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<title>
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Entry
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- #615952 - AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 1; ADMIO1
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- OMIM
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<span class="h4">#615952</span>
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<strong>Table of Contents</strong>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/phenotypicSeries/PS615952"> <strong>Phenotypic Series</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="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=(AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET) OR (STAT3)" class="mim-tip-hint" title="Clinical Trials" 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=23366&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/gtr/all/tests/?term=615952[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=438159" 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>
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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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</span>
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</span>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1197362009<br />
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<strong>ORPHA:</strong> 438159<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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615952
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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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AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 1; ADMIO1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
|
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<span class="mim-font">
|
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<a href="/geneMap/17/576?start=-3&limit=10&highlight=576">
|
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17q21.2
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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Autoimmune disease, multisystem, infantile-onset, 1
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/615952"> 615952 </a>
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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STAT3
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/102582"> 102582 </a>
|
|
</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/615952" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<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')">
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<span class="sr-only">Toggle Dropdown</span>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS615952" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
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</div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/615952" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/615952" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
|
</div>
|
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|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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|
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<div>
|
|
<span class="mim-font">
|
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|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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|
|
</span>
|
|
</div>
|
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|
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</div>
|
|
|
|
</div>
|
|
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|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GROWTH </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Height </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Short stature <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422065006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422065006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237836003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237836003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237837007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237837007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E34.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E34.31</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R62.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R62.52</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.43" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.43</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349588&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349588</a>, <a href="https://bioportal.bioontology.org/search?q=C0013336&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013336</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003510</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Teeth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Dental anomalies (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0262444&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0262444</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000164" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000164</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000164" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000164</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Lung </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Interstitial pneumonitis (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1306604007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1306604007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64667001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64667001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J84.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J84.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/J84.89" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J84.89</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5887144&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5887144</a>, <a href="https://bioportal.bioontology.org/search?q=C0206061&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0206061</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006515" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006515</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006515" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006515</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Autoimmune enteropathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/235728001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">235728001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0341305&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0341305</a>]</span><br /> -
|
|
Celiac disease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/396331005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">396331005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K90.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K90.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/579.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">579.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1332802&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1332802</a>, <a href="https://bioportal.bioontology.org/search?q=C0007570&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007570</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002608" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002608</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002608" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002608</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Arthritis (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/3723001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">3723001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M19.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M19.90</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003864&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003864</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001369" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001369</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001369" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001369</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- 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 /> -
