251850</a>). The enteropathy, which often necessitates parenteral feeding, may be the most life-threatening issue even after hematopoietic stem cell transplantation (HSCT). More variable features include sensorineural hearing loss and hypogammaglobulinemia. Treatment with immunosuppressive drugs and chemotherapy can ameliorate signs and symptoms of FHL in some patients, but the only curative therapy for FHL is HSCT. HSCT is not curative for enteropathy associated with the disorder, despite hematologic and immunologic reconstitution (summary by <a href="#7" class="mim-tip-reference" title="Meeths, M., Entesarian, M., Al-Herz, W., Chiang, S. C. C., Wood, S. M., Al-Ateeqi, W., Almazan, F., Boelens, J. J., Hasle, H., Ifversen, M., Lund, B., van den Bert, J. M., Gustafsson, B., Hjelmqvist, H., Nordenskojold, M., Bryceson, Y. T., Henter, J.-I. &lt;strong&gt;Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.&lt;/strong&gt; Blood 116: 2635-2643, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20558610/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20558610&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-05-282541&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20558610">Meeths et al., 2010</a>; <a href="#8" class="mim-tip-reference" title="Pagel, J., Beutel, K., Lehmberg, K., Koch, F., Maul-Pavicic, A., Rohlfs, A.-K., Al-Jefri, A., Beier, R., Ousager, L. B., Ehlert, K., Gross-Wieltsch, U., Jorch, N., Kremens, B., Pekrun, A., Sparber-Sauer, M., Mejstrikova, E., Wawer, A., Ehl, S., zur Stadt, U., Janka, G. &lt;strong&gt;Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5).&lt;/strong&gt; Blood 119: 6016-6024, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22451424/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22451424&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2011-12-398958&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22451424">Pagel et al., 2012</a>; <a href="#10" class="mim-tip-reference" title="Stepensky, P., Bartram, J., Barth, T. F., Lehmberg, K., Walther, P., Amann, K., Philips, A. D., Beringer, O., Zur Stadt, U., Schulz, A., Amrolia, P., Weintraub, M., Debatin, K.-M., Hoenig, M., Posovszky, C. &lt;strong&gt;Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18-2 mutations.&lt;/strong&gt; Pediat. Blood Cancer 60: 1215-1222, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23382066/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23382066&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/pbc.24475&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23382066">Stepensky et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20558610+22451424+23382066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a phenotypic description and a discussion of genetic heterogeneity of familial hemophagocytic lymphohistiocytosis (FHL, HLH), see <a href="/entry/267700">267700</a>.</p>
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<p><a href="#7" class="mim-tip-reference" title="Meeths, M., Entesarian, M., Al-Herz, W., Chiang, S. C. C., Wood, S. M., Al-Ateeqi, W., Almazan, F., Boelens, J. J., Hasle, H., Ifversen, M., Lund, B., van den Bert, J. M., Gustafsson, B., Hjelmqvist, H., Nordenskojold, M., Bryceson, Y. T., Henter, J.-I. &lt;strong&gt;Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.&lt;/strong&gt; Blood 116: 2635-2643, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20558610/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20558610&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-05-282541&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20558610">Meeths et al. (2010)</a> reported 11 patients from 8 unrelated families with FHL5. The median age at symptom onset was 15 months (range 2 months to 17 years). Three patients died, including 2 who did not have HSCT. Classic features of HLH found in these patients included fever, hepatosplenomegaly, increased ferritin and triglycerides, decreased fibrinogen, and elevated liver enzymes. Many patients also had EBV infection. Bone marrow showed hemophagocytosis in some patients. Patient NK cells showed impaired NK cell degranulation and defective cytotoxicity that could be rescued in vitro by interleukin-2 (IL2; <a href="/entry/147680">147680</a>) stimulation. About half of patients developed nonspecific neurologic symptoms, including seizures, hypotonia, facial palsy, nystagmus, strabismus, ataxia, and irritability. Some of these patients showed demyelination or abnormal signals on brain imaging, and some had elevated CSF cell counts. Other features observed in some patients included gastrointestinal involvement manifest as colitis or diarrhea, bleeding disorders, including thrombocytopenia and coagulation abnormalities, and hypogammaglobulinemia. The clinical features of patient A were described in detail. She was a 17-year-old girl of Russian descent who presented with fever, abdominal pain, and sore throat. Liver enzymes were increased and EBV was detected. After undergoing tonsillectomy, she had severe bleeding associated with low platelet count and developed renal failure. Laboratory studies were consistent with HLH and she was successfully treated, although she did not have a HSCT. History revealed that she may have had a prior HLH episode at age 6 years. In addition to the relatively late onset of HLH in this patient, the authors emphasized the unusual features of colitis, bleeding, and hypogammaglobulinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20558610" 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="#8" class="mim-tip-reference" title="Pagel, J., Beutel, K., Lehmberg, K., Koch, F., Maul-Pavicic, A., Rohlfs, A.-K., Al-Jefri, A., Beier, R., Ousager, L. B., Ehlert, K., Gross-Wieltsch, U., Jorch, N., Kremens, B., Pekrun, A., Sparber-Sauer, M., Mejstrikova, E., Wawer, A., Ehl, S., zur Stadt, U., Janka, G. &lt;strong&gt;Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5).&lt;/strong&gt; Blood 119: 6016-6024, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22451424/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22451424&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2011-12-398958&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22451424">Pagel et al. (2012)</a> reported 37 patients from 28 families of various ethnic origins with FHL5 confirmed by genetic analysis. Some of the patients had previously been reported (see, e.g., <a href="#6" class="mim-tip-reference" title="Matthes-Martin, S., Peters, C., Konigsrainer, A., Fritsch, G., Lion, T., Heitger, A., Kapelari, K., Kronberger, M., Offner, F., Wrba, F., Margreiter, R., Gadner, H. &lt;strong&gt;Successful stem cell transplantation following orthotopic liver transplantation from the same haploidentical family donor in a girl with hemophagocytic lymphohistiocytosis.&lt;/strong&gt; Blood 96: 3997-3999, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11090093/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11090093&lt;/a&gt;]" pmid="11090093">Matthes-Martin et al., 2000</a>; <a href="#12" class="mim-tip-reference" title="zur Stadt, U., Rohr, J., Seifert, W., Koch, F., Grieve, S., Pagel, J., Strauss, J., Kasper, B., Nurnberg, G., Becker, C., Maul-Pavicic, A., Beutel, K., Janka, G., Griffiths, G., Ehl, S., Hennies, H. C. &lt;strong&gt;Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.&lt;/strong&gt; Am. J. Hum. Genet. 85: 482-492, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19804848/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19804848&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19804848[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2009.09.005&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19804848">Zur Stadt et al., 2009</a>). There was considerable clinical variability: most patients had an early onset in infancy with severe and rapid disease progression, whereas a few had later onset in the first 2 decades and a chronic recurrent course with long episodes of well-being. Patients with early-onset disease had severe chronic diarrhea with failure to thrive, often necessitating a feeding tube or parenteral nutrition. Bowel histology showed nonspecific inflammatory changes and slight loss of villi or crypts. Six patients had sensorineural hearing loss apparent in the first decades of life. Several patients had abnormal bleeding, including platelet defects. Ten of 17 patients had hypogammaglobulinemia; this tended to be present in those with later onset and a more protracted disease course. One patient (<a href="#6" class="mim-tip-reference" title="Matthes-Martin, S., Peters, C., Konigsrainer, A., Fritsch, G., Lion, T., Heitger, A., Kapelari, K., Kronberger, M., Offner, F., Wrba, F., Margreiter, R., Gadner, H. &lt;strong&gt;Successful stem cell transplantation following orthotopic liver transplantation from the same haploidentical family donor in a girl with hemophagocytic lymphohistiocytosis.