3416 lines
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Entry
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- #304790 - IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED; IPEX
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- OMIM
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<p>
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<span class="h4">#304790</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="/clinicalSynopsis/304790"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#heterogeneity">Heterogeneity</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=10440&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1118/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/8674" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/immune-dysregulation-polyendocrinopathy-enteropathy-x-linked-syndrome" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=304790[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=37042" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/6d9fdbb3-0466-4be1-9b50-c800cc66a9f0/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0090110" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/304790" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0090110" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</div>
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 724276006<br />
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<strong>ORPHA:</strong> 37042<br />
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<strong>DO:</strong> 0090110<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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304790
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
|
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<span class="mim-font">
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IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED; IPEX
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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X-LINKED AUTOIMMUNITY-ALLERGIC DYSREGULATION SYNDROME; XLAAD<br />
|
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IDDM-SECRETORY DIARRHEA SYNDROME; DMSD<br />
|
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AUTOIMMUNITY-IMMUNODEFICIENCY SYNDROME, X-LINKED<br />
|
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DIARRHEA, POLYENDOCRINOPATHY, FATAL INFECTION SYNDROME, X-LINKED<br />
|
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ENTEROPATHY, AUTOIMMUNE, WITH HEMOLYTIC ANEMIA AND POLYENDOCRINOPATHY<br />
|
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POLYENDOCRINOPATHY, IMMUNE DYSFUNCTION, AND DIARRHEA, X-LINKED; XPID<br />
|
|
DIABETES MELLITUS, CONGENITAL INSULIN-DEPENDENT, WITH FATAL SECRETORY DIARRHEA<br />
|
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IMMUNODEFICIENCY, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED, FORMERLY
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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ISLETS OF LANGERHANS, ABSENCE OF, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
|
</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/X/277?start=-3&limit=10&highlight=277">
|
|
Xp11.23
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/304790"> 304790 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</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">
|
|
FOXP3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/300292"> 300292 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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|
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<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/304790" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/304790" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/304790" 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">
|
|
|
|
- X-linked recessive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845977</a>, <a href="https://bioportal.bioontology.org/search?q=C1279481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279481</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span><br />
|
|
|
|
</span>
|
|
</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> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Diarrhea, secretory <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15699003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15699003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0267557&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0267557</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005208" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005208</a>]</span><br /> -
|
|
Enteropathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85919009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85919009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K63.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K63.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/569.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">569.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021831&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021831</a>, <a href="https://bioportal.bioontology.org/search?q=C4316788&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4316788</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002242" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002242</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002242" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002242</a>]</span><br /> -
|
|
Ileus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/710572000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">710572000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1258215&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1258215</a>, <a href="https://bioportal.bioontology.org/search?q=C4019039&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4019039</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002595" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002595</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002595" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002595</a>]</span><br /> -
|
|
Villous atrophy seen on biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4012415&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4012415</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/275403002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">275403002</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011473" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011473</a>]</span><br /> -
|
|
Chronic inflammation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021376&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021376</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">
|
|
|
|
- Eczema <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43116000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43116000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L30.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L30.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013595&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013595</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000964" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000964</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000964" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000964</a>]</span><br /> -
|
|
Atopy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/55985003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">55985003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/115665000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">115665000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0392707&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0392707</a>, <a href="https://bioportal.bioontology.org/search?q=C3539705&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3539705</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ENDOCRINE FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Insulin-dependent diabetes mellitus (type I) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/46635009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">46635009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011854&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011854</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100651" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100651</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100651" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100651</a>]</span><br /> -
|
|
Hypothyroidism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40930008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40930008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E03.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E03.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/244.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">244.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020676&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020676</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000821" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000821</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000821" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000821</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">
|
|
|
|
- Hemolytic anemia, autoimmune <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413603009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413603009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/283.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">283.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002880&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002880</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001890" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001890</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001890" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001890</a>]</span><br /> -
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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 /> -
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Eosinophilia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386789004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386789004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.10</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0014457&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014457</a>, <a href="https://bioportal.bioontology.org/search?q=C2240374&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2240374</a>, <a href="https://bioportal.bioontology.org/search?q=C1306759&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1306759</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001880</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001880</a>]</span><br />