|
|
Dermatitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/703938007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">703938007</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=C0011603&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011603</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011123" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011123</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011123" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011123</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
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|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
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|
|
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|
|
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|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ENDOCRINE FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Type 1 diabetes mellitus <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><br /> -
|
|
Hypothyroidism (in some patients) <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 /> -
|
|
Delayed puberty (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/400003000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">400003000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/123526007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">123526007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E30.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E30.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034012&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034012</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000823" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000823</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000823" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000823</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">
|
|
|
|
- Autoimmune cytopenia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3274706&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3274706</a>]</span><br /> -
|
|
Autoimmune hemolytic anemia <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 /> -
|
|
Autoimmune thrombocytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128091003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128091003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13172003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13172003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D69.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D69.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/287.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">287.31</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242584&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242584</a>, <a href="https://bioportal.bioontology.org/search?q=C0398650&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0398650</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001973" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001973</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001973" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001973</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
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|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> IMMUNOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Serum autoantibodies <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014797&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014797</a>, <a href="https://bioportal.bioontology.org/search?q=C4760619&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4760619</a>]</span><br /> -
|
|
Recurrent infections (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/451991000124106" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">451991000124106</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239998&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239998</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002719" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002719</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002719" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002719</a>]</span><br /> -
|
|
Altered T-cell regulation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014798</a>]</span><br /> -
|
|
Hypogammaglobulinemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/119250001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">119250001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D80.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D80.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/279.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">279.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0086438&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0086438</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004313" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004313</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004313" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004313</a>]</span><br /> -
|
|
Increased numbers of double-negative T cells (CD4-, CD8-) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4314423&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4314423</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEOPLASIA </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Increased susceptibility to large granular lymphocytic T-cell leukemia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014796&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014796</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Onset in early childhood<br /> -
|
|
Variable features<br /> -
|
|
De novo gain-of-function mutation (in most patients)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the signal transducer and activator of transcription 3 gene (STAT3, <a href="/entry/102582#0008">102582.0008</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Autoimmune disease, multisystem, infantile-onset
|
|
- <a href="/phenotypicSeries/PS615952">PS615952</a>
|
|
- 3 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/491?start=-3&limit=10&highlight=491"> 2q11.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617006"> Autoimmune disease, multisystem, infantile-onset, 2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617006"> 617006 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176947"> ZAP70 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176947"> 176947 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/519?start=-3&limit=10&highlight=519"> 3q13.11 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620430"> Autoimmune disease, multisystem, infantile-onset, 3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620430"> 620430 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604491"> CBLB </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604491"> 604491 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