&lt;/strong&gt; Blood 96: 3997-3999, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11090093/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11090093&lt;/a&gt;]" pmid="11090093">Matthes-Martin et al., 2000</a>) presented in infancy with acute liver failure requiring liver transplant; she was found to have typical features of FHL and later underwent HSCT. Laboratory studies in the patients, when performed, showed abnormal or reduced NK and CD8+ T cell cytotoxicity and degranulation. Hematopoietic stem cell transplantation was performed in 26 patients with variable results. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19804848+22451424+11090093" 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="#10" class="mim-tip-reference" title="Stepensky, P., Bartram, J., Barth, T. F., Lehmberg, K., Walther, P., Amann, K., Philips, A. D., Beringer, O., Zur Stadt, U., Schulz, A., Amrolia, P., Weintraub, M., Debatin, K.-M., Hoenig, M., Posovszky, C. &lt;strong&gt;Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18-2 mutations.&lt;/strong&gt; Pediat. Blood Cancer 60: 1215-1222, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23382066/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23382066&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/pbc.24475&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23382066">Stepensky et al. (2013)</a> reported 6 children from 4 unrelated families who presented in the first weeks or months of life with intractable osmotic diarrhea and failure to thrive due to severe enteropathy, as well as classic hematologic and immunologic features of HLH. Three patients died in infancy or early childhood; the others were alive between ages 4 and 12 years of age. The diarrhea often caused metabolic acidosis and most patients required tube or total parenteral feeding. Histologic studies of the intestine showed villous atrophy, decreased crypt depth, and fine cytoplasmic vacuoles filled with an amorphous material in surface enterocytes. CD10 (<a href="/entry/120520">120520</a>) staining at the apical brush border membrane was abnormal and there was some accumulation of PAS-positive material. These findings were consistent with MVID. One patient had renal tubular dysfunction associated with cytoplasmic inclusions and PAS-positive material at the basal lamina and apical brush border in kidney epithelial cells, although apical membrane morphology was normal. Features of HLH included fever, hepatosplenomegaly, cytopenias, and increased fibrinogen, ferritin, and triglycerides. More variable features included abnormal liver function, coagulopathy, and sensorineural hearing loss. Most, but not all, patients had evidence of HLH on bone marrow studies. Serum CD25 (<a href="/entry/147730">147730</a>) was increased in the 2 patients studied. Despite HSCT in 4 probands, all continued to have enteropathy; renal disease also persisted. The authors emphasized that patients may have significant gastrointestinal problems even after HSCT, suggesting that cells other than hematologic or immunologic are involved in this disorder. The abnormalities may be related to defective cellular membrane trafficking in the gut and kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23382066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Vogel, G. F., van Rijn, J. M., Krainer, I. M., Janecke, A. R., Posovszky, C., Cohen, M., Searle, C., Jantchou, P., Escher, J. C., Patey, N., Cutz, E., Muller, T., Middendorp, S., Hess, M. W., Huber, L. A. &lt;strong&gt;Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations.&lt;/strong&gt; JCI Insight 2: e94564, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28724787/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28724787&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28724787[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/jci.insight.94564&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28724787">Vogel et al. (2017)</a> reported 5 unrelated children with FHL5, including 1 patient previously reported by <a href="#10" class="mim-tip-reference" title="Stepensky, P., Bartram, J., Barth, T. F., Lehmberg, K., Walther, P., Amann, K., Philips, A. D., Beringer, O., Zur Stadt, U., Schulz, A., Amrolia, P., Weintraub, M., Debatin, K.-M., Hoenig, M., Posovszky, C. &lt;strong&gt;Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18-2 mutations.&lt;/strong&gt; Pediat. Blood Cancer 60: 1215-1222, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23382066/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23382066&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/pbc.24475&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23382066">Stepensky et al. (2013)</a>. All patients presented with congenital intractable diarrhea due to an enteropathy in the first days or weeks of life resulting in failure to thrive. Histologic studies of intestinal biopsies showed features reminiscent of MVID, including aberrant intracellular PAS staining, shortening or complete loss of apical microvilli, and microvillus inclusions. The patients also had classic, if variable, features of HLH, such as pancytopenia, fever, coagulation abnormalities, hepatosplenomegaly, increased liver enzymes, and hemophagocytosis on bone marrow examination. All patients underwent HSCT in the first year of life due to HLH, but the enteropathy continued after transplant, a unique feature of FHL5. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23382066+28724787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#12" class="mim-tip-reference" title="zur Stadt, U., Rohr, J., Seifert, W., Koch, F., Grieve, S., Pagel, J., Strauss, J., Kasper, B., Nurnberg, G., Becker, C., Maul-Pavicic, A., Beutel, K., Janka, G., Griffiths, G., Ehl, S., Hennies, H. C. &lt;strong&gt;Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.&lt;/strong&gt; Am. J. Hum. Genet. 85: 482-492, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19804848/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19804848&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19804848[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2009.09.005&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19804848">Zur Stadt et al. (2009)</a> performed genomewide linkage analysis and homozygosity mapping in 1 Saudi Arabian and 14 unrelated Turkish probands, all from consanguineous backgrounds, who had familial hemophagocytic lymphohistiocytosis but did not have mutations in the 3 known FHL genes. A maximum heterogeneity lod (hlod) score of 5.9 was obtained on chromosome 19p; fine mapping yielded a hlod of 8.3 at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs634968;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs634968</a>, and detailed genotype analysis revealed an overlapping region of homozygosity in 7 of the 15 cases, a 1,040-kb interval containing 36 genes. Whole-genome analysis of another consanguineous FHL family from Saudi Arabia with 2 affected and 3 unaffected sibs revealed 3 homozygous regions with lod scores greater than 2.0, 1 of which overlapped with the previously identified interval on chromosome 19p. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19804848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 8 patients from 6 consanguineous families with FHL in which known causes had been excluded by genetic analysis, <a href="#3" class="mim-tip-reference" title="Cote, M., Menager, M. M., Burgess, A., Mahlaoui, N., Picard, C., Schaffner, C., Al-Manjomi, F., Al-Harbi, M., Alangari, A., Le Deist, F., Gennery, A. R., Prince, N., Cariou, A., Nitschke, P., Blank, U., El-Ghazali, G., Menasche, G., Latour, S., Fischer, A., de Saint Basile, G. &lt;strong&gt;Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.&lt;/strong&gt; J. Clin. Invest. 119: 3765-3773, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19884660/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19884660&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19884660[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI40732&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19884660">Cote et al. (2009)</a> performed genomewide SNP analysis and found a common region of homozygosity on chromosome 19p13.2-p13.3; of 40 genes within the interval, the STXBP2 gene appeared to be the most plausible candidate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19884660" 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>Clinical Management</strong>
