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Entry
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- #240300 - AUTOIMMUNE POLYENDOCRINE SYNDROME, TYPE I, WITH OR WITHOUT REVERSIBLE METAPHYSEAL DYSPLASIA; APS1
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- OMIM
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<span class="h4">#240300</span>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/240300"><strong>Clinical Synopsis</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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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><a href="https://clinicaltrials.gov/search?cond=(AUTOIMMUNE POLYENDOCRINE SYNDROME, TYPE I, WITH WITHOUT REVERSIBLE METAPHYSEAL DYSPLASIA) OR (AIRE)" 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=3035&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://medlineplus.gov/genetics/condition/autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy" 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=240300[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=3453" 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/f9c2ce21-58b1-4493-93a3-583510e98c40/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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<div style="display: table-row">
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<div style="display: table-cell;">Animal Models</div>
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</a>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0050167" 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/240300" 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://omia.org/results?search_type=advanced&omia_id=000519,000528,002797" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</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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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 11244009<br />
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<strong>ORPHA:</strong> 3453<br />
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<strong>DO:</strong> 0050167<br />
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">ICD+</a>
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</div>
|
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<div>
|
|
<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
|
|
<span class="text-danger"><strong>#</strong></span>
|
|
240300
|
|
</span>
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
AUTOIMMUNE POLYENDOCRINE SYNDROME, TYPE I, WITH OR WITHOUT REVERSIBLE METAPHYSEAL DYSPLASIA; APS1
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
APS I<br />
|
|
AUTOIMMUNE POLYENDOCRINOPATHY-CANDIDIASIS-ECTODERMAL DYSTROPHY; APECED<br />
|
|
AUTOIMMUNE POLYGLANDULAR SYNDROME, TYPE I<br />
|
|
POLYGLANDULAR AUTOIMMUNE SYNDROME, TYPE I<br />
|
|
PGA I<br />
|
|
HYPOADRENOCORTICISM WITH HYPOPARATHYROIDISM AND SUPERFICIAL MONILIASIS
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
AUTOIMMUNE POLYENDOCRINOPATHY SYNDROME, TYPE I, AUTOSOMAL DOMINANT, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
POLYGLANDULAR DEFICIENCY SYNDROME, PERSIAN-JEWISH TYPE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="phenotypeMap" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/21/157?start=-3&limit=10&highlight=157">
|
|
21q22.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/240300"> 240300 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <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">
|
|
AIRE
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607358"> 607358 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/240300" 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/240300" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/240300" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br /> -
|
|
Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Keratopathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235270&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235270</a>]</span><br /> -
|
|
Keratoconjunctivitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/88151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">88151007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H16.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H16.20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H16.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H16.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/370.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">370.40</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0022573&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022573</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001096" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001096</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001096" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001096</a>]</span><br /> -
|
|
Decreased visual acuity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13164000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234632&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234632</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007663" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007663</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007663" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007663</a>]</span><br /> -
|
|
Pigmentary retinopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28835009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28835009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H35.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H35.52</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551715&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551715</a>, <a href="https://bioportal.bioontology.org/search?q=C0035334&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035334</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000510</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000580" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000580</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000580" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000580</a>]</span><br /> -
|
|
Waxy optic nerve pallor <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4231159&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4231159</a>]</span><br /> -
|
|
Retinal vascular attenuation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4231158&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4231158</a>]</span><br /> -
|
|
Decreased rod ERG <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4231157&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4231157</a>]</span><br /> -
|
|