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<a href="/geneMap/17/576?start=-3&limit=10&highlight=576"> 17q21.2 </a>
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<a href="/entry/615952"> Autoimmune disease, multisystem, infantile-onset, 1 </a>
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<p>A number sign (#) is used with this entry because infantile-onset multisystem autoimmune disease-1 (ADMIO1) is caused by heterozygous gain-of-function mutation in the STAT3 gene (<a href="/entry/102582">102582</a>) on chromosome 17q21.</p><p>Heterozygous dominant-negative mutations in the STAT3 gene cause autosomal dominant hyper-IgE syndrome-1 with recurrent infections (HIES1; <a href="/entry/147060">147060</a>).</p>
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<p>Infantile-onset multisystem autoimmune disease-1 is characterized by early childhood onset of a spectrum of autoimmune disorders affecting multiple organs. Common manifestations include insulin-dependent diabetes mellitus and autoimmune enteropathy, or celiac disease, and autoimmune hematologic disorders. Other features include short stature and nonspecific dermatitis. More variable features include hypothyroidism, autoimmune arthritis, and delayed puberty. Some patients may show recurrent infections. The disorder results from an inborn error of cytokine signaling (summary by <a href="#1" class="mim-tip-reference" title="Flanagan, S. E., Haapaniemi, E., Russell, M. A., Caswell, R., Allen, H. L., De Franco, E., McDonald, T. J., Rajala, H., Ramelius, A., Barton, J., Heiskanen, K., Heiskanen-Kosma, T., and 11 others. <strong>Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.</strong> Nature Genet. 46: 812-814, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25038750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25038750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25038750[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/10.1038/ng.3040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25038750">Flanagan et al., 2014</a> and <a href="#4" class="mim-tip-reference" title="Milner, J. D., Vogel, T. P., Forbes, L., Ma, C. A., Stray-Pedersen, A., Niemela, J. E., Lyons, J. J., Engelhardt, K. R., Zhang, Y., Topcagic, N., Roberson, E. D. O., Matthews, H., and 32 others. <strong>Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.</strong> Blood 125: 591-599, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25359994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25359994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25359994[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/10.1182/blood-2014-09-602763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25359994">Milner et al., 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25038750+25359994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Infantile-Onset Multisystem Autoimmune Disease</em></strong></p><p>
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See also ADMIO2 (<a href="/entry/617006">617006</a>), caused by mutation in the ZAP70 gene (<a href="/entry/176947">176947</a>) on chromosome 2q12, and ADMIO3 (<a href="/entry/620430">620430</a>), caused by mutation in the CBLB gene (<a href="/entry/604491">604491</a>) on chromosome 3q13.</p>
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<p><a href="#1" class="mim-tip-reference" title="Flanagan, S. E., Haapaniemi, E., Russell, M. A., Caswell, R., Allen, H. L., De Franco, E., McDonald, T. J., Rajala, H., Ramelius, A., Barton, J., Heiskanen, K., Heiskanen-Kosma, T., and 11 others. <strong>Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.</strong> Nature Genet. 46: 812-814, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25038750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25038750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25038750[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/10.1038/ng.3040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25038750">Flanagan et al. (2014)</a> reported 5 unrelated patients with early-onset autoimmune disease. Three patients were diagnosed with type 1 insulin-dependent diabetes in the first weeks of life, and a fourth was diagnosed with diabetes at 43 weeks of age. Autoimmune enteropathy or celiac disease presented in the first 2 years of life in 3 patients. Additional autoimmune disorders diagnosed during childhood included autoimmune interstitial lung disease, juvenile-onset arthritis, and primary hypothyroidism. Other common features included short stature, eczema, delayed puberty, and dental abnormalities. Two patients had evidence of immunodeficiency with recurrent respiratory infections, and 1 patient developed large granular lymphocytic T-cell leukemia. Laboratory studies of 2 patients showed decreased numbers of regulatory T cells, and 1 patient had evidence of increased cytokine production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25038750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Haapaniemi, E. M., Kaustio, M., Rajala, H. L. M., van Adrichem, A. J., Kainulainen, L., Glumoff, V., Doffinger, R., Kuusanmaki, H., Heiskanen-Kosma, T., Trotta, L., Chiang, S., Kulmala, P., and 15 others. <strong>Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3.</strong> Blood 125: 639-648, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25349174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25349174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25349174[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/10.1182/blood-2014-04-570101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25349174">Haapaniemi et al. (2015)</a> reported further details of 2 of the patients reported by <a href="#1" class="mim-tip-reference" title="Flanagan, S. E., Haapaniemi, E., Russell, M. A., Caswell, R., Allen, H. L., De Franco, E., McDonald, T. J., Rajala, H., Ramelius, A., Barton, J., Heiskanen, K., Heiskanen-Kosma, T., and 11 others. <strong>Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.</strong> Nature Genet. 46: 812-814, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25038750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25038750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25038750[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/10.1038/ng.3040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25038750">Flanagan et al. (2014)</a> and presented a third patient with the disorder. All had recurrent infections and autoimmune features, 1 had lymphadenopathy, and 1 developed T-cell leukemia. The third patient was a 22-year-old woman with late-onset ADMIO. She had recurrent ear infections in childhood, but normal response to vaccination, including BCG. In her late teens, she presented with lymphocytic colitis, autoimmune thrombocytopenia, hypogammaglobulinemia, joint pain, eczema, and Mycobacterium avium pneumonia. Detailed laboratory studies of these patients showed increased numbers of double-negative (CD4-, CD8-) T cells, decreased dendritic, T regulatory, NK, and Th17 cells, as well as hypogammaglobulinemia associated with decreased switched memory B cells. Two patients had decreased numbers of circulating eosinophils. The findings indicated that the disorder can affect multiple immune cell lineages. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25038750+25349174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Milner, J. D., Vogel, T. P., Forbes, L., Ma, C. A., Stray-Pedersen, A., Niemela, J. E., Lyons, J. J., Engelhardt, K. R., Zhang, Y., Topcagic, N., Roberson, E. D. O., Matthews, H., and 32 others. <strong>Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.