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<p><a href="#5" 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. &lt;strong&gt;Emapalumab in children with primary hemophagocytic lymphohistiocytosis.&lt;/strong&gt; New Eng. J. Med. 382: 1811-1822, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32374962/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;32374962&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa1911326&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="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>The transmission pattern of FHL5 in the families reported by <a href="#12" class="mim-tip-reference" title="zur Stadt, U., Rohr, J., Seifert, W., Koch, F., Grieve, S., Pagel, J., Strauss, J., Kasper, B., Nurnberg, G., Becker, C., Maul-Pavicic, A., Beutel, K., Janka, G., Griffiths, G., Ehl, S., Hennies, H. C. &lt;strong&gt;Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.&lt;/strong&gt; Am. J. Hum. Genet. 85: 482-492, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19804848/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19804848&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19804848[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2009.09.005&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19804848">zur Stadt et al. (2009)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19804848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<p>In 8 unrelated probands with familial hemophagocytic lymphohistiocytosis mapping to chromosome 19p, from 2 Saudi Arabian and 6 Turkish consanguineous families, <a href="#12" class="mim-tip-reference" title="zur Stadt, U., Rohr, J., Seifert, W., Koch, F., Grieve, S., Pagel, J., Strauss, J., Kasper, B., Nurnberg, G., Becker, C., Maul-Pavicic, A., Beutel, K., Janka, G., Griffiths, G., Ehl, S., Hennies, H. C. &lt;strong&gt;Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.&lt;/strong&gt; Am. J. Hum. Genet. 85: 482-492, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19804848/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19804848&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19804848[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2009.09.005&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19804848">zur Stadt et al. (2009)</a> identified homozygous mutations in the STXBP2 gene in all 8 patients (see, e.g., <a href="/entry/601717#0001">601717.0001</a>-<a href="/entry/601717#0003">601717.0003</a>). Sequence analysis in other patients from nonconsanguineous FHL families revealed homozygosity or compound heterozygosity for additional mutations in the STXBP2 gene in 4 patients from Germany and the Czech Republic (see, e.g., <a href="/entry/601717#0004">601717.0004</a>-<a href="/entry/601717#0006">601717.0006</a>), 2 of whom had previously been reported (<a href="#1" class="mim-tip-reference" title="Beutel, K., Gross-Wieltsch, U., Wiesel, T., Stadt, U. Z., Janka, G., Wagner, H. J. &lt;strong&gt;Infection of T lymphocytes in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children of non-Asian origin.&lt;/strong&gt; Pediat. Blood Cancer 53: 184-190, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19353621/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19353621&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/pbc.22037&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19353621">Beutel et al., 2009</a>; <a href="#9" class="mim-tip-reference" title="Sparber-Sauer, M., Honig, M., Schulz, A. S., zur Stadt, U., Schutz, C., Debatin, K. M., Friedrich, W. &lt;strong&gt;Patients with early relapse of primary hemophagocytic syndromes or with persistent CNS involvement may benefit from immediate hematopoietic stem cell transplantation.&lt;/strong&gt; Bone Marrow Transplant 44: 333-338, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19252534/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19252534&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/bmt.2009.34&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19252534">Sparber-Sauer et al., 2009</a>). Corresponding heterozygous mutations were found in all available unaffected parents, and none of the mutations were detected in 210 chromosomes from ethnically matched controls. The 7 patients who were homozygous for missense mutations or a 3-bp deletion had early-onset disease, diagnosed before 1 year of age, whereas the remaining 5 patients, who were homozygous for a splice site mutation or compound heterozygous for the splice site mutation and another mutation, had disease that developed after 1 year of age. <a href="#12" class="mim-tip-reference" title="zur Stadt, U., Rohr, J., Seifert, W., Koch, F., Grieve, S., Pagel, J., Strauss, J., Kasper, B., Nurnberg, G., Becker, C., Maul-Pavicic, A., Beutel, K., Janka, G., Griffiths, G., Ehl, S., Hennies, H. C. &lt;strong&gt;Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.&lt;/strong&gt; Am. J. Hum. Genet. 85: 482-492, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19804848/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19804848&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19804848[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2009.09.005&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19804848">Zur Stadt et al. (2009)</a> identified STX11 (<a href="/entry/605014">605014</a>), mutations in which causes FHL4 (<a href="/entry/603552">603552</a>), as an interaction partner of STXBP2, and demonstrated that this interaction is eliminated by the missense mutations identified in the FHL5 patients, leading to decreased stability of both proteins. Analysis of CD107 degranulation in 3 early-onset and 2 late-onset patients demonstrated marked reduction or absence of natural killer and cytotoxic T-cell activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19804848+19353621+19252534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 6 consanguineous families with FHL mapping to chromosome 19p13.2-p13.3, <a href="#3" class="mim-tip-reference" title="Cote, M., Menager, M. M., Burgess, A., Mahlaoui, N., Picard, C., Schaffner, C., Al-Manjomi, F., Al-Harbi, M., Alangari, A., Le Deist, F., Gennery, A. R., Prince, N., Cariou, A., Nitschke, P., Blank, U., El-Ghazali, G., Menasche, G., Latour, S., Fischer, A., de Saint Basile, G. &lt;strong&gt;Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.&lt;/strong&gt; J. Clin. Invest. 119: 3765-3773, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19884660/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19884660&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19884660[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI40732&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19884660">Cote et al. (2009)</a> sequenced the STXBP2 gene and identified homozygosity for the P477L mutation (<a href="/entry/601717#0001">601717.0001</a>) in 3 Saudi Arabian families and for the IVS14 splice site mutation (<a href="/entry/601717#0003">601717.0003</a>) in 3 families of Turkish, Palestinian Arab, and Iranian origin, respectively. In all patients with the P477L mutation, FHL was early in onset and rapidly led to death in 3 of 5 patients, whereas FHL manifestations occurred several years later in patients with the splice site mutation, and 1 individual homozygous for the splice site mutation was asymptomatic at 32 months of age. <a href="#3" class="mim-tip-reference" title="Cote, M., Menager, M. M., Burgess, A., Mahlaoui, N., Picard, C., Schaffner, C., Al-Manjomi, F., Al-Harbi, M., Alangari, A., Le Deist, F., Gennery, A. R., Prince, N., Cariou, A., Nitschke, P., Blank, U., El-Ghazali, G., Menasche, G., Latour, S., Fischer, A., de Saint Basile, G. &lt;strong&gt;Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.&lt;/strong&gt; J. Clin. Invest. 119: 3765-3773, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19884660/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19884660&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19884660[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI40732&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19884660">Cote et al. (2009)</a> confirmed STX11 as the main partner of STXBP2 in lymphocytes, with STXBP2 being required for its expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19884660" 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="Cetica, V., Santoro, A., Gilmour, K. C., Sieni, E., Beutel, K., Pende, D., Marcenaro, S., Koch, F., Grieve, S., Wheeler, R., Zhao, F., zur Stadt, U., Griffiths, G. M., Arico, M. &lt;strong&gt;STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5.&lt;/strong&gt; J. Med. Genet. 47: 595-600, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20798128/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20798128&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20798128[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2009.075341&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20798128">Cetica et al. (2010)</a> analyzed the STXBP2 gene in 28 FHL families in which mutations in known FHL genes had been excluded by sequence analysis, and identified homozygosity for 4 different missense mutations in the STXBP2 gene in 4 (14%) of the 28 families, originating from Italy, England, Kuwait, and Pakistan, respectively (see, e.g., P477L, <a href="/entry/601717#0001">601717.0001</a> and G541S, <a href="/entry/601717#0007">601717.0007</a>). <a href="#2" class="mim-tip-reference" title="Cetica, V., Santoro, A., Gilmour, K. C., Sieni, E., Beutel, K., Pende, D., Marcenaro, S., Koch, F., Grieve, S., Wheeler, R., Zhao, F., zur Stadt, U., Griffiths, G. M., Arico, M. &lt;strong&gt;STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5.&lt;/strong&gt; J. Med. Genet. 