Constricted visual field <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1151008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1151008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235095&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235095</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001133" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001133</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001133" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001133</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Teeth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Dental enamel hypoplasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26597004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26597004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011351&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011351</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006297</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006297</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Liver </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Chronic active hepatitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197284004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197284004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0520463&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0520463</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0200120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0200120</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0200120" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0200120</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Biliary Tract </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Cholelithiasis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/266474003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">266474003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K80" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K80</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/574" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">574</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0008350&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008350</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001081" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001081</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001081" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001081</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Spleen </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Asplenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1003551006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1003551006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/702624008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">702624008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/707147002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">707147002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/93030006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">93030006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q89.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q89.01</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5779621&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5779621</a>, <a href="https://bioportal.bioontology.org/search?q=C0600031&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0600031</a>, <a href="https://bioportal.bioontology.org/search?q=C5574735&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5574735</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001746" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001746</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001746" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001746</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Malabsorption <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32230006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32230006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197476001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197476001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K90.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K90.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K90</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/579.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">579.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/579" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">579</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0024523&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024523</a>, <a href="https://bioportal.bioontology.org/search?q=C3714745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714745</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002024" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002024</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002024" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002024</a>]</span><br /> -
|
|
Diarrhea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267060006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267060006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/62315008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">62315008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R19.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R19.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011991&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011991</a>, <a href="https://bioportal.bioontology.org/search?q=C2169706&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2169706</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span><br /> -
|
|
Chronic atrophic gastritis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/84568007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">84568007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K29.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K29.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/535.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">535.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0017154&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017154</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002582" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002582</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002582" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002582</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GENITOURINARY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> External Genitalia (Male) </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hypogonadism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48130008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48130008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020619&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020619</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000135" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000135</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000135" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000135</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Internal Genitalia (Female) </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hypogonadism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48130008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48130008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020619&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020619</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000135" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000135</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000135" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000135</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">