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<span class="h5 mim-font">
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<strong> IMMUNOLOGY </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Immune dysregulation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844666&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844666</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002958" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002958</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002958" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002958</a>]</span><br /> -
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Variable autoimmune disorders <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844667&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844667</a>]</span><br /> -
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Lymphadenopathy may occur <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844668&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844668</a>]</span> <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">[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 /> -
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Autoantibodies <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/314067002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">314067002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30621004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30621004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004358&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004358</a>, <a href="https://bioportal.bioontology.org/search?q=C1272321&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1272321</a>]</span><br /> -
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Increased serum IgE <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2673464&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2673464</a>]</span><br />
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Variable severity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861403&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861403</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span><br /> -
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Death usually occurs in infancy or childhood if untreated<br />
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</span>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Caused by mutation in the forkhead box P3 gene (FOXP3, <a href="/entry/300292#0001">300292.0001</a>)<br />
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because X-linked immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) is caused by mutation in the FOXP3 gene (<a href="/entry/300292">300292</a>) on chromosome Xp11.</p>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Description</strong>
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<p>IPEX is an X-linked recessive immunologic disorder characterized by onset in infancy of severe diarrhea due to enteropathy, type 1 diabetes mellitus, and dermatitis. Other features may include hypothyroidism, autoimmune hemolytic anemia, thrombocytopenia, lymphadenopathy, hepatitis, and nephritis. The disorder may be fatal before age 2 years if not aggressively treated. Long-term therapeutic options include immunosuppression and hematopoietic stem cell transplantation (review by <a href="#7" class="mim-tip-reference" title="d'Hennezel, E., Bin Dhuban, K., Torgerson, T., Piccirillo, C. A. <strong>The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome.</strong> J. Med. Genet. 49: 291-302, 2012. Note: Erratum: J. Med. Genet. 49: 784 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22581967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22581967</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-100759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22581967">d'Hennezel et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22581967" 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 Features</strong>
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<p><a href="#21" class="mim-tip-reference" title="Powell, B. R., Buist, N. R. M., Stenzel, P. <strong>An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy.</strong> J. Pediat. 100: 731-737, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7040622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7040622</a>] [<a href="https://doi.org/10.1016/s0022-3476(82)80573-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7040622">Powell et al. (1982)</a> described a 'new' X-linked syndrome in a large kindred in which 8 males in 3 generations connected through females had various combinations of intractable diarrhea, eczema, hemolytic anemia, diabetes mellitus, or thyroid autoimmunity. Exaggerated responses to viral infections were noted. Only 2 of the 8 survived the first decade. Death in infancy or early childhood occurred in 11 additional males in the kindred; these occurred with infections or shortly after immunizations. B-cell function, T-cell numbers, polymorph chemotaxis, and complement concentrations were normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7040622" 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="#23" class="mim-tip-reference" title="Satake, N., Nakanishi, M., Okano, M., Tomizawa, K., Ishizaka, A., Kojima, K., Onodera, M., Ariga, T., Satake, A., Sakiyama, Y., Ishikawa, N., Matsumoto, S. <strong>A Japanese family of X-linked auto-immune enteropathy with haemolytic anaemia and polyendocrinopathy.</strong> Europ. J. Pediat. 152: 313-315, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8482279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8482279</a>] [<a href="https://doi.org/10.1007/BF01956741" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8482279">Satake et al. (1993)</a> described a Japanese family in which 2 brothers and their maternal uncle suffered from a presumably X-linked autoimmune enteropathy with hemolytic anemia and polyendocrinopathy. Two of the boys died from severe diarrhea accompanied by total or subtotal intestinal villous atrophy. The third affected male showed the same symptoms and had circulating IgG antibodies against enterocytes, but his condition improved dramatically and he became well following the use of cyclosporin A (CSA). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8482279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Peake, J. E., McCrossin, R. B., Byrne, G., Shepard, R. <strong>X-linked immune dysregulation, neonatal insulin dependent diabetes, and intractable diarrhoea.</strong> Arch. Dis. Child. Fetal Neonatal Ed. 74: F195-199, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8777684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8777684</a>] [<a href="https://doi.org/10.1136/fn.74.3.f195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8777684">Peake et al. (1996)</a> reported the cases of 4 related male infants who presented with neonatal diabetes mellitus, immune dysregulation with extremely high concentrations of immunoglobulin E, and intractable diarrhea. All of the infants were from 1 family, and all of them died. They had an exfoliative skin eruption and frequent infections. The diabetes was insulin-dependent and very difficult to regulate. One of the patients sustained a cardiac arrest 10 minutes after he was 'introduced to a branched chain amino acid supplement.' He was believed to have had an anaphylactic reaction to the formula. Necropsy showed apparent agenesis of the islets of Langerhans, a normal exocrine pancreas, normal small bowel, generalized mild to moderate lymphoid hyperplasia, and low-grade, nonspecific hepatitis. In a second case, the child died at 19 months of age from overwhelming sepsis. A third boy died at 10 weeks of age. Postmortem examination showed no macroscopic abnormalities; microscopic specimens were not available for interpretation. The same disorder may have been described by <a href="#17" class="mim-tip-reference" title="Meyer, B., Nezelof, C., Lemoine, N. I., Charlas, J., Caille, B., Viallate, J. <strong>A propos de deux cas de diabete neonatal.</strong> Ann. Pediat. 17: 569-573, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5460170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5460170</a>]" pmid="5460170">Meyer et al. (1970)</a>. Two brothers had absent islet cells, neonatal IDDM, diarrhea, and failure to thrive. One brother had numerous infections (including fungal infections, thigh abscess, and discharging ears) and died at 4 months; the other died at 32 days, also of infection. The mother had 10 brothers who died of unknown causes in infancy, and a healthy sister. Some of the features were similar to those of Omenn syndrome (<a href="/entry/603554">603554</a>), but diabetes does not occur in that disorder which is inherited as an autosomal recessive. The disorder in this family appeared to be X-linked recessive. The 4 affected males occurred in separate sibships in 3 generations, connected through presumably carrier females. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5460170+8777684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Goulet, O. J., Brousse, N., Canioni, D., Walker-Smith, J. A., Schmitz, J., Phillips, A. D. <strong>Syndrome of intractable diarrhoea with persistent villous atrophy in early childhood: a clinicopathological survey of 47 cases.</strong> J. Pediat. Gastroent. Nutr. 26: 151-161, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9481629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9481629</a>] [<a href="https://doi.org/10.1097/00005176-199802000-00006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9481629">Goulet et al. (1998)</a> studied the clinical and histopathologic features of 47 infants with intractable diarrhea and villous atrophy of varying degrees, dividing them into 2 groups, with or without lamina propria mononuclear cell infiltration. Of the 24 patients with an infiltrate, 12 had extraintestinal manifestations of autoimmunity, including arthritis, diabetes, nephrotic syndrome, dermatitis, anemia, thrombocytopenia, and tended to have a later onset of diarrhea (median, 5 months of age) with larger volumes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9481629" 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>Additional families were reported by <a href="#22" class="mim-tip-reference" title="Roberts, J., Searle, J. <strong>Neonatal diabetes mellitus associated with severe diarrhea, hyperimmunoglobulin E syndrome, and absence of islets of Langerhans.