47: 595-600, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20798128/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20798128&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20798128[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2009.075341&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20798128">Cetica et al. (2010)</a> noted that the presenting features of these FHL5 patients appeared largely comparable to those of other FHL subgroups, in particular FHL2 (<a href="/entry/603553">603553</a>) and FHL3 (<a href="/entry/608898">608898</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20798128" 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 9 patients from 8 families with FHL5, <a href="#7" class="mim-tip-reference" title="Meeths, M., Entesarian, M., Al-Herz, W., Chiang, S. C. C., Wood, S. M., Al-Ateeqi, W., Almazan, F., Boelens, J. J., Hasle, H., Ifversen, M., Lund, B., van den Bert, J. M., Gustafsson, B., Hjelmqvist, H., Nordenskojold, M., Bryceson, Y. T., Henter, J.-I. &lt;strong&gt;Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.&lt;/strong&gt; Blood 116: 2635-2643, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20558610/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20558610&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-05-282541&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20558610">Meeths et al. (2010)</a> identified biallelic mutations in the STXBP2 gene (see, e.g., <a href="/entry/601717#0003">601717.0003</a>). There were 4 missense, 1 nonsense, 3 short deletions, and 3 splice site mutations; the mutations were scattered throughout the gene. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20558610" 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="#8" class="mim-tip-reference" title="Pagel, J., Beutel, K., Lehmberg, K., Koch, F., Maul-Pavicic, A., Rohlfs, A.-K., Al-Jefri, A., Beier, R., Ousager, L. B., Ehlert, K., Gross-Wieltsch, U., Jorch, N., Kremens, B., Pekrun, A., Sparber-Sauer, M., Mejstrikova, E., Wawer, A., Ehl, S., zur Stadt, U., Janka, G. &lt;strong&gt;Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5).&lt;/strong&gt; Blood 119: 6016-6024, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22451424/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22451424&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2011-12-398958&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22451424">Pagel et al. (2012)</a> reported 37 patients from 28 families of various ethnic origins with FHL5 due to homozygous or compound heterozygous mutations in the STXBP2 gene. Some of the patients had previously been reported. There was a spectrum of mutation types, including missense, splice site, and frameshift, which were scattered across the coding region. There were some recurrent mutations: P477L was observed in patients of Arab origin, G541S mainly in white Europeans, and a splice site mutation affecting exon 15 (<a href="/entry/601717#0003">601717.0003</a>) was found in 12 patients (5 homozygous and 7 compound heterozygous with another STXBP2 mutation). Patient NK and cytotoxic T cells showed variable abnormal degranulation compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22451424" 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 5 unrelated children with FHL5, including 1 patient previously reported by <a href="#10" class="mim-tip-reference" title="Stepensky, P., Bartram, J., Barth, T. F., Lehmberg, K., Walther, P., Amann, K., Philips, A. D., Beringer, O., Zur Stadt, U., Schulz, A., Amrolia, P., Weintraub, M., Debatin, K.-M., Hoenig, M., Posovszky, C. &lt;strong&gt;Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18-2 mutations.&lt;/strong&gt; Pediat. Blood Cancer 60: 1215-1222, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23382066/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23382066&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/pbc.24475&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23382066">Stepensky et al. (2013)</a>, <a href="#11" class="mim-tip-reference" title="Vogel, G. F., van Rijn, J. M., Krainer, I. M., Janecke, A. R., Posovszky, C., Cohen, M., Searle, C., Jantchou, P., Escher, J. C., Patey, N., Cutz, E., Muller, T., Middendorp, S., Hess, M. W., Huber, L. A. &lt;strong&gt;Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations.&lt;/strong&gt; JCI Insight 2: e94564, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28724787/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28724787&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28724787[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/jci.insight.94564&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28724787">Vogel et al. (2017)</a> identified homozygous loss-of-function mutations in the STXBP2 gene (see, e.g., <a href="/entry/601717#0009">601717.0009</a> and <a href="/entry/601717#0010">601717.0010</a>). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. In addition to interrupting the interaction with STX11, an interaction important for proper leukocyte function, in vitro studies showed that loss of the STXBP2 protein also abolished the interaction with STX3 (<a href="/entry/600876">600876</a>) in polarized epithelial cells, which is pivotal for vesicle fusion at the apical plasma membrane. Studies in an STXBP2-null human enterocyte cell line grown on a porous membrane and patient-derived cells or organoids showed that loss of STXBP2 disrupted enterocyte polarity and resulted in shortening or loss of apical microvilli and aberrant accumulation of subapical vesicles. The cellular model system thus recapitulated the MVID phenotype observed in the patients. Expression of the Ile232del mutation (<a href="/entry/601717#0002">601717.0002</a>) was unable to rescue these defects in vitro. Additional in vitro studies showed that the mutations interrupted SNARE/STX3-mediated fusion of cargo vesicles at the apical membrane of polarized cells. This was associated with also abnormal localization of brush border transporters, such as NHE3 (SLC9A3; <a href="/entry/182307">182307</a>), at the apical membrane; these are critical for proper enterocyte function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28724787+23382066" 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="#8" class="mim-tip-reference" title="Pagel, J., Beutel, K., Lehmberg, K., Koch, F., Maul-Pavicic, A., Rohlfs, A.-K., Al-Jefri, A., Beier, R., Ousager, L. B., Ehlert, K., Gross-Wieltsch, U., Jorch, N., Kremens, B., Pekrun, A., Sparber-Sauer, M., Mejstrikova, E., Wawer, A., Ehl, S., zur Stadt, U., Janka, G. &lt;strong&gt;Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5).&lt;/strong&gt; Blood 119: 6016-6024, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22451424/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22451424&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2011-12-398958&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22451424">Pagel et al. (2012)</a> delineated 2 main phenotypic groups based on STXBP2 mutation type, suggesting a possible genotype/phenotype correlation. Patients without exon 15 splice site mutations (see, e.g., <a href="/entry/601717#0003">601717.0003</a>) had early disease onset in the first months of life and a rapidly fatal course if HSCT could not be performed. All 14 of the patients in this group had chronic diarrhea. In contrast, 13 patients with an exon 15 splice site mutation on at least 1 allele had later disease onset with a more protracted course. None of the patients in this group had diarrhea or MVID, but 9 had hypogammaglobulinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22451424" 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="#4" class="mim-tip-reference" title="Dhekne, H. S., Pylypenko, O., Overeem, A. W., Ferreira, R. J., van der Velde, K. J., Rings, E. H. H. M., Posovszky, C., Swertz, M. A., Houdusse, A., van IJzendoorn, S. C. D. &lt;strong&gt;MYO5B, STX3, and STXBP2 mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: a mutation update.&lt;/strong&gt; Hum. Mutat. 39: 333-344, 2018. Note: Erratum: Hum. Mutat. 39: 1468 only, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29266534/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29266534&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29266534[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.23386&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29266534">Dhekne et al. (2018)</a> provided a mutation update on 3 genes involved in MVID: STXBP2, MYO5B (<a href="/entry/606540">606540</a>), and STX3. These 3 genes are functionally linked in the process of brush border development and apical membrane protein trafficking, suggesting a common pathogenetic mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29266534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="Beutel2009" class="mim-anchor"></a>
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Beutel, K., Gross-Wieltsch, U., Wiesel, T., Stadt, U. Z., Janka, G., Wagner, H. J.