|
|
|
|
- Vitiligo <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56727007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56727007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L80" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L80</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/709.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">709.01</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1847835&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1847835</a>, <a href="https://bioportal.bioontology.org/search?q=C0042900&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042900</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001045" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001045</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001045" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001045</a>]</span><br /> -
|
|
Ectodermal dystrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855873&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855873</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Hair </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Alopecia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/278040002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">278040002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56317004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56317004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L65.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L65.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/704.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">704.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/704.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">704.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002170&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002170</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001596" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001596</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0002293" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002293</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001596" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001596</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> ENDOCRINE FEATURES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Adrenal insufficiency (Addison disease) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/363732003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">363732003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E27.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E27.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001403&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001403</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008207" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008207</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/255.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">255.4</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000846" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000846</a>]</span><br /> -
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Hypoparathyroidism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36976004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36976004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/E20.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E20.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/252.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">252.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020626&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020626</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000829</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000829</a>]</span><br /> -
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Hypogonadism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48130008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48130008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020619&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020619</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000135" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000135</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000135" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000135</a>]</span><br /> -
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Insulin-dependent 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> <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 /> -
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Hypoaldosteronism, transient, isolated <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855870&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855870</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/60086000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">60086000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E27.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E27.40</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004319</a>]</span><br /> -
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Pituitary defects <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855871&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855871</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> HEMATOLOGY </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Pernicious anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/84027009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">84027009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D51.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D51.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/281.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">281.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002892&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002892</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> IMMUNOLOGY </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Chronic mucocutaneous candidiasis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/234568006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">234568006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0006845&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0006845</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002728" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002728</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002728" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002728</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Multiple autoantibodies <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855872&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855872</a>]</span><br /> -