</strong> Pediat. Path. Lab. Med. 15: 477-483, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8597835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8597835</a>] [<a href="https://doi.org/10.3109/15513819509026984" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8597835">Roberts and Searle (1995)</a> and <a href="#8" class="mim-tip-reference" title="Di Rocco, M., Marta, R. <strong>X-linked immune dysregulation, neonatal insulin dependent diabetes, and intractable diarrhoea.</strong> Arch. Dis. Child. Fetal Neonatal Ed. 75: F144 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8949705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8949705</a>] [<a href="https://doi.org/10.1136/fn.75.2.f144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8949705">Di Rocco and Marta (1996)</a>. Most of the affected males developed autoimmune phenomena and immunologic abnormalities within the first 6 months of life, and most died within the first year of life. Immunologic abnormalities were highly variable, but intermittent eosinophilia and elevated IgE levels were documented in several patients. <a href="#11" class="mim-tip-reference" title="Ferguson, P. J., Blanton, S. H., Saulsbury, F. T., McDuffie, M. J., Lemahieu, V., Gastier, J. M., Francke, U., Borowitz, S. M., Sutphen, J. L., Kelly, T. E. <strong>Manifestations and linkage analysis in X-Linked autoimmunity-immunodeficiency syndrome.</strong> Am. J. Med. Genet. 90: 390-397, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10706361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10706361</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000228)90:5<390::aid-ajmg9>3.0.co;2-m" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10706361">Ferguson et al. (2000)</a> identified a family with a similar X-linked disorder characterized by autoimmunity and variable immunodeficiency. Affected males developed autoimmune endocrinopathy (type I diabetes mellitus and/or hypothyroidism), enteropathy characterized by villous atrophy, chronic dermatitis, and variable immunodeficiency. Only 1 affected male in this family survived beyond the age of 2 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8597835+8949705+10706361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Levy-Lahad, E., Wildin, R. S. <strong>Neonatal diabetes mellitus, enteropathy, thrombocytopenia, and endocrinopathy: further evidence for an X-linked lethal syndrome.</strong> J. Pediat. 138: 577-580, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11295725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11295725</a>] [<a href="https://doi.org/10.1067/mpd.2001.111502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11295725">Levy-Lahad and Wildin (2001)</a> described 2 premature male sibs and 1 maternal half brother with intrauterine growth retardation/failure to thrive, an inflammatory enteropathy presenting as bowel hypomobility with mucosal erosion and relatively primitive-appearing gut epithelium, endocrinopathy (neonatal diabetes mellitus in 2, hypothyroidism in 1, and parathyroid hormone resistance in 1), and thrombocytopenia and coagulopathy in 2. All died by 5 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11295725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Gambineri, E., Perroni, L., Passerini, L., Bianchi, L., Doglioni, C., Meschi, F., Bonfanti, R., Sznajer, Y., Tommasini, A., Lawitschka, A., Junker, A., Dunstheimer, D., and 13 others. <strong>Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity.</strong> J. Allergy Clin. Immun. 122: 1105-1112, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18951619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18951619</a>] [<a href="https://doi.org/10.1016/j.jaci.2008.09.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18951619">Gambineri et al. (2008)</a> reported the clinical features of 14 unrelated male patients with genetically confirmed IPEX syndrome. All patients presented with symptoms in the first year of life, mainly severe watery diarrhea due to enteropathy and/or hyperglycemia or ketoacidosis due to diabetes mellitus. Dermatitis or eczema was also common. Less common features included thyroid disease (3 patients), hemolytic anemia (3 patients), thrombocytopenia (2 patients), and hepatitis (3 patients). Immunologic studies before immunosuppressive treatment showed normal white blood cell counts and normal immunoglobulin levels, except in 1 patient who had intestinal protein loss. Most patients had increased serum IgE and eosinophilia, and many had serum autoantibodies despite immunosuppressive therapy. There was variable severity: 3 patients with null mutations or mutations in functional domains had a severe form of the disease, whereas patients with splicing mutations had a less severe form. However, there was no correlation between FOXP3 protein expression and disease severity, since nonfunctional mutant proteins were expressed at normal levels. <a href="#12" class="mim-tip-reference" title="Gambineri, E., Perroni, L., Passerini, L., Bianchi, L., Doglioni, C., Meschi, F., Bonfanti, R., Sznajer, Y., Tommasini, A., Lawitschka, A., Junker, A., Dunstheimer, D., and 13 others. <strong>Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity.</strong> J. Allergy Clin. Immun. 122: 1105-1112, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18951619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18951619</a>] [<a href="https://doi.org/10.1016/j.jaci.2008.09.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18951619">Gambineri et al. (2008)</a> suggested that patients who present in infancy with autoimmune enteropathy or diabetes should be screened for FOXP3 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18951619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Congenital Absence of Islets of Langerhans</em></strong></p><p>
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<a href="#14" class="mim-tip-reference" title="Jonas, M. M., Bell, M. D., Eidson, M. S., Koutouby, R., Hensley, G. T. <strong>Congenital diabetes mellitus and fatal secretory diarrhea in two infants.</strong> J. Pediat. Gastroent. Nutr. 13: 415-425, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1779317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1779317</a>] [<a href="https://doi.org/10.1097/00005176-199111000-00013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1779317">Jonas et al. (1991)</a> reported the cases of 2 unrelated male infants who presented in the first days of life with brittle insulin-dependent diabetes mellitus and subsequently developed severe secretory diarrhea with stool volumes of more than 100 ml/kg/day. No etiology or effective therapy was discovered for the diarrhea and both infants succumbed to septicemia, malnutrition, and poor control of hyperglycemia. At autopsy, both were found to have absence of islets of Langerhans in the pancreas and diffuse dysplastic changes in the mucosa of the small and large intestine. The entire alimentary tract in each case was lined by epithelia more typical of foregut mucosa: secretory-like glands, absent crypts of Lieberkuhn, and absent villi. One of the infants was Asian and one Caucasian. <a href="#17" class="mim-tip-reference" title="Meyer, B., Nezelof, C., Lemoine, N. I., Charlas, J., Caille, B., Viallate, J. <strong>A propos de deux cas de diabete neonatal.</strong> Ann. Pediat. 17: 569-573, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5460170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5460170</a>]" pmid="5460170">Meyer et al. (1970)</a> described congenital IDDM due to hypoplastic pancreas in 2 infant brothers who had 10 maternal uncles who had died in infancy of unknown causes. <a href="#9" class="mim-tip-reference" title="Dodge, J. A., Laurence, K. M. <strong>Congenital absence of islets of Langerhans.</strong> Arch. Dis. Child. 52: 411-419, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/326201/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">326201</a>] [<a href="https://doi.org/10.1136/adc.52.5.411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="326201">Dodge and Laurence (1977)</a> described congenital IDDM and absent islets in a male infant who died on the second day of life and whose brother was likewise very small for dates and died at the age of 40 days. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1779317+5460170+326201" 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="Eisenbarth, G. S., Gottlieb, P. A. <strong>Autoimmune polyendocrine syndromes.</strong> New Eng. J. Med. 350: 2068-2079, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15141045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15141045</a>] [<a href="https://doi.org/10.1056/NEJMra030158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15141045">Eisenbarth and Gottlieb (2004)</a> compared the features of 3 autoimmune polyendocrine syndromes: autoimmune polyendocrine syndrome type I (<a href="/entry/240300">240300</a>); autoimmune polyendocrine syndrome type II, or Schmidt syndrome (<a href="/entry/269200">269200</a>); and X-linked polyendocrinopathy with immune dysfunction and diarrhea. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15141045" 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="#24" class="mim-tip-reference" title="Seidman, E. G., Lacaille, F., Russo, P., Galeano, N., Murphy, G., Roy, C. C. <strong>Successful treatment of autoimmune enteropathy with cyclosporine.</strong> J. Pediat. 117: 929-932, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246696</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)80140-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2246696">Seidman et al. (1990)</a> had reported the successful treatment of autoimmune enteropathy with cyclosporin A (CSA). In the Japanese family described by <a href="#23" class="mim-tip-reference" title="Satake, N., Nakanishi, M., Okano, M., Tomizawa, K., Ishizaka, A., Kojima, K., Onodera, M., Ariga, T., Satake, A., Sakiyama, Y., Ishikawa, N., Matsumoto, S. <strong>A Japanese family of X-linked auto-immune enteropathy with haemolytic anaemia and polyendocrinopathy.</strong> Europ. J. Pediat. 152: 313-315, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8482279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8482279</a>] [<a href="https://doi.org/10.1007/BF01956741" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8482279">Satake et al. (1993)</a>, 1 of the 3 affected males became well following the use of CSA, although he showed the same symptoms as the others and had circulating IgG antibodies against enterocytes. <a href="#23" class="mim-tip-reference" title="Satake, N., Nakanishi, M., Okano, M., Tomizawa, K., Ishizaka, A., Kojima, K., Onodera, M., Ariga, T., Satake, A., Sakiyama, Y., Ishikawa, N., Matsumoto, S. <strong>A Japanese family of X-linked auto-immune enteropathy with haemolytic anaemia and polyendocrinopathy.</strong> Europ. J. Pediat. 