<strong>Infection of T lymphocytes in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children of non-Asian origin.</strong>
Pediat. Blood Cancer 53: 184-190, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19353621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19353621</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19353621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/pbc.22037" target="_blank">Full Text</a>]
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<a id="Cetica2010" class="mim-anchor"></a>
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Cetica, V., Santoro, A., Gilmour, K. C., Sieni, E., Beutel, K., Pende, D., Marcenaro, S., Koch, F., Grieve, S., Wheeler, R., Zhao, F., zur Stadt, U., Griffiths, G. M., Arico, M.
<strong>STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5.</strong>
J. Med. Genet. 47: 595-600, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20798128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20798128</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20798128[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=20798128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.2009.075341" target="_blank">Full Text</a>]
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<a id="Cote2009" class="mim-anchor"></a>
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Cote, M., Menager, M. M., Burgess, A., Mahlaoui, N., Picard, C., Schaffner, C., Al-Manjomi, F., Al-Harbi, M., Alangari, A., Le Deist, F., Gennery, A. R., Prince, N., Cariou, A., Nitschke, P., Blank, U., El-Ghazali, G., Menasche, G., Latour, S., Fischer, A., de Saint Basile, G.
<strong>Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.</strong>
J. Clin. Invest. 119: 3765-3773, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19884660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19884660</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19884660[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=19884660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI40732" target="_blank">Full Text</a>]
</p>
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<a id="4" class="mim-anchor"></a>
<a id="Dhekne2018" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Dhekne, H. S., Pylypenko, O., Overeem, A. W., Ferreira, R. J., van der Velde, K. J., Rings, E. H. H. M., Posovszky, C., Swertz, M. A., Houdusse, A., van IJzendoorn, S. C. D.
<strong>MYO5B, STX3, and STXBP2 mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: a mutation update.</strong>
Hum. Mutat. 39: 333-344, 2018. Note: Erratum: Hum. Mutat. 39: 1468 only, 2018.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29266534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29266534</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29266534[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=29266534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/humu.23386" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
<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.
<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://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>]
[<a href="https://doi.org/10.1056/NEJMoa1911326" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
<a id="Matthes-Martin2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Matthes-Martin, S., Peters, C., Konigsrainer, A., Fritsch, G., Lion, T., Heitger, A., Kapelari, K., Kronberger, M., Offner, F., Wrba, F., Margreiter, R., Gadner, H.
<strong>Successful stem cell transplantation following orthotopic liver transplantation from the same haploidentical family donor in a girl with hemophagocytic lymphohistiocytosis.</strong>
Blood 96: 3997-3999, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11090093/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11090093</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11090093" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="7" class="mim-anchor"></a>
<a id="Meeths2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Meeths, M., Entesarian, M., Al-Herz, W., Chiang, S. C. C., Wood, S. M., Al-Ateeqi, W., Almazan, F., Boelens, J. J., Hasle, H., Ifversen, M., Lund, B., van den Bert, J. M., Gustafsson, B., Hjelmqvist, H., Nordenskojold, M., Bryceson, Y. T., Henter, J.-I.
<strong>Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.</strong>
Blood 116: 2635-2643, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20558610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20558610</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20558610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1182/blood-2010-05-282541" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
<a id="Pagel2012" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Pagel, J., Beutel, K., Lehmberg, K., Koch, F., Maul-Pavicic, A., Rohlfs, A.-K., Al-Jefri, A., Beier, R., Ousager, L. B., Ehlert, K., Gross-Wieltsch, U., Jorch, N., Kremens, B., Pekrun, A., Sparber-Sauer, M., Mejstrikova, E., Wawer, A., Ehl, S., zur Stadt, U., Janka, G.
<strong>Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5).</strong>
Blood 119: 6016-6024, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22451424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22451424</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22451424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1182/blood-2011-12-398958" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
<a id="Sparber-Sauer2009" class="mim-anchor"></a>
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Sparber-Sauer, M., Honig, M., Schulz, A. S., zur Stadt, U., Schutz, C., Debatin, K. M., Friedrich, W.
<strong>Patients with early relapse of primary hemophagocytic syndromes or with persistent CNS involvement may benefit from immediate hematopoietic stem cell transplantation.</strong>
Bone Marrow Transplant 44: 333-338, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19252534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19252534</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19252534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/bmt.2009.34" target="_blank">Full Text</a>]
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<a id="Stepensky2013" class="mim-anchor"></a>
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Stepensky, P., Bartram, J., Barth, T. F., Lehmberg, K., Walther, P., Amann, K., Philips, A. D., Beringer, O., Zur Stadt, U., Schulz, A., Amrolia, P., Weintraub, M., Debatin, K.-M., Hoenig, M., Posovszky, C.
<strong>Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18-2 mutations.</strong>
Pediat. Blood Cancer 60: 1215-1222, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23382066/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23382066</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23382066" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/pbc.24475" target="_blank">Full Text</a>]
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<a id="Vogel2017" class="mim-anchor"></a>
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Vogel, G. F., van Rijn, J. M., Krainer, I. M., Janecke, A. R., Posovszky, C., Cohen, M., Searle, C., Jantchou, P., Escher, J. C., Patey, N., Cutz, E., Muller, T., Middendorp, S., Hess, M. W., Huber, L. A.
<strong>Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations.</strong>
JCI Insight 2: e94564, 2017.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28724787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28724787</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28724787[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=28724787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/jci.insight.94564" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
<a id="zur Stadt2009" class="mim-anchor"></a>
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<p class="mim-text-font">
zur Stadt, U., Rohr, J., Seifert, W., Koch, F., Grieve, S., Pagel, J., Strauss, J., Kasper, B., Nurnberg, G., Becker, C., Maul-Pavicic, A., Beutel, K., Janka, G., Griffiths, G., Ehl, S., Hennies, H. C.