</strong> Blood 125: 591-599, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25359994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25359994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25359994[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/10.1182/blood-2014-09-602763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25359994">Milner et al. (2015)</a> reported 13 patients from 10 families with childhood-onset of various autoimmune disorders associated with lymphoproliferation. The age at onset ranged from infancy to 15 years, but most presented before age 5. There was a high prevalence of autoimmune hematologic disorders, including hemolytic anemia, thrombocytopenia, and neutropenia. Two developed insulin-dependent diabetes mellitus and 5 had autoimmune enteropathy. Several had various other manifestations, such as scleroderma, arthritis, atopic dermatitis, and inflammatory lung disease. Almost all had lymphadenopathy, often with hepatosplenomegaly. Several patients had short stature and poor overall growth. Many patients also had recurrent infections, including 4 with fungal infections, and some of these patients showed hypogammaglobulinemia. Results of immunologic work-ups were variable, but showed moderate T-cell lymphopenia, hypogammaglobulinemia, and increased double-negative (CD4-, CD8-) T cells. Two families showed evidence of incomplete penetrance. All patients required significant immunosuppression to control their diseases, and 2 patients underwent hematopoietic stem cell transplant. One patient who was treated with pharmacologic IL6 blockade demonstrated a dramatic improvement in his arthritis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25359994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Forbes, L. R., Vogel, T. P., Cooper, M. A., Castro-Wagner, J., Schussler, E., Weinacht, K. G., Plant, A. S., Su, H. C., Allenspach, E. J., Slatter, M., Abinun, M., Lilic, D., and 14 others. <strong>Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations.</strong> J. Allergy Clin. Immun 142: 1665-1669, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30092289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30092289</a>] [<a href="https://doi.org/10.1016/j.jaci.2018.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30092289">Forbes et al. (2018)</a> reported treatment with a jakinib (ruxolitinib or tofacitinib), a small-molecule inhibitor that blocks cytokine-induced JAK activation, in 6 patients with STAT3 gain-of-function mutations. Five patients received ruxolitinib and 1 received tofacitinib; all had received prior immunosuppression, continued concurrently in several. Most infectious complications were from viral respiratory tract infections. All patients had severe autoimmunity, including hepatitis, enteropathy (2 were TPN dependent), cytopenias, lymphoproliferation (including HLH), serositis, and severe growth failure. One patient had polyarticular arthritis, and 2 had thyroid disease. Two patients were oxygen-dependent due to lymphocytic interstitial pneumonia/interstitial lung disease. Autoimmune cytopenias improved in 4 patients, and the patient with HLH achieved remission. All patients received tocilizumab before, with, or after jakinib therapy. For those who received tocilizumab before the ruxolitinib, it was ineffective on its own. Two patients, one with Pneumocystis jirovecii pneumonia and gram-negative sepsis, disseminated intravascular coagulopathy, and multiorgan failure, and the other, with end-stage lung disease, died despite therapy. <a href="#2" class="mim-tip-reference" title="Forbes, L. R., Vogel, T. P., Cooper, M. A., Castro-Wagner, J., Schussler, E., Weinacht, K. G., Plant, A. S., Su, H. C., Allenspach, E. J., Slatter, M., Abinun, M., Lilic, D., and 14 others. <strong>Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations.</strong> J. Allergy Clin. Immun 142: 1665-1669, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30092289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30092289</a>] [<a href="https://doi.org/10.1016/j.jaci.2018.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30092289">Forbes et al. (2018)</a> recommended acyclovir prophylaxis to prevent herpes virus infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30092289" 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 5 unrelated patients with ADMIO1, <a href="#1" class="mim-tip-reference" title="Flanagan, S. E., Haapaniemi, E., Russell, M. A., Caswell, R., Allen, H. L., De Franco, E., McDonald, T. J., Rajala, H., Ramelius, A., Barton, J., Heiskanen, K., Heiskanen-Kosma, T., and 11 others. <strong>Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.</strong> Nature Genet. 46: 812-814, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25038750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25038750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25038750[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/10.1038/ng.3040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25038750">Flanagan et al. (2014)</a> identified 4 different de novo heterozygous missense mutations in the STAT3 gene (<a href="/entry/102582#0008">102582.0008</a>-<a href="/entry/102582#0011">102582.0011</a>). The mutation in the first patient was found by exome sequencing, and the mutations in the subsequent patients were found by sequencing the coding exons of the STAT3 gene in 24 individuals with early-onset autoimmune disorder. In vitro functional expression studies showed that all the mutations resulted in a gain of function, with increased STAT3-responsive reporter activity and an increase in cytokine-related function compared to wildtype and compared to dominant-negative inactivating STAT3 mutations associated with HIES (<a href="/entry/147060">147060</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25038750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 13 patients from 10 families with ADMIO1, <a href="#4" class="mim-tip-reference" title="Milner, J. D., Vogel, T. P., Forbes, L., Ma, C. A., Stray-Pedersen, A., Niemela, J. E., Lyons, J. J., Engelhardt, K. R., Zhang, Y., Topcagic, N., Roberson, E. D. O., Matthews, H., and 32 others. <strong>Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.</strong> Blood 125: 591-599, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25359994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25359994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25359994[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/10.1182/blood-2014-09-602763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25359994">Milner et al. (2015)</a> identified 9 different heterozygous missense mutations in the STAT3 gene (see, e.g., <a href="/entry/102582#0008">102582.0008</a>; <a href="/entry/102582#0012">102582.0012</a>-<a href="/entry/102582#0014">102582.0014</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, occurred throughout the gene and affected multiple protein domains. In vitro functional expression studies showed that all the mutant proteins had increased basal transcriptional activity and increased activity in response to cytokines compared to wildtype, consistent with a gain of function. The mutations also caused secondary defects in STAT5 (<a href="/entry/601511">601511</a>) and STAT1 (<a href="/entry/600555">600555</a>) phosphorylation. Patient cells showed increased expression of the downstream target SOCS3 (<a href="/entry/604176">604176</a>) and diminished numbers of regulatory T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25359994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="Flanagan2014" class="mim-anchor"></a>
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Flanagan, S. E., Haapaniemi, E., Russell, M. A., Caswell, R., Allen, H. L., De Franco, E., McDonald, T. J., Rajala, H., Ramelius, A., Barton, J., Heiskanen, K., Heiskanen-Kosma, T., and 11 others.