152: 313-315, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8482279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8482279</a>] [<a href="https://doi.org/10.1007/BF01956741" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8482279">Satake et al. (1993)</a> stated that a patient in the family reported by <a href="#21" class="mim-tip-reference" title="Powell, B. R., Buist, N. R. M., Stenzel, P. <strong>An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy.</strong> J. Pediat. 100: 731-737, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7040622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7040622</a>] [<a href="https://doi.org/10.1016/s0022-3476(82)80573-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7040622">Powell et al. (1982)</a> developed autoimmune diabetes mellitus and was successfully treated with CSA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8482279+7040622+2246696" 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>Supportive therapy with total parenteral nutrition, insulin, and blood transfusions is beneficial in patients with IPEX, and prolonged immunosuppressive therapy with steroids and cyclosporin has been attempted. Nevertheless, the prognosis is poor and most reported cases have been fatal. <a href="#1" class="mim-tip-reference" title="Baud, O., Goulet, O., Canioni, D., Le Deist, F., Radford, I., Rieu, D., Dupuis-Girod, S., Cerf-Bensussan, N., Cavazzana-Calvo, M., Brousse, N., Fischer, A., Casanova, J.-L. <strong>Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation.</strong> New Eng. J. Med. 344: 1758-1762, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11396442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11396442</a>] [<a href="https://doi.org/10.1056/NEJM200106073442304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11396442">Baud et al. (2001)</a> performed transplantation of allogeneic bone marrow from an HLA-identical family member in a Moroccan boy with IPEX. A brother had died at the age of 4.5 months from intractable diarrhea, thrombocytopenia, insulin-dependent diabetes mellitus, and ichthyosiform dermatitis. The proband had onset of persistent secretory diarrhea at the age of 4 weeks. Insulin-dependent diabetes mellitus was diagnosed at 2.5 months of age. Ichthyosis had been observed 2 weeks after birth. It became a widespread exfoliative skin eruption that responded partially to emollients and hydrocortisone cream. Hemolytic anemia was diagnosed at the age of 4 weeks. The patient was found to carry the F371C mutation in the FOXP3 gene (<a href="/entry/300292#0003">300292.0003</a>), inherited from his mother. Bone marrow transplantation from his HLA-identical sister who did not have the F371C mutation was performed at the age of 4 months. On day 19, analysis of sex chromosomes by fluorescence in situ hybridization showed that 95% of white cells were of the female XX genotype. Diarrhea improved and stools were normal 1 month after transplantation. Two weeks later, enteral feeding was successfully reinstated. Six months after bone marrow transplantation, the patient's diet was normal and was associated with a normal intestinal transit time. Duodenal, jejunal, and colonic biopsies showed normal tissues with recovered villous architecture and mucous membranes. Insulin therapy was stopped 7 days before bone marrow transplantation, the pretransplantation conditioning regimen having been associated with progressive improvement in blood glucose control. In this case, bone marrow transplantation was followed by a complete remission. The conditioning regimen, consisting of intravenous rabbit anti-T-lymphocyte globulin, oral busulfan, and intravenous cyclophosphamide, controlled most of the clinical and biologic features of the disease, including the diarrhea, hyperglycemia, and dermatitis. Engraftment probably facilitated a sustained remission, and the patient remained in clinical and biologic remission for more than 2 years after bone marrow transplantation. Unexplained rapidly progressive hemophagocytic syndrome, which proved fatal, occurred 29 months after bone marrow transplantation, when the child was nearly 3 years of age. <a href="#1" class="mim-tip-reference" title="Baud, O., Goulet, O., Canioni, D., Le Deist, F., Radford, I., Rieu, D., Dupuis-Girod, S., Cerf-Bensussan, N., Cavazzana-Calvo, M., Brousse, N., Fischer, A., Casanova, J.-L. <strong>Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation.</strong> New Eng. J. Med. 344: 1758-1762, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11396442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11396442</a>] [<a href="https://doi.org/10.1056/NEJM200106073442304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11396442">Baud et al. (2001)</a> stated that there were only 3 known long-term survivors of this disease (<a href="#21" class="mim-tip-reference" title="Powell, B. R., Buist, N. R. M., Stenzel, P. <strong>An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy.</strong> J. Pediat. 100: 731-737, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7040622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7040622</a>] [<a href="https://doi.org/10.1016/s0022-3476(82)80573-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7040622">Powell et al., 1982</a>; <a href="#23" class="mim-tip-reference" title="Satake, N., Nakanishi, M., Okano, M., Tomizawa, K., Ishizaka, A., Kojima, K., Onodera, M., Ariga, T., Satake, A., Sakiyama, Y., Ishikawa, N., Matsumoto, S. <strong>A Japanese family of X-linked auto-immune enteropathy with haemolytic anaemia and polyendocrinopathy.</strong> Europ. J. Pediat. 152: 313-315, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8482279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8482279</a>] [<a href="https://doi.org/10.1007/BF01956741" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8482279">Satake et al., 1993</a>; <a href="#24" class="mim-tip-reference" title="Seidman, E. G., Lacaille, F., Russo, P., Galeano, N., Murphy, G., Roy, C. C. <strong>Successful treatment of autoimmune enteropathy with cyclosporine.</strong> J. Pediat. 117: 929-932, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246696</a>] [<a href="https://doi.org/10.1016/s0022-3476(05)80140-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2246696">Seidman et al., 1990</a>; <a href="#26" class="mim-tip-reference" title="Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.-L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Bricarelli, F. D., Byrne, G., McEuen, M., Proll, S., Appleby, M., Brunkow, M. E. <strong>X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.</strong> Nature Genet. 27: 18-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137992</a>] [<a href="https://doi.org/10.1038/83707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137992">Wildin et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8482279+11137992+7040622+11396442+2246696" 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="#25" class="mim-tip-reference" title="Shigeoka, A. O., Chance, P. F., Fain, P. R., Barker, D. F., Book, L. S., Rallison, M. L. <strong>Regional localization of a novel X-linked immunodeficiency with autoimmune disease and endocrinopathies to the Wiskott-Aldrich locus Xp11.2 (Abstract)</strong> Pediat. Res. 33S: 158A only, 1993."None>Shigeoka et al. (1993)</a> reported that the locus for this disorder maps to Xp11.2, where the Wiskott-Aldrich syndrome gene (WAS; <a href="/entry/301000">301000</a>) had been assigned. <a href="#11" class="mim-tip-reference" title="Ferguson, P. J., Blanton, S. H., Saulsbury, F. T., McDuffie, M. J., Lemahieu, V., Gastier, J. M., Francke, U., Borowitz, S. M., Sutphen, J. L., Kelly, T. E. <strong>Manifestations and linkage analysis in X-Linked autoimmunity-immunodeficiency syndrome.</strong> Am. J. Med. Genet. 90: 390-397, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10706361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10706361</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000228)90:5<390::aid-ajmg9>3.0.co;2-m" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10706361">Ferguson et al. (2000)</a> performed linkage analysis on 20 members of an affected kindred. Informative recombinations limited the region of the locus to an approximately 20-cM interval bordered by DXS1055 and DXS1196/DXS1050. Multipoint analysis demonstrated a lod score greater than 3 for the region contained between DXS8024 and DXS8031, mapping the locus to the pericentromeric region Xp11.23-q21.1. Evaluation of the WAS gene by SSCP analysis, heteroduplex analysis, and direct sequencing of the 12 exons in an affected male and 2 carrier females revealed no abnormalities. <a href="#11" class="mim-tip-reference" title="Ferguson, P. J., Blanton, S. H., Saulsbury, F. T., McDuffie, M. J., Lemahieu, V., Gastier, J. M., Francke, U., Borowitz, S. M., Sutphen, J. L., Kelly, T. E. <strong>Manifestations and linkage analysis in X-Linked autoimmunity-immunodeficiency syndrome.</strong> Am. J. Med. Genet. 90: 390-397, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10706361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10706361</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000228)90:5<390::aid-ajmg9>3.0.co;2-m" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10706361">Ferguson et al. (2000)</a> concluded that this kindred has an X-linked disorder, distinct from Wiskott-Aldrich syndrome, that results in autoimmunity and variable immunodeficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10706361" 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>By linkage analysis in a large pedigree, <a href="#3" class="mim-tip-reference" title="Bennett, C. L., Yoshioka, R., Kiyosawa, H., Barker, D. F., Fain, P. R., Shigeoka, A. O., Chance, P. F. <strong>X-linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea maps to Xp11.23-Xq13.3.</strong> Am. J. Hum. Genet. 66: 461-468, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677306</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677306[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677306">Bennett et al. (2000)</a> mapped the locus for X-linked polyendocrinopathy, immune dysfunction, and diarrhea (IPEX) to a 17-cM interval defined by markers DXS8083 and DXS8107 at Xp11.23-q13.3. The maximum lod score was 3.99 with DXS1235 at theta of 0.0. No mutations were identified in the WAS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677306" 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="#5" class="mim-tip-reference" title="Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C., Bowcock, A. M. <strong>JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation (sic) syndrome.</strong> J. Clin. Invest. 