|
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Antiretinal antibodies <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4231156&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4231156</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Onset in childhood<br /> -
|
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Manifestations continue to appear until 5th decade<br /> -
|
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Candidiasis is usually the first symptom<br /> -
|
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Autosomal dominant inheritance has been reported in a single family<br /> -
|
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Prevalence in Finland is 1 in 25,000<br /> -
|
|
Prevalence in Sardinia is 1 in 14,000<br /> -
|
|
Prevalence in Norway is 1 in 80,000<br /> -
|
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Prevalence in Slovenia is 1 in 43,000<br /> -
|
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Prevalence in Poland is 1 in 129,000<br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the autoimmune regulator gene (AIRE, <a href="/entry/607358#0001">607358.0001</a>)<br />
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</span>
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</div>
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</div>
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that autoimmune polyendocrinopathy syndrome type I (APS1) is caused by homozygous, compound heterozygous, or heterozygous mutation in the autoimmune regulator gene (AIRE; <a href="/entry/607358">607358</a>) on chromosome 21q22.</p>
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<div>
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<br />
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<div>
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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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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Autoimmune polyglandular syndrome type I (APS1) is characterized by the presence of 2 of 3 major clinical symptoms: Addison disease, and/or hypoparathyroidism, and/or chronic mucocutaneous candidiasis (<a href="#51" class="mim-tip-reference" title="Neufeld, M., Maclaren, N. K., Blizzard, R. M. <strong>Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes.</strong> Medicine 60: 355-362, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7024719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7024719</a>] [<a href="https://doi.org/10.1097/00005792-198109000-00003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7024719">Neufeld et al., 1981</a>). However, variable APS1 phenotypes have been observed, even among sibs. In addition, some patients may exhibit apparent isolated hypoparathyroidism, an early manifestation of APS1 with peak incidence at around age 5 years; over long-term follow-up, the development of additional features of APS1 may be observed (<a href="#17" class="mim-tip-reference" title="Cranston, T., Boon, H., Olesen, M. K., Ryan, F. J., Shears, D., London, R., Rostom, H., Elajnaf, T., Thakker, R. V., Hannan, F. M. <strong>Spectrum of germline AIRE mutations causing APS-1 and familial hypoparathyroidism.</strong> Europ. J. Endocr. 187: 111-122, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35521792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35521792</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35521792[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/10.1530/EJE-21-0730" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35521792">Cranston et al., 2022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7024719+35521792" 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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<br />
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<div>
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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</div>
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<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>Malabsorption and diarrhea can be very striking and even dominate the clinical picture (<a href="#55" class="mim-tip-reference" title="Prader, A. <strong>Personal Communication.</strong> Zurich, Switzerland 1972."None>Prader, 1972</a>).</p><p><a href="#50" class="mim-tip-reference" title="Neufeld, M., Maclaren, N., Blizzard, R. <strong>Autoimmune polyglandular syndrome.</strong> Pediat. Ann. 9: 154-162, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6990358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6990358</a>]" pmid="6990358">Neufeld et al. (1980)</a> recognized 3 types of the polyglandular autoimmune syndrome. <a href="#51" class="mim-tip-reference" title="Neufeld, M., Maclaren, N. K., Blizzard, R. M. <strong>Two types of autoimmune Addison's disease associated with different polyglandular autoimmune (PGA) syndromes.</strong> Medicine 60: 355-362, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7024719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7024719</a>] [<a href="https://doi.org/10.1097/00005792-198109000-00003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7024719">Neufeld et al. (1981)</a> collated information on 295 patients with autoimmune Addison disease as part of a polyglandular autoimmune syndrome. The information was supplied to them by members of the Lawson Wilkins Pediatric Endocrine Society and obtained from the literature. PGA I is represented by patients who have at least 2 of the triad of Addison disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. Associated immune disorders may be present. The Addison disease of PGA I has its predominant age of onset in childhood or early adulthood. It is also frequently associated with chronic active hepatitis, malabsorption, juvenile-onset pernicious anemia, alopecia, and primary hypogonadism. Insulin-dependent diabetes mellitus (IDDM; see <a href="/entry/222100">222100</a>) and/or autoimmune thyroid disease are infrequent. PGA II (Schmidt syndrome; <a href="/entry/269200">269200</a>) is represented by patients who have Addison disease with autoimmune thyroid disease and/or insulin-dependent diabetes mellitus, but do not have hypoparathyroidism or candidiasis, although other autoimmune disorders may be present. Although not confined to one age group or sex, PGA II is predominantly a disease of middle-aged females. The autoimmune disorders that occur with PGA I (e.g., chronic active hepatitis) are rare in PGA II, except for a low frequency of gonadal failure. Addison disease probably has a different genetic basis in PGA I than in PGA II. PGA III is represented by patients who have autoimmune thyroid disease and one or more other autoimmune disorders but do not have Addison disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7024719+6990358" 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 autoimmune adrenal insufficiency, isolated hypoaldosteronism may occur as a transient state on the way to Addison disease (<a href="#59" class="mim-tip-reference" title="Saenger, P. <strong>Primary hypoaldosteronism due to zona glomerulosa defect. (Letter)</strong> New Eng. J. Med. 310: 1394 only, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6717516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6717516</a>] [<a href="https://doi.org/10.1056/NEJM198405243102120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6717516">Saenger, 1984</a>). In a patient reported by <a href="#58" class="mim-tip-reference" title="Saenger, P., Levine, L. S., Irvine, W. J., Gottesdiener, K., Rauh, W., Sonino, N., Chow, D., New, M. I. <strong>Progressive adrenal failure in polyglandular autoimmune disease.