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<strong>Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.</strong>
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Nature Genet. 46: 812-814, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25038750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25038750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25038750[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=25038750" 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/ng.3040" target="_blank">Full Text</a>]
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Forbes, L. R., Vogel, T. P., Cooper, M. A., Castro-Wagner, J., Schussler, E., Weinacht, K. G., Plant, A. S., Su, H. C., Allenspach, E. J., Slatter, M., Abinun, M., Lilic, D., and 14 others.
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<strong>Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations.</strong>
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J. Allergy Clin. Immun 142: 1665-1669, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30092289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30092289</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30092289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jaci.2018.07.020" target="_blank">Full Text</a>]
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Haapaniemi, E. M., Kaustio, M., Rajala, H. L. M., van Adrichem, A. J., Kainulainen, L., Glumoff, V., Doffinger, R., Kuusanmaki, H., Heiskanen-Kosma, T., Trotta, L., Chiang, S., Kulmala, P., and 15 others.
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<strong>Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3.</strong>
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Blood 125: 639-648, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25349174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25349174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25349174[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=25349174" 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/10.1182/blood-2014-04-570101" target="_blank">Full Text</a>]
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Milner, J. D., Vogel, T. P., Forbes, L., Ma, C. A., Stray-Pedersen, A., Niemela, J. E., Lyons, J. J., Engelhardt, K. R., Zhang, Y., Topcagic, N., Roberson, E. D. O., Matthews, H., and 32 others.
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<strong>Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.</strong>
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Blood 125: 591-599, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25359994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25359994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25359994[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=25359994" 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/10.1182/blood-2014-09-602763" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 03/08/2021
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Cassandra L. Kniffin - updated : 5/23/2016
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Cassandra L. Kniffin : 8/20/2014
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carol : 10/05/2023
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ckniffin : 10/03/2023<br>alopez : 06/28/2023<br>ckniffin : 06/27/2023<br>alopez : 03/08/2021<br>carol : 01/29/2018<br>alopez : 06/29/2016<br>ckniffin : 6/27/2016<br>carol : 6/24/2016<br>alopez : 5/25/2016<br>ckniffin : 5/23/2016<br>carol : 8/21/2014<br>mcolton : 8/21/2014<br>ckniffin : 8/21/2014
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<strong>#</strong> 615952
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AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 1; ADMIO1
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<strong>SNOMEDCT:</strong> 1197362009;
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<strong>ORPHA:</strong> 438159;
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<strong>Phenotype-Gene Relationships</strong>
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17q21.2
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Autoimmune disease, multisystem, infantile-onset, 1
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Autosomal dominant
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STAT3
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102582
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<p>A number sign (#) is used with this entry because infantile-onset multisystem autoimmune disease-1 (ADMIO1) is caused by heterozygous gain-of-function mutation in the STAT3 gene (102582) on chromosome 17q21.</p><p>Heterozygous dominant-negative mutations in the STAT3 gene cause autosomal dominant hyper-IgE syndrome-1 with recurrent infections (HIES1; 147060).</p>