<strong>Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.</strong>
Am. J. Hum. Genet. 85: 482-492, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19804848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19804848</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19804848[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=19804848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ajhg.2009.09.005" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 07/22/2021
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Ada Hamosh - updated : 12/01/2020<br>Marla J. F. O'Neill - updated : 1/5/2011<br>Marla J. F. O'Neill - updated : 6/10/2010
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Marla J. F. O&#x27;Neill : 10/22/2009
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carol : 05/20/2022
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alopez : 05/19/2022<br>carol : 07/24/2021<br>ckniffin : 07/22/2021<br>alopez : 12/01/2020<br>carol : 09/01/2020<br>carol : 05/23/2017<br>wwang : 01/10/2011<br>terry : 1/5/2011<br>wwang : 6/11/2010<br>terry : 6/10/2010<br>carol : 11/18/2009<br>wwang : 10/23/2009
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<strong>#</strong> 613101
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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5, WITH OR WITHOUT MICROVILLUS INCLUSION DISEASE; FHL5
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<strong>ORPHA:</strong> 540; &nbsp;
<strong>DO:</strong> 0110925; &nbsp;
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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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19p13.2
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Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease
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613101
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Autosomal recessive
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3
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STXBP2
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601717
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because familial hemophagocytic lymphohistiocytosis-5 with or without microvillus inclusion disease (FHL5) is caused by homozygous or compound heterozygous mutation in the syntaxin-binding protein-2 gene (STXBP2; 601717) on chromosome 19p13.</p>
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<strong>Description</strong>
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<p>Familial hemophagocytic lymphohistiocytosis-5 with or without microvillus inclusion disease (FHL5) is an autosomal recessive hyperinflammatory disorder characterized clinically by fever, hepatosplenomegaly, pancytopenia, coagulation abnormalities, and other laboratory findings. Some patients have neurologic symptoms due to inflammatory CNS disease. There is uncontrolled and ineffective proliferation and activation of T lymphocytes, NK cells, and macrophages that infiltrate multiple organs, including liver, spleen, lymph nodes, and the CNS. The phenotype is variable: some patients may present in early infancy with severe diarrhea, prior to the onset of typical FHL features, whereas others present later in childhood and have a more protracted course without diarrhea. The early-onset diarrhea is due to enteropathy reminiscent of microvillus inclusion disease (see MVID, 251850). The enteropathy, which often necessitates parenteral feeding, may be the most life-threatening issue even after hematopoietic stem cell transplantation (HSCT). More variable features include sensorineural hearing loss and hypogammaglobulinemia. Treatment with immunosuppressive drugs and chemotherapy can ameliorate signs and symptoms of FHL in some patients, but the only curative therapy for FHL is HSCT. HSCT is not curative for enteropathy associated with the disorder, despite hematologic and immunologic reconstitution (summary by Meeths et al., 2010; Pagel et al., 2012; Stepensky et al., 2013). </p><p>For a phenotypic description and a discussion of genetic heterogeneity of familial hemophagocytic lymphohistiocytosis (FHL, HLH), see 267700.</p>
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<strong>Clinical Features</strong>
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<p>Meeths et al. (2010) reported 11 patients from 8 unrelated families with FHL5. The median age at symptom onset was 15 months (range 2 months to 17 years). Three patients died, including 2 who did not have HSCT. Classic features of HLH found in these patients included fever, hepatosplenomegaly, increased ferritin and triglycerides, decreased fibrinogen, and elevated liver enzymes. Many patients also had EBV infection. Bone marrow showed hemophagocytosis in some patients. Patient NK cells showed impaired NK cell degranulation and defective cytotoxicity that could be rescued in vitro by interleukin-2 (IL2; 147680) stimulation. About half of patients developed nonspecific neurologic symptoms, including seizures, hypotonia, facial palsy, nystagmus, strabismus, ataxia, and irritability. Some of these patients showed demyelination or abnormal signals on brain imaging, and some had elevated CSF cell counts. Other features observed in some patients included gastrointestinal involvement manifest as colitis or diarrhea, bleeding disorders, including thrombocytopenia and coagulation abnormalities, and hypogammaglobulinemia. The clinical features of patient A were described in detail. She was a 17-year-old girl of Russian descent who presented with fever, abdominal pain, and sore throat. Liver enzymes were increased and EBV was detected. After undergoing tonsillectomy, she had severe bleeding associated with low platelet count and developed renal failure. Laboratory studies were consistent with HLH and she was successfully treated, although she did not have a HSCT. History revealed that she may have had a prior HLH episode at age 6 years. In addition to the relatively late onset of HLH in this patient, the authors emphasized the unusual features of colitis, bleeding, and hypogammaglobulinemia. </p><p>Pagel et al. (2012) reported 37 patients from 28 families of various ethnic origins with FHL5 confirmed by genetic analysis. Some of the patients had previously been reported (see, e.g., Matthes-Martin et al., 2000; Zur Stadt et al., 2009). There was considerable clinical variability: most patients had an early onset in infancy with severe and rapid disease progression, whereas a few had later onset in the first 2 decades and a chronic recurrent course with long episodes of well-being. Patients with early-onset disease had severe chronic diarrhea with failure to thrive, often necessitating a feeding tube or parenteral nutrition. Bowel histology showed nonspecific inflammatory changes and slight loss of villi or crypts. Six patients had sensorineural hearing loss apparent in the first decades of life. Several patients had abnormal bleeding, including platelet defects. Ten of 17 patients had hypogammaglobulinemia; this tended to be present in those with later onset and a more protracted disease course. One patient (Matthes-Martin et al., 2000) presented in infancy with acute liver failure requiring liver transplant; she was found to have typical features of FHL and later underwent HSCT. Laboratory studies in the patients, when performed, showed abnormal or reduced NK and CD8+ T cell cytotoxicity and degranulation. Hematopoietic stem cell transplantation was performed in 26 patients with variable results. </p><p>Stepensky et al. (2013) reported 6 children from 4 unrelated families who presented in the first weeks or months of life with intractable osmotic diarrhea and failure to thrive due to severe enteropathy, as well as classic hematologic and immunologic features of HLH. Three patients died in infancy or early childhood; the others were alive between ages 4 and 12 years of age. The diarrhea often caused metabolic acidosis and most patients required tube or total parenteral feeding. Histologic studies of the intestine showed villous atrophy, decreased crypt depth, and fine cytoplasmic vacuoles filled with an amorphous material in surface enterocytes. CD10 (120520) staining at the apical brush border membrane was abnormal and there was some accumulation of PAS-positive material. These findings were consistent with MVID. One patient had renal tubular dysfunction associated with cytoplasmic inclusions and PAS-positive material at the basal lamina and apical brush border in kidney epithelial cells, although apical membrane morphology was normal. Features of HLH included fever, hepatosplenomegaly, cytopenias, and increased fibrinogen, ferritin, and triglycerides. More variable features included abnormal liver function, coagulopathy, and sensorineural hearing loss. Most, but not all, patients had evidence of HLH on bone marrow studies. Serum CD25 (147730) was increased in the 2 patients studied. Despite HSCT in 4 probands, all continued to have enteropathy; renal disease also persisted. The authors emphasized that patients may have significant gastrointestinal problems even after HSCT, suggesting that cells other than hematologic or immunologic are involved in this disorder. The abnormalities may be related to defective cellular membrane trafficking in the gut and kidney. </p><p>Vogel et al. (2017) reported 5 unrelated children with FHL5, including 1 patient previously reported by Stepensky et al. (2013). All patients presented with congenital intractable diarrhea due to an enteropathy in the first days or weeks of life resulting in failure to thrive. Histologic studies of intestinal biopsies showed features reminiscent of MVID, including aberrant intracellular PAS staining, shortening or complete loss of apical microvilli, and microvillus inclusions. The patients also had classic, if variable, features of HLH, such as pancytopenia, fever, coagulation abnormalities, hepatosplenomegaly, increased liver enzymes, and hemophagocytosis on bone marrow examination. All patients underwent HSCT in the first year of life due to HLH, but the enteropathy continued after transplant, a unique feature of FHL5. </p>