106: R75-R81, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI11679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11120765">Chatila et al. (2000)</a> referred to this disorder as X-linked autoimmunity-allergic dysregulation syndrome (XLAAD). Consistent with the allergic phenotype, analysis of 2 kindreds with this disorder revealed marked skewing of patient T lymphocytes toward the Th2 phenotype. Using a positional-candidate approach, they identified in both kindreds mutations in JM2 (called by others FOXP3; <a href="/entry/300292">300292</a>), which encodes a forkhead domain-containing protein. One kindred carried a splice junction mutation; the other involved an in-frame, 3-bp deletion that was predicted to impair the function of a leucine zipper dimerization domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11120765" 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="#26" class="mim-tip-reference" title="Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.-L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Bricarelli, F. D., Byrne, G., McEuen, M., Proll, S., Appleby, M., Brunkow, M. E. <strong>X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.</strong> Nature Genet. 27: 18-20, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137992</a>] [<a href="https://doi.org/10.1038/83707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137992">Wildin et al. (2001)</a> identified mutations in the FOXP3 gene in patients with IPEX, including those reported by <a href="#15" class="mim-tip-reference" title="Levy-Lahad, E., Wildin, R. S. <strong>Neonatal diabetes mellitus, enteropathy, thrombocytopenia, and endocrinopathy: further evidence for an X-linked lethal syndrome.</strong> J. Pediat. 138: 577-580, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11295725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11295725</a>] [<a href="https://doi.org/10.1067/mpd.2001.111502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11295725">Levy-Lahad and Wildin (2001)</a>. <a href="#2" class="mim-tip-reference" title="Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., Ochs, H. D. <strong>The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.</strong> Nature Genet. 27: 20-21, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137993</a>] [<a href="https://doi.org/10.1038/83713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137993">Bennett et al. (2001)</a> also identified mutations in the FOXP3 gene in patients with IPEX. See <a href="/entry/300292#0001">300292.0001</a>-<a href="/entry/300292#0005">300292.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11137993+11137992+11295725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 1 of the families studied by <a href="#18" class="mim-tip-reference" title="Owen, C. J., Jennings, C. E., Imrie, H., Lachaux, A., Bridges, N. A., Cheetham, T. D., Pearce, S. H. S. <strong>Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome.</strong> J. Clin. Endocr. Metab. 88: 6034-6039, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14671208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14671208</a>] [<a href="https://doi.org/10.1210/jc.2003-031080" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14671208">Owen et al. (2003)</a>, the FOXP3 locus was excluded by recombination, and no FOXP3 mutations were found. The authors concluded that their data provided evidence for a nonlinked autosomal locus, suggesting genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14671208" 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>'Scurfy' (sf) is an X-linked recessive mouse mutant that results in lethality in hemizygous males 16 to 25 days after birth and is characterized by overproliferation of CD4+/CD8- T lymphocytes, extensive multiorgan infiltration, and elevation of numerous cytokines (<a href="#16" class="mim-tip-reference" title="Lyon, M. F., Peters, J., Glenister, P. H., Ball, S., Wright, E. <strong>The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome.</strong> Proc. Nat. Acad. Sci. 87: 2433-2437, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2320565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2320565</a>] [<a href="https://doi.org/10.1073/pnas.87.7.2433" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2320565">Lyon et al., 1990</a>; <a href="#6" class="mim-tip-reference" title="Clark, L. B., Appleby, M. W., Brunkow, M. E., Wilkinson, J. E., Ziegler, S. F., Ramsdell, F. <strong>Cellular and molecular characterization of the scurfy mouse mutant.</strong> J. Immun. 162: 2546-2554, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10072494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10072494</a>]" pmid="10072494">Clark et al., 1999</a>). Similar to animals that lack expression of either Ctla4 (<a href="/entry/123890">123890</a>) or Tgf-beta (TGFB1; <a href="/entry/190180">190180</a>), the pathology observed in sf mice seems to result from an inability to regulate properly CD4+/CD8- T-cell activity. By combining high-resolution genetic and physical mapping with large-scale sequence analysis, <a href="#4" class="mim-tip-reference" title="Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S.-A., Wilkinson, J. E., Galas, D., Ziegler, S. F., Ramsdell, F. <strong>Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.</strong> Nature Genet. 27: 68-73, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11138001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11138001</a>] [<a href="https://doi.org/10.1038/83784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11138001">Brunkow et al. (2001)</a> identified the gene defective in sf mice. The protein encoded by this gene, designated Foxp3, is a new member of the forkhead/winged-helix family of transcriptional regulators and is highly conserved in humans. In sf mice, a frameshift mutation results in a product lacking the forkhead domain. Genetic complementation demonstrated that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2320565+10072494+11138001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Patel, D. D. <strong>Escape from tolerance in the human X-linked autoimmunity-allergic disregulation (sic) syndrome and the scurfy mouse.</strong> J. Clin. Invest. 107: 155-157, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11160129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11160129</a>] [<a href="https://doi.org/10.1172/JCI11966" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11160129">Patel (2001)</a> discussed the escape from tolerance in XLAAD and in the 'scurfy' mouse. Options for treatment of the disorder are limited to immunosuppressive agents and supportive care, with death usually occurring within the first year of life. Consistent with the decreased sensitivity of scurfy T cells to cyclosporin A, cyclosporin is often not effective in controlling XLAAD. <a href="#19" class="mim-tip-reference" title="Patel, D. D. <strong>Escape from tolerance in the human X-linked autoimmunity-allergic disregulation (sic) syndrome and the scurfy mouse.</strong> J. Clin. Invest. 107: 155-157, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11160129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11160129</a>] [<a href="https://doi.org/10.1172/JCI11966" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11160129">Patel (2001)</a> referred to the observation in the scurfy mouse that normal cells can control scurfy T cells and prevent disease manifestation. Thus, using minimally toxic, nonmyeloablative conditioning regimens followed by transplantation of normal allogeneic stem cells to induce mixed chimerism may be an effective treatment strategy for XLAAD. Alternatively, XLAAD may be one of the diseases that respond well to gene therapy, since a small percentage of wildtype T cells may be sufficient to control the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11160129" 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="#27" class="mim-tip-reference" title="Wildin, R. S. <strong>Personal Communication.</strong> Portland, Ore. 7/2/2001."None>Wildin (2001)</a> pointed out that the 'I' in IPEX now stands for 'immunodysregulation' rather than 'immunodeficiency' because patients have shown immunodeficiency only when taking immunosuppressive drugs.</p><p><a href="#5" class="mim-tip-reference" title="Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C., Bowcock, A. M. <strong>JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation (sic) syndrome.</strong> J. Clin. Invest. 106: R75-R81, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120765[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI11679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11120765">Chatila et al. (2000)</a> incorrectly referred to this as a 'disregulation' syndrome. They presumably meant 'dysregulation' syndrome. The prefix 'dis' refers to separation or division; the prefix 'dys,' appropriate here, refers to abnormal or deranged. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11120765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1038/83784" target="_blank">Full Text</a>]
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Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C., Bowcock, A. M.
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<strong>JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation (sic) syndrome.</strong>
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J. Clin. Invest. 106: R75-R81, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120765</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120765[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=11120765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(20000228)90:5<390::aid-ajmg9>3.0.co;2-m" target="_blank">Full Text</a>]
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<strong>Neonatal diabetes mellitus, enteropathy, thrombocytopenia, and endocrinopathy: further evidence for an X-linked lethal syndrome.</strong>
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J. Pediat. 138: 577-580, 2001.
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[<a href="https://doi.org/10.1067/mpd.2001.111502" target="_blank">Full Text</a>]
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<a id="Lyon1990" class="mim-anchor"></a>
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Lyon, M. F., Peters, J., Glenister, P. H., Ball, S., Wright, E.
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<strong>The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2320565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2320565</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2320565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.87.7.2433" target="_blank">Full Text</a>]
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<a id="Meyer1970" class="mim-anchor"></a>
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Meyer, B., Nezelof, C., Lemoine, N. I., Charlas, J., Caille, B., Viallate, J.