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<p>Infantile-onset multisystem autoimmune disease-1 is characterized by early childhood onset of a spectrum of autoimmune disorders affecting multiple organs. Common manifestations include insulin-dependent diabetes mellitus and autoimmune enteropathy, or celiac disease, and autoimmune hematologic disorders. Other features include short stature and nonspecific dermatitis. More variable features include hypothyroidism, autoimmune arthritis, and delayed puberty. Some patients may show recurrent infections. The disorder results from an inborn error of cytokine signaling (summary by Flanagan et al., 2014 and Milner et al., 2015). </p><p><strong><em>Genetic Heterogeneity of Infantile-Onset Multisystem Autoimmune Disease</em></strong></p><p>
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See also ADMIO2 (617006), caused by mutation in the ZAP70 gene (176947) on chromosome 2q12, and ADMIO3 (620430), caused by mutation in the CBLB gene (604491) on chromosome 3q13.</p>
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<p>Flanagan et al. (2014) reported 5 unrelated patients with early-onset autoimmune disease. Three patients were diagnosed with type 1 insulin-dependent diabetes in the first weeks of life, and a fourth was diagnosed with diabetes at 43 weeks of age. Autoimmune enteropathy or celiac disease presented in the first 2 years of life in 3 patients. Additional autoimmune disorders diagnosed during childhood included autoimmune interstitial lung disease, juvenile-onset arthritis, and primary hypothyroidism. Other common features included short stature, eczema, delayed puberty, and dental abnormalities. Two patients had evidence of immunodeficiency with recurrent respiratory infections, and 1 patient developed large granular lymphocytic T-cell leukemia. Laboratory studies of 2 patients showed decreased numbers of regulatory T cells, and 1 patient had evidence of increased cytokine production. </p><p>Haapaniemi et al. (2015) reported further details of 2 of the patients reported by Flanagan et al. (2014) and presented a third patient with the disorder. All had recurrent infections and autoimmune features, 1 had lymphadenopathy, and 1 developed T-cell leukemia. The third patient was a 22-year-old woman with late-onset ADMIO. She had recurrent ear infections in childhood, but normal response to vaccination, including BCG. In her late teens, she presented with lymphocytic colitis, autoimmune thrombocytopenia, hypogammaglobulinemia, joint pain, eczema, and Mycobacterium avium pneumonia. Detailed laboratory studies of these patients showed increased numbers of double-negative (CD4-, CD8-) T cells, decreased dendritic, T regulatory, NK, and Th17 cells, as well as hypogammaglobulinemia associated with decreased switched memory B cells. Two patients had decreased numbers of circulating eosinophils. The findings indicated that the disorder can affect multiple immune cell lineages. </p><p>Milner et al. (2015) reported 13 patients from 10 families with childhood-onset of various autoimmune disorders associated with lymphoproliferation. The age at onset ranged from infancy to 15 years, but most presented before age 5. There was a high prevalence of autoimmune hematologic disorders, including hemolytic anemia, thrombocytopenia, and neutropenia. Two developed insulin-dependent diabetes mellitus and 5 had autoimmune enteropathy. Several had various other manifestations, such as scleroderma, arthritis, atopic dermatitis, and inflammatory lung disease. Almost all had lymphadenopathy, often with hepatosplenomegaly. Several patients had short stature and poor overall growth. Many patients also had recurrent infections, including 4 with fungal infections, and some of these patients showed hypogammaglobulinemia. Results of immunologic work-ups were variable, but showed moderate T-cell lymphopenia, hypogammaglobulinemia, and increased double-negative (CD4-, CD8-) T cells. Two families showed evidence of incomplete penetrance. All patients required significant immunosuppression to control their diseases, and 2 patients underwent hematopoietic stem cell transplant. One patient who was treated with pharmacologic IL6 blockade demonstrated a dramatic improvement in his arthritis. </p>
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<strong>Clinical Management</strong>
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<p>Forbes et al. (2018) reported treatment with a jakinib (ruxolitinib or tofacitinib), a small-molecule inhibitor that blocks cytokine-induced JAK activation, in 6 patients with STAT3 gain-of-function mutations. Five patients received ruxolitinib and 1 received tofacitinib; all had received prior immunosuppression, continued concurrently in several. Most infectious complications were from viral respiratory tract infections. All patients had severe autoimmunity, including hepatitis, enteropathy (2 were TPN dependent), cytopenias, lymphoproliferation (including HLH), serositis, and severe growth failure. One patient had polyarticular arthritis, and 2 had thyroid disease. Two patients were oxygen-dependent due to lymphocytic interstitial pneumonia/interstitial lung disease. Autoimmune cytopenias improved in 4 patients, and the patient with HLH achieved remission. All patients received tocilizumab before, with, or after jakinib therapy. For those who received tocilizumab before the ruxolitinib, it was ineffective on its own. Two patients, one with Pneumocystis jirovecii pneumonia and gram-negative sepsis, disseminated intravascular coagulopathy, and multiorgan failure, and the other, with end-stage lung disease, died despite therapy. Forbes et al. (2018) recommended acyclovir prophylaxis to prevent herpes virus infection. </p>