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<strong>Mapping</strong>
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<p>Zur Stadt et al. (2009) performed genomewide linkage analysis and homozygosity mapping in 1 Saudi Arabian and 14 unrelated Turkish probands, all from consanguineous backgrounds, who had familial hemophagocytic lymphohistiocytosis but did not have mutations in the 3 known FHL genes. A maximum heterogeneity lod (hlod) score of 5.9 was obtained on chromosome 19p; fine mapping yielded a hlod of 8.3 at rs634968, and detailed genotype analysis revealed an overlapping region of homozygosity in 7 of the 15 cases, a 1,040-kb interval containing 36 genes. Whole-genome analysis of another consanguineous FHL family from Saudi Arabia with 2 affected and 3 unaffected sibs revealed 3 homozygous regions with lod scores greater than 2.0, 1 of which overlapped with the previously identified interval on chromosome 19p. </p><p>In 8 patients from 6 consanguineous families with FHL in which known causes had been excluded by genetic analysis, Cote et al. (2009) performed genomewide SNP analysis and found a common region of homozygosity on chromosome 19p13.2-p13.3; of 40 genes within the interval, the STXBP2 gene appeared to be the most plausible candidate. </p>
</span>
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<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
</span>
</h4>
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<span class="mim-text-font">
<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>
</span>
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</div>
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<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The transmission pattern of FHL5 in the families reported by zur Stadt et al. (2009) was consistent with autosomal recessive inheritance. </p>
</span>
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</div>
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<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In 8 unrelated probands with familial hemophagocytic lymphohistiocytosis mapping to chromosome 19p, from 2 Saudi Arabian and 6 Turkish consanguineous families, zur Stadt et al. (2009) identified homozygous mutations in the STXBP2 gene in all 8 patients (see, e.g., 601717.0001-601717.0003). Sequence analysis in other patients from nonconsanguineous FHL families revealed homozygosity or compound heterozygosity for additional mutations in the STXBP2 gene in 4 patients from Germany and the Czech Republic (see, e.g., 601717.0004-601717.0006), 2 of whom had previously been reported (Beutel et al., 2009; Sparber-Sauer et al., 2009). Corresponding heterozygous mutations were found in all available unaffected parents, and none of the mutations were detected in 210 chromosomes from ethnically matched controls. The 7 patients who were homozygous for missense mutations or a 3-bp deletion had early-onset disease, diagnosed before 1 year of age, whereas the remaining 5 patients, who were homozygous for a splice site mutation or compound heterozygous for the splice site mutation and another mutation, had disease that developed after 1 year of age. Zur Stadt et al. (2009) identified STX11 (605014), mutations in which causes FHL4 (603552), as an interaction partner of STXBP2, and demonstrated that this interaction is eliminated by the missense mutations identified in the FHL5 patients, leading to decreased stability of both proteins. Analysis of CD107 degranulation in 3 early-onset and 2 late-onset patients demonstrated marked reduction or absence of natural killer and cytotoxic T-cell activity. </p><p>In affected members of 6 consanguineous families with FHL mapping to chromosome 19p13.2-p13.3, Cote et al. (2009) sequenced the STXBP2 gene and identified homozygosity for the P477L mutation (601717.0001) in 3 Saudi Arabian families and for the IVS14 splice site mutation (601717.0003) in 3 families of Turkish, Palestinian Arab, and Iranian origin, respectively. In all patients with the P477L mutation, FHL was early in onset and rapidly led to death in 3 of 5 patients, whereas FHL manifestations occurred several years later in patients with the splice site mutation, and 1 individual homozygous for the splice site mutation was asymptomatic at 32 months of age. Cote et al. (2009) confirmed STX11 as the main partner of STXBP2 in lymphocytes, with STXBP2 being required for its expression. </p><p>Cetica et al. (2010) analyzed the STXBP2 gene in 28 FHL families in which mutations in known FHL genes had been excluded by sequence analysis, and identified homozygosity for 4 different missense mutations in the STXBP2 gene in 4 (14%) of the 28 families, originating from Italy, England, Kuwait, and Pakistan, respectively (see, e.g., P477L, 601717.0001 and G541S, 601717.0007). Cetica et al. (2010) noted that the presenting features of these FHL5 patients appeared largely comparable to those of other FHL subgroups, in particular FHL2 (603553) and FHL3 (608898). </p><p>In 9 patients from 8 families with FHL5, Meeths et al. (2010) identified biallelic mutations in the STXBP2 gene (see, e.g., 601717.0003). There were 4 missense, 1 nonsense, 3 short deletions, and 3 splice site mutations; the mutations were scattered throughout the gene. Functional studies of the variants were not performed. </p><p>Pagel et al. (2012) reported 37 patients from 28 families of various ethnic origins with FHL5 due to homozygous or compound heterozygous mutations in the STXBP2 gene. Some of the patients had previously been reported. There was a spectrum of mutation types, including missense, splice site, and frameshift, which were scattered across the coding region. There were some recurrent mutations: P477L was observed in patients of Arab origin, G541S mainly in white Europeans, and a splice site mutation affecting exon 15 (601717.0003) was found in 12 patients (5 homozygous and 7 compound heterozygous with another STXBP2 mutation). Patient NK and cytotoxic T cells showed variable abnormal degranulation compared to controls. </p><p>In 5 unrelated children with FHL5, including 1 patient previously reported by Stepensky et al. (2013), Vogel et al. (2017) identified homozygous loss-of-function mutations in the STXBP2 gene (see, e.g., 601717.0009 and 601717.0010). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. In addition to interrupting the interaction with STX11, an interaction important for proper leukocyte function, in vitro studies showed that loss of the STXBP2 protein also abolished the interaction with STX3 (600876) in polarized epithelial cells, which is pivotal for vesicle fusion at the apical plasma membrane. Studies in an STXBP2-null human enterocyte cell line grown on a porous membrane and patient-derived cells or organoids showed that loss of STXBP2 disrupted enterocyte polarity and resulted in shortening or loss of apical microvilli and aberrant accumulation of subapical vesicles. The cellular model system thus recapitulated the MVID phenotype observed in the patients. Expression of the Ile232del mutation (601717.0002) was unable to rescue these defects in vitro. Additional in vitro studies showed that the mutations interrupted SNARE/STX3-mediated fusion of cargo vesicles at the apical membrane of polarized cells. This was associated with also abnormal localization of brush border transporters, such as NHE3 (SLC9A3; 182307), at the apical membrane; these are critical for proper enterocyte function. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Pagel et al. (2012) delineated 2 main phenotypic groups based on STXBP2 mutation type, suggesting a possible genotype/phenotype correlation. Patients without exon 15 splice site mutations (see, e.g., 601717.0003) had early disease onset in the first months of life and a rapidly fatal course if HSCT could not be performed. All 14 of the patients in this group had chronic diarrhea. In contrast, 13 patients with an exon 15 splice site mutation on at least 1 allele had later disease onset with a more protracted course. None of the patients in this group had diarrhea or MVID, but 9 had hypogammaglobulinemia. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Dhekne et al. (2018) provided a mutation update on 3 genes involved in MVID: STXBP2, MYO5B (606540), and STX3. These 3 genes are functionally linked in the process of brush border development and apical membrane protein trafficking, suggesting a common pathogenetic mechanism. </p>
</span>
<div>
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</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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</h4>
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<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Beutel, K., Gross-Wieltsch, U., Wiesel, T., Stadt, U. Z., Janka, G., Wagner, H. J.