</strong> J. Clin. Endocr. Metab. 54: 863-868, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6277984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6277984</a>] [<a href="https://doi.org/10.1210/jcem-54-4-863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6277984">Saenger et al. (1982)</a> and in one reported by <a href="#46" class="mim-tip-reference" title="Marieb, N. J., Melby, J. C., Lyall, S. S. <strong>Isolated hypoaldosteronism associated with idiopathic hypoparathyroidism.</strong> Arch. Intern. Med. 134: 424-429, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4368847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4368847</a>]" pmid="4368847">Marieb et al. (1974)</a>, impairment of fasciculata function or Addison disease developed over a period of several years after initial presentation with isolated hypoaldosteronism due to an early selective damage to the zona glomerulosa. At an early stage, primary hypoaldosteronism (<a href="/entry/203400">203400</a>, <a href="/entry/610600">610600</a>) might be incorrectly diagnosed. Selective testing for antibodies against the 3 layers of the adrenal cortex is possible (<a href="#59" class="mim-tip-reference" title="Saenger, P. <strong>Primary hypoaldosteronism due to zona glomerulosa defect. (Letter)</strong> New Eng. J. Med. 310: 1394 only, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6717516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6717516</a>] [<a href="https://doi.org/10.1056/NEJM198405243102120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6717516">Saenger, 1984</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6717516+6277984+4368847" 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="#47" class="mim-tip-reference" title="McKusick, V. A. <strong>Personal Communication.</strong> Baltimore, Md. 1985."None>McKusick (1985)</a> observed achalasia in this syndrome. The association is observed also in the achalasia-addisonianism-alacrima syndrome (<a href="/entry/231550">231550</a>). <a href="#33" class="mim-tip-reference" title="Hendrix, T. R. <strong>Personal Communication.</strong> Baltimore, Md. 1/14/1985."None>Hendrix (1985)</a> pointed out that although achalasia predisposes to esophageal candidiasis through lack of the normal cleansing effect of peristalsis, it is doubtful that invasive candidiasis can produce true achalasia, nor in ordinary achalasia is there evidence, it seems, of an autoimmune basis. Association of achalasia with autoimmune thyroiditis has not been observed, for example.</p><p><a href="#2" class="mim-tip-reference" title="Ahonen, P., Myllarniemi, S., Sipila, I., Perheentupa, J. <strong>Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients.</strong> New Eng. J. Med. 322: 1829-1836, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2348835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2348835</a>] [<a href="https://doi.org/10.1056/NEJM199006283222601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2348835">Ahonen et al. (1990)</a> reported data from a 10-month to 31-year follow-up of 68 patients from 54 families, aged 10 months to 53 years at the time of report. The largest previous reported series, aside from earlier studies in Finnish patients, involved 9 patients. <a href="#2" class="mim-tip-reference" title="Ahonen, P., Myllarniemi, S., Sipila, I., Perheentupa, J. <strong>Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients.</strong> New Eng. J. Med. 322: 1829-1836, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2348835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2348835</a>] [<a href="https://doi.org/10.1056/NEJM199006283222601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2348835">Ahonen et al. (1990)</a> emphasized the broad clinical spectrum. Hypoplasia of the dental enamel and keratopathy were frequent and were not attributable to hypoparathyroidism. Some of the manifestations of the disorder did not appear until the fifth decade. Thus, all patients need lifelong follow-up for the detection of new components of the disease. Candidiasis was the initial manifestation in 60% of the patients and was present in all patients at some time. Hypoparathyroidism was present in 79%, adrenocortical failure in 72%, and gonadal failure in 60% of female patients over 13 years of age, and in 14% of male patients over 16 years of age. Half of the patients had multiple endocrine deficiencies. Two affected women had given birth, and 3 men reported having fathered healthy children. No genetic data were presented. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2348835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Betterle, C., Greggio, N. A., Volpato, M. <strong>Autoimmune polyglandular syndrome type 1.</strong> J. Clin. Endocr. Metab. 83: 1049-1055, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9543115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9543115</a>] [<a href="https://doi.org/10.1210/jcem.83.4.4682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9543115">Betterle et al. (1998)</a> reviewed the clinical findings of APECED. They found that the spectrum of associated minor clinical diseases includes other autoimmune endocrinopathies (hypergonadotropic hypogonadism, insulin-dependent diabetes mellitus, autoimmune thyroid diseases, and pituitary defects), autoimmune or immuno-mediated gastrointestinal diseases (chronic atrophic gastritis, pernicious anemia, and malabsorption), chronic active hepatitis, autoimmune skin diseases (vitiligo and alopecia), ectodermal dystrophy, keratoconjunctivitis, immunologic defects (cellular and humoral), asplenia, and cholelithiasis. The first manifestations usually occur in childhood with the 3 main diseases developing in the first 20 years of life, and other accompanying diseases continue to appear until at least the fifth decade. In a majority of cases, candidiasis is the first clinical manifestation to appear, usually before the age of 5 years, followed by hypoparathyroidism (usually before the age of 10 years), and later by Addison disease (usually before the age of 15 years). Overall, the 3 main components of APECED occur in chronologic order, but they are present together in only about one-third to one-half of the cases. Generally, the earlier the first components appear, the more likely it is that multiple components will develop; conversely, patients who have late manifestations of the disease are likely to have fewer components. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9543115" 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>Among 79 patients with central diabetes insipidus, <a href="#45" class="mim-tip-reference" title="Maghnie, M., Cosi, G., Genovese, E., Manca-Bitti, M. L., Cohen, A., Zecca, S., Tinelli, C., Gallucci, M., Bernasconi, S., Boscherini, B., Severi, F., Arico, M. <strong>Central diabetes insipidus in children and young adults.</strong> New Eng. J. Med. 343: 998-1007, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11018166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11018166</a>] [<a href="https://doi.org/10.1056/NEJM200010053431403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11018166">Maghnie et al. (2000)</a> identified 1 patient with autoimmune polyendocrinopathy. The patient was almost 25 years old at the time of presentation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11018166" 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="#21" class="mim-tip-reference" title="Faiyaz-Ul-Haque, M., Bin-Abbas, B., Al-Abdullatif, A., Abdullah Abalkhail, H., Toulimat, M., Al-Gazlan, S., Almutawa, A. M., Al-Sagheir, A., Peltekova, I., Al-Dayel, F., Zaidi, S. H. E. <strong>Novel and recurrent mutations in the AIRE gene of autoimmune polyendocrinopathy syndrome type 1 (APS1) patients.</strong> Clin. Genet. 76: 431-440, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19758376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19758376</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01278.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19758376">Faiyaz-Ul-Haque et al. (2009)</a> studied 18 patients with APS1 from 7 consanguineous Arab families and noted that although the patients displayed characteristic features of APS1, there was unusually early expression of hypoparathyroidism and mucocutaneous candidiasis, with onset during the neonatal period in 3 of 14 and 7 of 14 patients, respectively. Seven APS1 patients from 4 of the families had alopecia universalis, and scalp biopsies from 2 unrelated patients showed peribulbar lymphocytic inflammation of hair follicles associated with reduced follicle density, decreased presence of the anagen phase, increased presence of the catagen/telogen phase, and predominance of vellus hair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19758376" 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="#69" class="mim-tip-reference" title="Zaidi, G., Sahu, R. P., Zhang, L., George, G., Bhavani, N., Shah, N., Bhatia, V., Bhansali, A., Jevalikar, G., Jayakumar, R. V., Eisenbarth, G. S., Bhatia, E. <strong>Two novel AIRE mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) among Indians.</strong> Clin. Genet. 76: 441-448, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19807739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19807739</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01280.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19807739">Zaidi et al. (2009)</a> reported 9 Indian patients with APS1 from 8 families, 3 of whom had unusual manifestations, including presentation with type 1 diabetes, chronic sinusitis and otitis media, and facial dysmorphism. Two patients died of septicemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19807739" 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="Bourgault, S., Baril, C., Vincent, A., Heon, E., Ali, A., MacDonald, I., Lueder, G. T., Colleaux, K. M., Laliberte, I. <strong>Retinal degeneration in autoimmune polyglandular syndrome, type 1: a case series.</strong> Brit. J. Ophthal. 99: 1536-1542, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25926518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25926518</a>] [<a href="https://doi.org/10.1136/bjophthalmol-2014-305897" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25926518">Bourgault et al. (2015)</a> reported the ocular features and characterized the retinal phenotype in a retrospective study of 5 patients with molecularly confirmed APS1. Age at presentation ranged from 19 months to 44 years, and follow-up ranged from 4 to 13 years (average, 8 years). All but 1 patient, aged 11 years, had decreased vision on presentation, and acuity did not correlate with age. The youngest patient at presentation had no light perception acuity. All cases had peripheral pigmentary retinal changes ranging from isolated patchy atrophy of the retinal pigment epithelium to a retinitis pigmentosa-like fundus with bone spicules, waxy pallor of the optic disc, and attenuated vasculature. Macular atrophy was noted in 4 patients. The most common feature on spectral-domain optical coherence tomography, which was found in 3 patients, was a disruption of the external limiting membrane and the inner segment ellipsoid band. The 4 patients who were tested for antiretinal antibodies were found to be positive by immunohistochemistry and/or Western blot analysis. Visual fields were constricted in all 3 patients tested. The rod ERG was abnormal in all of the patients, but the relative involvement of rods and cones differed. <a href="#10" class="mim-tip-reference" title="Bourgault, S., Baril, C., Vincent, A., Heon, E., Ali, A., MacDonald, I., Lueder, G. T., Colleaux, K. M., Laliberte, I. <strong>Retinal degeneration in autoimmune polyglandular syndrome, type 1: a case series.</strong> Brit. J. Ophthal. 99: 1536-1542, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25926518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25926518</a>] [<a href="https://doi.org/10.1136/bjophthalmol-2014-305897" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25926518">Bourgault et al. (2015)</a> concluded that photoreceptor degeneration is part of the APS1 phenotype and that the presence of antiretinal antibodies strongly supports an etiology similar to that of nonparaneoplastic autoimmune retinopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25926518" 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="#42" class="mim-tip-reference" title="Li, D., Streeten, E. A., Chan, A., Lwin, W., Tian, L., Pellegrino da Silva, R., Kim, C. E., Anderson, M. S., Hakonarson, H., Levine, M. A. <strong>Exome sequencing reveals mutations in AIRE as a cause of isolated hypoparathyroidism.</strong> J. Clin. Endocr. Metab. 102: 1726-1733, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28323927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28323927</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28323927[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/10.1210/jc.2016-3836" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28323927">Li et al. (2017)</a> reported 2 brothers and a sister with AIPS1 and mutation in the AIRE gene. The sibs, aged 63, 57, and 53 years, were diagnosed with hypoparathyroidism at ages 2, 5, and 7 years, respectively. In addition, the sister developed premature ovarian failure at age 33 years. The patients lacked clinical or biochemical signs of thyroid or adrenal insufficiency, mucocutaneous candidiasis, or ectodermal dysplasia, and conventional autoantibodies against thyroid and intestinal antigens were negative in all 3. Further testing in the brothers revealed that the proband had positive autoantibodies to GAD65 (GAD2; <a href="/entry/138275">138275</a>) and islet cells, whereas his brother was negative; both showed IFN-alpha (IFNA1; <a href="/entry/147660">147660</a>) antibodies but were negative for the NALP5 (NLRP5; <a href="/entry/609658">609658</a>) antibody. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28323927" 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>Polyglandular Deficiency Syndrome, Persian-Jewish Type</em></strong></p><p>