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<strong>Molecular Genetics</strong>
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<p>In 5 unrelated patients with ADMIO1, Flanagan et al. (2014) identified 4 different de novo heterozygous missense mutations in the STAT3 gene (102582.0008-102582.0011). The mutation in the first patient was found by exome sequencing, and the mutations in the subsequent patients were found by sequencing the coding exons of the STAT3 gene in 24 individuals with early-onset autoimmune disorder. In vitro functional expression studies showed that all the mutations resulted in a gain of function, with increased STAT3-responsive reporter activity and an increase in cytokine-related function compared to wildtype and compared to dominant-negative inactivating STAT3 mutations associated with HIES (147060). </p><p>In 13 patients from 10 families with ADMIO1, Milner et al. (2015) identified 9 different heterozygous missense mutations in the STAT3 gene (see, e.g., 102582.0008; 102582.0012-102582.0014). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, occurred throughout the gene and affected multiple protein domains. In vitro functional expression studies showed that all the mutant proteins had increased basal transcriptional activity and increased activity in response to cytokines compared to wildtype, consistent with a gain of function. The mutations also caused secondary defects in STAT5 (601511) and STAT1 (600555) phosphorylation. Patient cells showed increased expression of the downstream target SOCS3 (604176) and diminished numbers of regulatory T cells. </p>
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<strong>REFERENCES</strong>
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Flanagan, S. E., Haapaniemi, E., Russell, M. A., Caswell, R., Allen, H. L., De Franco, E., McDonald, T. J., Rajala, H., Ramelius, A., Barton, J., Heiskanen, K., Heiskanen-Kosma, T., and 11 others.
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<strong>Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.</strong>
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Nature Genet. 46: 812-814, 2014.
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[PubMed: 25038750]
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[Full Text: https://doi.org/10.1038/ng.3040]
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Forbes, L. R., Vogel, T. P., Cooper, M. A., Castro-Wagner, J., Schussler, E., Weinacht, K. G., Plant, A. S., Su, H. C., Allenspach, E. J., Slatter, M., Abinun, M., Lilic, D., and 14 others.
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<strong>Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations.</strong>
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J. Allergy Clin. Immun 142: 1665-1669, 2018.
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[PubMed: 30092289]
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[Full Text: https://doi.org/10.1016/j.jaci.2018.07.020]
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Haapaniemi, E. M., Kaustio, M., Rajala, H. L. M., van Adrichem, A. J., Kainulainen, L., Glumoff, V., Doffinger, R., Kuusanmaki, H., Heiskanen-Kosma, T., Trotta, L., Chiang, S., Kulmala, P., and 15 others.
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<strong>Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3.</strong>
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Blood 125: 639-648, 2015.
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[PubMed: 25349174]
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[Full Text: https://doi.org/10.1182/blood-2014-04-570101]
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Milner, J. D., Vogel, T. P., Forbes, L., Ma, C. A., Stray-Pedersen, A., Niemela, J. E., Lyons, J. J., Engelhardt, K. R., Zhang, Y., Topcagic, N., Roberson, E. D. O., Matthews, H., and 32 others.
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<strong>Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.</strong>
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Blood 125: 591-599, 2015.
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[PubMed: 25359994]
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[Full Text: https://doi.org/10.1182/blood-2014-09-602763]
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Ada Hamosh - updated : 03/08/2021<br>Cassandra L. Kniffin - updated : 5/23/2016
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Cassandra L. Kniffin : 8/20/2014
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carol : 10/05/2023<br>ckniffin : 10/03/2023<br>alopez : 06/28/2023<br>ckniffin : 06/27/2023<br>alopez : 03/08/2021<br>carol : 01/29/2018<br>alopez : 06/29/2016<br>ckniffin : 6/27/2016<br>carol : 6/24/2016<br>alopez : 5/25/2016<br>ckniffin : 5/23/2016<br>carol : 8/21/2014<br>mcolton : 8/21/2014<br>ckniffin : 8/21/2014
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