<strong>Infection of T lymphocytes in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children of non-Asian origin.</strong>
Pediat. Blood Cancer 53: 184-190, 2009.
[PubMed: 19353621]
[Full Text: https://doi.org/10.1002/pbc.22037]
</p>
</li>
<li>
<p class="mim-text-font">
Cetica, V., Santoro, A., Gilmour, K. C., Sieni, E., Beutel, K., Pende, D., Marcenaro, S., Koch, F., Grieve, S., Wheeler, R., Zhao, F., zur Stadt, U., Griffiths, G. M., Arico, M.
<strong>STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5.</strong>
J. Med. Genet. 47: 595-600, 2010.
[PubMed: 20798128]
[Full Text: https://doi.org/10.1136/jmg.2009.075341]
</p>
</li>
<li>
<p class="mim-text-font">
Cote, M., Menager, M. M., Burgess, A., Mahlaoui, N., Picard, C., Schaffner, C., Al-Manjomi, F., Al-Harbi, M., Alangari, A., Le Deist, F., Gennery, A. R., Prince, N., Cariou, A., Nitschke, P., Blank, U., El-Ghazali, G., Menasche, G., Latour, S., Fischer, A., de Saint Basile, G.
<strong>Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.</strong>
J. Clin. Invest. 119: 3765-3773, 2009.
[PubMed: 19884660]
[Full Text: https://doi.org/10.1172/JCI40732]
</p>
</li>
<li>
<p class="mim-text-font">
Dhekne, H. S., Pylypenko, O., Overeem, A. W., Ferreira, R. J., van der Velde, K. J., Rings, E. H. H. M., Posovszky, C., Swertz, M. A., Houdusse, A., van IJzendoorn, S. C. D.
<strong>MYO5B, STX3, and STXBP2 mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: a mutation update.</strong>
Hum. Mutat. 39: 333-344, 2018. Note: Erratum: Hum. Mutat. 39: 1468 only, 2018.
[PubMed: 29266534]
[Full Text: https://doi.org/10.1002/humu.23386]
</p>
</li>
<li>
<p class="mim-text-font">
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: 32374962]
[Full Text: https://doi.org/10.1056/NEJMoa1911326]
</p>
</li>
<li>
<p class="mim-text-font">
Matthes-Martin, S., Peters, C., Konigsrainer, A., Fritsch, G., Lion, T., Heitger, A., Kapelari, K., Kronberger, M., Offner, F., Wrba, F., Margreiter, R., Gadner, H.
<strong>Successful stem cell transplantation following orthotopic liver transplantation from the same haploidentical family donor in a girl with hemophagocytic lymphohistiocytosis.</strong>
Blood 96: 3997-3999, 2000.
[PubMed: 11090093]
</p>
</li>
<li>
<p class="mim-text-font">
Meeths, M., Entesarian, M., Al-Herz, W., Chiang, S. C. C., Wood, S. M., Al-Ateeqi, W., Almazan, F., Boelens, J. J., Hasle, H., Ifversen, M., Lund, B., van den Bert, J. M., Gustafsson, B., Hjelmqvist, H., Nordenskojold, M., Bryceson, Y. T., Henter, J.-I.
<strong>Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.</strong>
Blood 116: 2635-2643, 2010.
[PubMed: 20558610]
[Full Text: https://doi.org/10.1182/blood-2010-05-282541]
</p>
</li>
<li>
<p class="mim-text-font">
Pagel, J., Beutel, K., Lehmberg, K., Koch, F., Maul-Pavicic, A., Rohlfs, A.-K., Al-Jefri, A., Beier, R., Ousager, L. B., Ehlert, K., Gross-Wieltsch, U., Jorch, N., Kremens, B., Pekrun, A., Sparber-Sauer, M., Mejstrikova, E., Wawer, A., Ehl, S., zur Stadt, U., Janka, G.
<strong>Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5).</strong>
Blood 119: 6016-6024, 2012.
[PubMed: 22451424]
[Full Text: https://doi.org/10.1182/blood-2011-12-398958]
</p>
</li>
<li>
<p class="mim-text-font">
Sparber-Sauer, M., Honig, M., Schulz, A. S., zur Stadt, U., Schutz, C., Debatin, K. M., Friedrich, W.
<strong>Patients with early relapse of primary hemophagocytic syndromes or with persistent CNS involvement may benefit from immediate hematopoietic stem cell transplantation.</strong>
Bone Marrow Transplant 44: 333-338, 2009.
[PubMed: 19252534]
[Full Text: https://doi.org/10.1038/bmt.2009.34]
</p>
</li>
<li>
<p class="mim-text-font">
Stepensky, P., Bartram, J., Barth, T. F., Lehmberg, K., Walther, P., Amann, K., Philips, A. D., Beringer, O., Zur Stadt, U., Schulz, A., Amrolia, P., Weintraub, M., Debatin, K.-M., Hoenig, M., Posovszky, C.
<strong>Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18-2 mutations.</strong>
Pediat. Blood Cancer 60: 1215-1222, 2013.
[PubMed: 23382066]
[Full Text: https://doi.org/10.1002/pbc.24475]
</p>
</li>
<li>
<p class="mim-text-font">
Vogel, G. F., van Rijn, J. M., Krainer, I. M., Janecke, A. R., Posovszky, C., Cohen, M., Searle, C., Jantchou, P., Escher, J. C., Patey, N., Cutz, E., Muller, T., Middendorp, S., Hess, M. W., Huber, L. A.
<strong>Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations.</strong>
JCI Insight 2: e94564, 2017.
[PubMed: 28724787]
[Full Text: https://doi.org/10.1172/jci.insight.94564]
</p>
</li>
<li>
<p class="mim-text-font">
zur Stadt, U., Rohr, J., Seifert, W., Koch, F., Grieve, S., Pagel, J., Strauss, J., Kasper, B., Nurnberg, G., Becker, C., Maul-Pavicic, A., Beutel, K., Janka, G., Griffiths, G., Ehl, S., Hennies, H. C.
<strong>Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.</strong>
Am. J. Hum. Genet. 85: 482-492, 2009.
[PubMed: 19804848]
[Full Text: https://doi.org/10.1016/j.ajhg.2009.09.005]
</p>
</li>
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Cassandra L. Kniffin - updated : 07/22/2021<br>Ada Hamosh - updated : 12/01/2020<br>Marla J. F. O&#x27;Neill - updated : 1/5/2011<br>Marla J. F. O&#x27;Neill - updated : 6/10/2010
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