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<strong>A propos de deux cas de diabete neonatal.</strong>
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<a id="Owen2003" class="mim-anchor"></a>
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Owen, C. J., Jennings, C. E., Imrie, H., Lachaux, A., Bridges, N. A., Cheetham, T. D., Pearce, S. H. S.
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<strong>Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome.</strong>
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J. Clin. Endocr. Metab. 88: 6034-6039, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14671208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14671208</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14671208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1210/jc.2003-031080" target="_blank">Full Text</a>]
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<a id="Patel2001" class="mim-anchor"></a>
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Patel, D. D.
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<strong>Escape from tolerance in the human X-linked autoimmunity-allergic disregulation (sic) syndrome and the scurfy mouse.</strong>
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J. Clin. Invest. 107: 155-157, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11160129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11160129</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11160129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI11966" target="_blank">Full Text</a>]
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Peake, J. E., McCrossin, R. B., Byrne, G., Shepard, R.
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<strong>X-linked immune dysregulation, neonatal insulin dependent diabetes, and intractable diarrhoea.</strong>
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Arch. Dis. Child. Fetal Neonatal Ed. 74: F195-199, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8777684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8777684</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8777684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/fn.74.3.f195" target="_blank">Full Text</a>]
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Powell, B. R., Buist, N. R. M., Stenzel, P.
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<strong>An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy.</strong>
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J. Pediat. 100: 731-737, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7040622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7040622</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7040622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(82)80573-8" target="_blank">Full Text</a>]
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<a id="Roberts1995" class="mim-anchor"></a>
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Roberts, J., Searle, J.
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<strong>Neonatal diabetes mellitus associated with severe diarrhea, hyperimmunoglobulin E syndrome, and absence of islets of Langerhans.</strong>
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Pediat. Path. Lab. Med. 15: 477-483, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8597835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8597835</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8597835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.3109/15513819509026984" target="_blank">Full Text</a>]
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<a id="Satake1993" class="mim-anchor"></a>
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Satake, N., Nakanishi, M., Okano, M., Tomizawa, K., Ishizaka, A., Kojima, K., Onodera, M., Ariga, T., Satake, A., Sakiyama, Y., Ishikawa, N., Matsumoto, S.
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<strong>A Japanese family of X-linked auto-immune enteropathy with haemolytic anaemia and polyendocrinopathy.</strong>
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Europ. J. Pediat. 152: 313-315, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8482279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8482279</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8482279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF01956741" target="_blank">Full Text</a>]
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Seidman, E. G., Lacaille, F., Russo, P., Galeano, N., Murphy, G., Roy, C. C.
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<strong>Successful treatment of autoimmune enteropathy with cyclosporine.</strong>
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J. Pediat. 117: 929-932, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246696</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2246696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(05)80140-4" target="_blank">Full Text</a>]
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Shigeoka, A. O., Chance, P. F., Fain, P. R., Barker, D. F., Book, L. S., Rallison, M. L.
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<strong>Regional localization of a novel X-linked immunodeficiency with autoimmune disease and endocrinopathies to the Wiskott-Aldrich locus Xp11.2 (Abstract)</strong>
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Pediat. Res. 33S: 158A only, 1993.
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Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.-L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Bricarelli, F. D., Byrne, G., McEuen, M., Proll, S., Appleby, M., Brunkow, M. E.
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<strong>X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.</strong>
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Nature Genet. 27: 18-20, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137992</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/83707" target="_blank">Full Text</a>]
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Wildin, R. S.
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<strong>Personal Communication.</strong>
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Portland, Ore. 7/2/2001.
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Cassandra L. Kniffin - updated : 11/6/2014
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 8/23/2012<br>Marla J. F. O'Neill - updated : 1/12/2010<br>John A. Phillips, III - updated : 4/1/2005<br>Natalie E. Krasikov - updated : 2/10/2004<br>Victor A. McKusick - updated : 5/28/2003<br>Victor A. McKusick - updated : 12/5/2001
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<span class="mim-text-font">
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Victor A. McKusick : 2/21/1992
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alopez : 08/08/2023
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alopez : 03/21/2022<br>carol : 11/21/2014<br>mcolton : 11/10/2014<br>ckniffin : 11/6/2014<br>carol : 1/25/2013<br>carol : 8/28/2012<br>ckniffin : 8/23/2012<br>carol : 1/12/2010<br>carol : 4/17/2009<br>alopez : 4/1/2005<br>tkritzer : 5/19/2004<br>carol : 2/10/2004<br>cwells : 6/4/2003<br>terry : 5/28/2003<br>alopez : 12/13/2001<br>terry : 12/5/2001<br>mimadm : 4/14/1994<br>warfield : 3/15/1994<br>supermim : 3/17/1992<br>carol : 2/26/1992<br>carol : 2/21/1992
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<strong>#</strong> 304790
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IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED; IPEX
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X-LINKED AUTOIMMUNITY-ALLERGIC DYSREGULATION SYNDROME; XLAAD<br />
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IDDM-SECRETORY DIARRHEA SYNDROME; DMSD<br />
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AUTOIMMUNITY-IMMUNODEFICIENCY SYNDROME, X-LINKED<br />
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DIARRHEA, POLYENDOCRINOPATHY, FATAL INFECTION SYNDROME, X-LINKED<br />
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ENTEROPATHY, AUTOIMMUNE, WITH HEMOLYTIC ANEMIA AND POLYENDOCRINOPATHY<br />
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POLYENDOCRINOPATHY, IMMUNE DYSFUNCTION, AND DIARRHEA, X-LINKED; XPID<br />
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DIABETES MELLITUS, CONGENITAL INSULIN-DEPENDENT, WITH FATAL SECRETORY DIARRHEA<br />
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IMMUNODEFICIENCY, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED, FORMERLY
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Other entities represented in this entry:
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<span class="h3 mim-font">
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ISLETS OF LANGERHANS, ABSENCE OF, INCLUDED
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<strong>SNOMEDCT:</strong> 724276006;
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<strong>ORPHA:</strong> 37042;
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<strong>DO:</strong> 0090110;
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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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<span class="mim-font">
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Xp11.23
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<span class="mim-font">
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Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked
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<span class="mim-font">
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304790
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<span class="mim-font">
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X-linked recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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FOXP3