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<a href="#61" class="mim-tip-reference" title="Shapiro, M. S., Zamir, R., Weiss, E., Radnay, J., Shenkman, L. <strong>The polyglandular deficiency syndrome: a new variant in Persian Jews.</strong> J. Endocr. Invest. 10: 1-7, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3496374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3496374</a>] [<a href="https://doi.org/10.1007/BF03347139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3496374">Shapiro et al. (1987)</a> detected a seemingly new variant of the polyglandular deficiency syndrome in 5 Persian Jews. All 5 had primary hypoparathyroidism and hypogonadism, 2 had adrenal insufficiency, 1 had insulin-dependent diabetes mellitus, and 1 had latent hypothyroidism. The last patient also had antithyroid and antinuclear antibodies. Two of the 5 patients were cousins, and 2 had first-cousin parents. Isolated primary hypoparathyroidism was found in the 16-year-old sister of 1 of the 5. One of the patients had alopecia totalis. Primary sertoli cell insufficiency was detected by laboratory evaluation. Pernicious anemia was documented in 1 patient. One patient had mild hypogammaglobulinemia and a low T4/T8 cell ratio. A high frequency of hypogonadism was considered a distinctive feature in this group of patients. Hypoparathyroidism was the most common initial presenting disorder, occurring before the age of 10 in 4 of the 5 subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3496374" 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>Although the accepted criterion for diagnosis of type I polyglandular autoimmune syndrome is the presence of at least 2 of the 3 components (hypoparathyroidism, candidiasis, and adrenal insufficiency), hypoparathyroidism may be the only manifestation. <a href="#70" class="mim-tip-reference" title="Zlotogora, J., Shapiro, M. S. <strong>Polyglandular autoimmune syndrome type I among Iranian Jews.</strong> J. Med. Genet. 29: 824-826, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1453436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1453436</a>] [<a href="https://doi.org/10.1136/jmg.29.11.824" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1453436">Zlotogora and Shapiro (1992)</a> reported on 19 families of patients with hypoparathyroidism from the Iranian Jewish community in which 23 persons (11 males and 12 females) were affected with what these workers considered to be PGA I. All but 1 had hypoparathyroidism (96%), and most were diagnosed by the age of 20 years (91%). Adrenal insufficiency was diagnosed in 5 of the patients; in all cases but 1, it appeared after hypoparathyroidism. Mild oral candidiasis was present in 4 patients, and 6 of the patients (3 males and 3 females) had hypogonadism. Other features of the syndrome found in some patients were pernicious anemia, hypothyroidism, and alopecia. The inheritance was clearly autosomal recessive. The prevalence among Iranian Jews was estimated to be between 1:6,500 and 1:9,000. This is comparable to the high incidence among Finns. Compared with the Finns, the disorder showed relative rarity of candidiasis and absence of keratopathy among the Iranian Jews. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1453436" 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>To investigate the question of locus heterogeneity in this disorder. <a href="#7" class="mim-tip-reference" title="Bjorses, P., Aaltonen, J., Vikman, A., Perheentupa, J., Ben-Zion, G., Chiumello, G., Dahl, N., Heideman, P., Hoorweg-Nijman, J. J. G., Mathivon, L., Mullis, P. E., Pohl, M., Ritzen, M., Romeo, G., Shapiro, M. S., Smith, C. S., Solyom, J., Zlotogora, J., Peltonen, L. <strong>Genetic homogeneity of autoimmune polyglandular disease type I.</strong> Am. J. Hum. Genet. 59: 879-886, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8808604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8808604</a>]" pmid="8808604">Bjorses et al. (1996)</a> performed linkage and haplotype analyses on APECED families from these 2 isolated populations and in other population groups. Six microsatellite markers on the critical chromosomal region of 2.6 cM on 21q22.3 were analyzed. Pairwise linkage analyses revealed significant lod scores for all these markers (maximum lod = 10.23). The haplotype data and the geographic distribution of the great-grandparents of the Finnish APECED patients suggested the existence of 1 major, relatively old mutation responsible for approximately 90% of the Finnish cases. Similar evidence for one founder mutation was also found in analyses of Iranian Jewish APECED haplotypes. These haplotypes, however, differed totally from the Finnish ones. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for linkage to the same chromosomal region on 21q22.3 and revealed no evidence of locus heterogeneity. The haplotype analyses suggested to <a href="#7" class="mim-tip-reference" title="Bjorses, P., Aaltonen, J., Vikman, A., Perheentupa, J., Ben-Zion, G., Chiumello, G., Dahl, N., Heideman, P., Hoorweg-Nijman, J. J. G., Mathivon, L., Mullis, P. E., Pohl, M., Ritzen, M., Romeo, G., Shapiro, M. S., Smith, C. S., Solyom, J., Zlotogora, J., Peltonen, L. <strong>Genetic homogeneity of autoimmune polyglandular disease type I.</strong> Am. J. Hum. Genet. 59: 879-886, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8808604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8808604</a>]" pmid="8808604">Bjorses et al. (1996)</a> that in different populations APECED is due to a number of different mutations in a gene on chromosome 21. Thus, linkage studies demonstrated that the condition previously called polyglandular deficiency syndrome, Persian-Jewish type, is the same as APECED. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8808604" 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="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, autoimmune polyendocrine syndrome type II, and X-linked polyendocrinopathy with immune dysfunction and diarrhea (<a href="/entry/304790">304790</a>). <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="Fox, M., Mirada, A., Guardia, J. <strong>Endocrine disorders in a family. (Letter)</strong> Lancet 296: 269 only, 1970. Note: Originally Volume II."None>Fox et al. (1970)</a> made a brief note of a sibship, offspring of first-cousin parents, containing 2 female sibs with idiopathic Addison disease. One also had primary hypoparathyroidism and one had oral candidiasis. <a href="#3" class="mim-tip-reference" title="Ahonen, P. <strong>Autoimmune polyendocrinopathy--candidosis--ectodermal dystrophy (APECED): autosomal recessive inheritance.