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<span class="mim-font">
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300292
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because X-linked immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) is caused by mutation in the FOXP3 gene (300292) on chromosome Xp11.</p>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>IPEX is an X-linked recessive immunologic disorder characterized by onset in infancy of severe diarrhea due to enteropathy, type 1 diabetes mellitus, and dermatitis. Other features may include hypothyroidism, autoimmune hemolytic anemia, thrombocytopenia, lymphadenopathy, hepatitis, and nephritis. The disorder may be fatal before age 2 years if not aggressively treated. Long-term therapeutic options include immunosuppression and hematopoietic stem cell transplantation (review by d'Hennezel et al., 2012). </p>
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<strong>Clinical Features</strong>
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<p>Powell et al. (1982) described a 'new' X-linked syndrome in a large kindred in which 8 males in 3 generations connected through females had various combinations of intractable diarrhea, eczema, hemolytic anemia, diabetes mellitus, or thyroid autoimmunity. Exaggerated responses to viral infections were noted. Only 2 of the 8 survived the first decade. Death in infancy or early childhood occurred in 11 additional males in the kindred; these occurred with infections or shortly after immunizations. B-cell function, T-cell numbers, polymorph chemotaxis, and complement concentrations were normal. </p><p>Satake et al. (1993) described a Japanese family in which 2 brothers and their maternal uncle suffered from a presumably X-linked autoimmune enteropathy with hemolytic anemia and polyendocrinopathy. Two of the boys died from severe diarrhea accompanied by total or subtotal intestinal villous atrophy. The third affected male showed the same symptoms and had circulating IgG antibodies against enterocytes, but his condition improved dramatically and he became well following the use of cyclosporin A (CSA). </p><p>Peake et al. (1996) reported the cases of 4 related male infants who presented with neonatal diabetes mellitus, immune dysregulation with extremely high concentrations of immunoglobulin E, and intractable diarrhea. All of the infants were from 1 family, and all of them died. They had an exfoliative skin eruption and frequent infections. The diabetes was insulin-dependent and very difficult to regulate. One of the patients sustained a cardiac arrest 10 minutes after he was 'introduced to a branched chain amino acid supplement.' He was believed to have had an anaphylactic reaction to the formula. Necropsy showed apparent agenesis of the islets of Langerhans, a normal exocrine pancreas, normal small bowel, generalized mild to moderate lymphoid hyperplasia, and low-grade, nonspecific hepatitis. In a second case, the child died at 19 months of age from overwhelming sepsis. A third boy died at 10 weeks of age. Postmortem examination showed no macroscopic abnormalities; microscopic specimens were not available for interpretation. The same disorder may have been described by Meyer et al. (1970). Two brothers had absent islet cells, neonatal IDDM, diarrhea, and failure to thrive. One brother had numerous infections (including fungal infections, thigh abscess, and discharging ears) and died at 4 months; the other died at 32 days, also of infection. The mother had 10 brothers who died of unknown causes in infancy, and a healthy sister. Some of the features were similar to those of Omenn syndrome (603554), but diabetes does not occur in that disorder which is inherited as an autosomal recessive. The disorder in this family appeared to be X-linked recessive. The 4 affected males occurred in separate sibships in 3 generations, connected through presumably carrier females. </p><p>Goulet et al. (1998) studied the clinical and histopathologic features of 47 infants with intractable diarrhea and villous atrophy of varying degrees, dividing them into 2 groups, with or without lamina propria mononuclear cell infiltration. Of the 24 patients with an infiltrate, 12 had extraintestinal manifestations of autoimmunity, including arthritis, diabetes, nephrotic syndrome, dermatitis, anemia, thrombocytopenia, and tended to have a later onset of diarrhea (median, 5 months of age) with larger volumes. </p><p>Additional families were reported by Roberts and Searle (1995) and Di Rocco and Marta (1996). Most of the affected males developed autoimmune phenomena and immunologic abnormalities within the first 6 months of life, and most died within the first year of life. Immunologic abnormalities were highly variable, but intermittent eosinophilia and elevated IgE levels were documented in several patients. Ferguson et al. (2000) identified a family with a similar X-linked disorder characterized by autoimmunity and variable immunodeficiency. Affected males developed autoimmune endocrinopathy (type I diabetes mellitus and/or hypothyroidism), enteropathy characterized by villous atrophy, chronic dermatitis, and variable immunodeficiency. Only 1 affected male in this family survived beyond the age of 2 years. </p><p>Levy-Lahad and Wildin (2001) described 2 premature male sibs and 1 maternal half brother with intrauterine growth retardation/failure to thrive, an inflammatory enteropathy presenting as bowel hypomobility with mucosal erosion and relatively primitive-appearing gut epithelium, endocrinopathy (neonatal diabetes mellitus in 2, hypothyroidism in 1, and parathyroid hormone resistance in 1), and thrombocytopenia and coagulopathy in 2. All died by 5 months of age. </p><p>Gambineri et al. (2008) reported the clinical features of 14 unrelated male patients with genetically confirmed IPEX syndrome. All patients presented with symptoms in the first year of life, mainly severe watery diarrhea due to enteropathy and/or hyperglycemia or ketoacidosis due to diabetes mellitus. Dermatitis or eczema was also common. Less common features included thyroid disease (3 patients), hemolytic anemia (3 patients), thrombocytopenia (2 patients), and hepatitis (3 patients). Immunologic studies before immunosuppressive treatment showed normal white blood cell counts and normal immunoglobulin levels, except in 1 patient who had intestinal protein loss. Most patients had increased serum IgE and eosinophilia, and many had serum autoantibodies despite immunosuppressive therapy. There was variable severity: 3 patients with null mutations or mutations in functional domains had a severe form of the disease, whereas patients with splicing mutations had a less severe form. However, there was no correlation between FOXP3 protein expression and disease severity, since nonfunctional mutant proteins were expressed at normal levels. Gambineri et al. (2008) suggested that patients who present in infancy with autoimmune enteropathy or diabetes should be screened for FOXP3 mutations. </p><p><strong><em>Congenital Absence of Islets of Langerhans</em></strong></p><p>
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Jonas et al. (1991) reported the cases of 2 unrelated male infants who presented in the first days of life with brittle insulin-dependent diabetes mellitus and subsequently developed severe secretory diarrhea with stool volumes of more than 100 ml/kg/day. No etiology or effective therapy was discovered for the diarrhea and both infants succumbed to septicemia, malnutrition, and poor control of hyperglycemia. At autopsy, both were found to have absence of islets of Langerhans in the pancreas and diffuse dysplastic changes in the mucosa of the small and large intestine. The entire alimentary tract in each case was lined by epithelia more typical of foregut mucosa: secretory-like glands, absent crypts of Lieberkuhn, and absent villi. One of the infants was Asian and one Caucasian. Meyer et al. (1970) described congenital IDDM due to hypoplastic pancreas in 2 infant brothers who had 10 maternal uncles who had died in infancy of unknown causes. Dodge and Laurence (1977) described congenital IDDM and absent islets in a male infant who died on the second day of life and whose brother was likewise very small for dates and died at the age of 40 days. </p><p>Eisenbarth and Gottlieb (2004) compared the features of 3 autoimmune polyendocrine syndromes: autoimmune polyendocrine syndrome type I (240300); autoimmune polyendocrine syndrome type II, or Schmidt syndrome (269200); and X-linked polyendocrinopathy with immune dysfunction and diarrhea. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Management</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Seidman et al. (1990) had reported the successful treatment of autoimmune enteropathy with cyclosporin A (CSA). In the Japanese family described by Satake et al. (1993), 1 of the 3 affected males became well following the use of CSA, although he showed the same symptoms as the others and had circulating IgG antibodies against enterocytes. Satake et al. (1993) stated that a patient in the family reported by Powell et al. (1982) developed autoimmune diabetes mellitus and was successfully treated with CSA. </p><p>Supportive therapy with total parenteral nutrition, insulin, and blood transfusions is beneficial in patients with IPEX, and prolonged immunosuppressive therapy with steroids and cyclosporin has been attempted. Nevertheless, the prognosis is poor and most reported cases have been fatal. Baud et al. (2001) performed transplantation of allogeneic bone marrow from an HLA-identical family member in a Moroccan boy with IPEX. A brother had died at the age of 4.5 months from intractable diarrhea, thrombocytopenia, insulin-dependent diabetes mellitus, and ichthyosiform dermatitis. The proband had onset of persistent secretory diarrhea at the age of 4 weeks. Insulin-dependent diabetes mellitus was diagnosed at 2.5 months of age. Ichthyosis had been observed 2 weeks after birth. It became a widespread exfoliative skin eruption that responded partially to emollients and hydrocortisone cream. Hemolytic anemia was diagnosed at the age of 4 weeks. The patient was found to carry the F371C mutation in the FOXP3 gene (300292.0003), inherited from his mother. Bone marrow transplantation from his HLA-identical sister who did not have the F371C mutation was performed at the age of 4 months. On day 19, analysis of sex chromosomes by fluorescence in situ hybridization showed that 95% of white cells were of the female XX genotype. Diarrhea improved and stools were normal 1 month after transplantation. Two weeks later, enteral feeding was successfully reinstated. Six months after bone marrow transplantation, the patient's diet was normal and was associated with a normal intestinal transit time. Duodenal, jejunal, and colonic biopsies showed normal tissues with recovered villous architecture and mucous membranes. Insulin therapy was stopped 7 days before bone marrow transplantation, the pretransplantation conditioning regimen having been associated with progressive improvement in blood glucose control. In this case, bone marrow transplantation was followed by a complete remission. The conditioning regimen, consisting of intravenous rabbit anti-T-lymphocyte globulin, oral busulfan, and intravenous cyclophosphamide, controlled most of the clinical and biologic features of the disease, including the diarrhea, hyperglycemia, and dermatitis. Engraftment probably facilitated a sustained remission, and the patient remained in clinical and biologic remission for more than 2 years after bone marrow transplantation. Unexplained rapidly progressive hemophagocytic syndrome, which proved fatal, occurred 29 months after bone marrow transplantation, when the child was nearly 3 years of age. Baud et al. (2001) stated that there were only 3 known long-term survivors of this disease (Powell et al., 1982; Satake et al., 1993; Seidman et al., 1990; Wildin et al., 2001). </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Shigeoka et al. (1993) reported that the locus for this disorder maps to Xp11.2, where the Wiskott-Aldrich syndrome gene (WAS; 301000) had been assigned. Ferguson et al. (2000) performed linkage analysis on 20 members of an affected kindred. Informative recombinations limited the region of the locus to an approximately 20-cM interval bordered by DXS1055 and DXS1196/DXS1050. Multipoint analysis demonstrated a lod score greater than 3 for the region contained between DXS8024 and DXS8031, mapping the locus to the pericentromeric region Xp11.23-q21.1. Evaluation of the WAS gene by SSCP analysis, heteroduplex analysis, and direct sequencing of the 12 exons in an affected male and 2 carrier females revealed no abnormalities. Ferguson et al. (2000) concluded that this kindred has an X-linked disorder, distinct from Wiskott-Aldrich syndrome, that results in autoimmunity and variable immunodeficiency. </p><p>By linkage analysis in a large pedigree, Bennett et al. (2000) mapped the locus for X-linked polyendocrinopathy, immune dysfunction, and diarrhea (IPEX) to a 17-cM interval defined by markers DXS8083 and DXS8107 at Xp11.23-q13.3. The maximum lod score was 3.99 with DXS1235 at theta of 0.0. No mutations were identified in the WAS gene. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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<span class="mim-text-font">
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<p>Chatila et al. (2000) referred to this disorder as X-linked autoimmunity-allergic dysregulation syndrome (XLAAD). Consistent with the allergic phenotype, analysis of 2 kindreds with this disorder revealed marked skewing of patient T lymphocytes toward the Th2 phenotype. Using a positional-candidate approach, they identified in both kindreds mutations in JM2 (called by others FOXP3; 300292), which encodes a forkhead domain-containing protein. One kindred carried a splice junction mutation; the other involved an in-frame, 3-bp deletion that was predicted to impair the function of a leucine zipper dimerization domain. </p><p>Wildin et al. (2001) identified mutations in the FOXP3 gene in patients with IPEX, including those reported by Levy-Lahad and Wildin (2001). Bennett et al. (2001) also identified mutations in the FOXP3 gene in patients with IPEX. See 300292.0001-300292.0005. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Heterogeneity</strong>
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</span>
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<span class="mim-text-font">
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<p>In 1 of the families studied by Owen et al. (2003), the FOXP3 locus was excluded by recombination, and no FOXP3 mutations were found. The authors concluded that their data provided evidence for a nonlinked autosomal locus, suggesting genetic heterogeneity. </p>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>'Scurfy' (sf) is an X-linked recessive mouse mutant that results in lethality in hemizygous males 16 to 25 days after birth and is characterized by overproliferation of CD4+/CD8- T lymphocytes, extensive multiorgan infiltration, and elevation of numerous cytokines (Lyon et al., 1990; Clark et al., 1999). Similar to animals that lack expression of either Ctla4 (123890) or Tgf-beta (TGFB1; 190180), the pathology observed in sf mice seems to result from an inability to regulate properly CD4+/CD8- T-cell activity. By combining high-resolution genetic and physical mapping with large-scale sequence analysis, Brunkow et al. (2001) identified the gene defective in sf mice. The protein encoded by this gene, designated Foxp3, is a new member of the forkhead/winged-helix family of transcriptional regulators and is highly conserved in humans. In sf mice, a frameshift mutation results in a product lacking the forkhead domain. Genetic complementation demonstrated that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis. </p><p>Patel (2001) discussed the escape from tolerance in XLAAD and in the 'scurfy' mouse. Options for treatment of the disorder are limited to immunosuppressive agents and supportive care, with death usually occurring within the first year of life. Consistent with the decreased sensitivity of scurfy T cells to cyclosporin A, cyclosporin is often not effective in controlling XLAAD. Patel (2001) referred to the observation in the scurfy mouse that normal cells can control scurfy T cells and prevent disease manifestation. Thus, using minimally toxic, nonmyeloablative conditioning regimens followed by transplantation of normal allogeneic stem cells to induce mixed chimerism may be an effective treatment strategy for XLAAD. Alternatively, XLAAD may be one of the diseases that respond well to gene therapy, since a small percentage of wildtype T cells may be sufficient to control the disease. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Wildin (2001) pointed out that the 'I' in IPEX now stands for 'immunodysregulation' rather than 'immunodeficiency' because patients have shown immunodeficiency only when taking immunosuppressive drugs.</p><p>Chatila et al. (2000) incorrectly referred to this as a 'disregulation' syndrome. They presumably meant 'dysregulation' syndrome. The prefix 'dis' refers to separation or division; the prefix 'dys,' appropriate here, refers to abnormal or deranged. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Baud, O., Goulet, O., Canioni, D., Le Deist, F., Radford, I., Rieu, D., Dupuis-Girod, S., Cerf-Bensussan, N., Cavazzana-Calvo, M., Brousse, N., Fischer, A., Casanova, J.-L.
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<strong>Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation.</strong>
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New Eng. J. Med. 344: 1758-1762, 2001.
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[PubMed: 11396442]
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[Full Text: https://doi.org/10.1056/NEJM200106073442304]
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</li>
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<li>
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<p class="mim-text-font">
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Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., Ochs, H. D.
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<strong>The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.</strong>
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Nature Genet. 27: 20-21, 2001.
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[PubMed: 11137993]
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[Full Text: https://doi.org/10.1038/83713]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bennett, C. L., Yoshioka, R., Kiyosawa, H., Barker, D. F., Fain, P. R., Shigeoka, A. O., Chance, P. F.
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<strong>X-linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea maps to Xp11.23-Xq13.3.</strong>
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Am. J. Hum. Genet. 66: 461-468, 2000.
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[PubMed: 10677306]
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[Full Text: https://doi.org/10.1086/302761]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S.-A., Wilkinson, J. E., Galas, D., Ziegler, S. F., Ramsdell, F.
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<strong>Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse.</strong>
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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