</strong> Clin. Genet. 27: 535-542, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4017274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4017274</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1985.tb02037.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4017274">Ahonen (1985)</a> provided a genetic analysis of 58 patients in 42 families and corroborated autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4017274" 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="Cetani, F., Barbesino, G., Borsari, S., Pardi, E., Cianferotti, L., Pinchera, A., Marcocci, C. <strong>A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis.</strong> J. Clin. Endocr. Metab. 86: 4747-4752, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11600535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11600535</a>] [<a href="https://doi.org/10.1210/jcem.86.10.7884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11600535">Cetani et al. (2001)</a> identified an Italian family with autoimmune polyendocrinopathy syndrome and a pattern of inheritance suggestive of a dominant mechanism (see MOLECULAR GENETICS). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11600535" 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>Taking advantage of the high frequency of APECED in Finland, <a href="#1" class="mim-tip-reference" title="Aaltonen, J., Bjorses, P., Sandkuijl, L., Perheentupa, J., Peltonen, L. <strong>An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21.</strong> Nature Genet. 8: 83-87, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987397</a>] [<a href="https://doi.org/10.1038/ng0994-83" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987397">Aaltonen et al. (1994)</a> did linkage studies and mapped the locus to 21q22.3 with DNA markers. Studies of linkage disequilibrium increased the informativeness of the analyses and helped to locate the gene to a 500-kb segment. This was perhaps the first gene involving an autoimmune disorder that had been located outside the major histocompatibility complex (MHC) region on chromosome 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7987397" 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="#9" class="mim-tip-reference" title="Blizzard, R. M., Kyle, M. A. <strong>Studies of the adrenal antigens and antibodies in Addison's disease.</strong> J. Clin. Invest. 42: 1653-1660, 1963.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14074360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14074360</a>] [<a href="https://doi.org/10.1172/JCI104851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14074360">Blizzard and Kyle (1963)</a> offered the first substantial evidence for the autoimmune concept. They found antiadrenal antibodies in 36 of 71 patients with Addison disease and antithyroid antibodies in 22. <a href="#35" class="mim-tip-reference" title="Hung, W., Migeon, C. J., Parrott, R. H. <strong>A possible autoimmune basis for Addison's disease in three siblings, one with idiopathic hypoparathyroidism, pernicious anemia and superficial moniliasis.</strong> New Eng. J. Med. 269: 658-663, 1963.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14050969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14050969</a>] [<a href="https://doi.org/10.1056/NEJM196309262691303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14050969">Hung et al. (1963)</a> found circulating adrenal antibodies in 2 sibs with Addison disease. A third sib had died from Addison disease. One of the affected sibs also had hypoparathyroidism, pernicious anemia, and superficial moniliasis. The authors suggested the disorder may not be inherited as a simple mendelian recessive but may be autoimmune in nature. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14074360+14050969" 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 studies performed in Finland and Estonia, <a href="#39" class="mim-tip-reference" title="Krohn, K., Uibo, R., Aavik, E., Peterson, P., Savilahti, K. <strong>Identification by molecular cloning of an autoantigen associated with Addison's disease as steroid 17-alpha-hydroxylase.</strong> Lancet 339: 770-773, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1347802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1347802</a>] [<a href="https://doi.org/10.1016/0140-6736(92)91894-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1347802">Krohn et al. (1992)</a> screened serum samples from patients with Addison disease as part of the type I polyendocrine autoimmunity syndrome. In 3 patients they demonstrated precipitating antibodies against adrenal proteins. They cloned these proteins and found that one of them was 17-alpha-hydroxylase, the steroid hormone that is deficient or defective in one form of congenital adrenal hypoplasia (<a href="/entry/202110">202110</a>). Patients with idiopathic Addison disease likewise showed antibodies to this protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1347802" 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="#36" class="mim-tip-reference" title="Husebye, E. S., Gebre-Medhin, G., Tuomi, T., Perheentupa, J., Landin-Olsson, M., Gustafsson, J., Rorsman, F., Kampe, O. <strong>Autoantibodies against aromatic L-amino acid decarboxylase in autoimmune polyendocrine syndrome type I.</strong> J. Clin. Endocr. Metab. 82: 147-150, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8989249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8989249</a>] [<a href="https://doi.org/10.1210/jcem.82.1.3647" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8989249">Husebye et al. (1997)</a> investigated the presence of autoantibodies against the enzyme aromatic L-amino acid decarboxylase (AADC) of pancreatic beta-cells in a cohort of PGA I and isolated IDDM patients. They found AADC autoantibodies in 35 of 69 (51%) PGA I patients but in none of 138 isolated IDDM patients or 91 controls. Among PGA I patients, anti-AADC antibodies were found more often in those with hepatitis (11 of 12, 92%) than in those without hepatitis (24 of 57, 42%) (P = 0.003). Similarly, 12 of 15 (80%) patients with vitiligo had antibodies, compared with 23 of 54 (43%) without vitiligo (P = 0.021). Of the 9 PGA I patients with IDDM, 5 had antibodies against both AADC and glutamate decarboxylase, 2 against AADC only, and 2 against glutamate decarboxylase only. Thus, an autoimmune reactivity against AADC may be involved in the pathogenesis of autoimmune chronic active hepatitis and vitiligo in PGA I patients, but the role of AADC in the development of IDDM in these patients remains to be determined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8989249" 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="Clemente, M. G., Obermayer-Straub, P., Meloni, A., Strassburg, C. P., Arangino, V., Tukey, R. H., de Virgiliis, S., Manns, M. P. <strong>Cytochrome P450 1A2 is a hepatic autoantigen in autoimmune polyglandular syndrome type 1.</strong> J. Clin. Endocr. Metab. 82: 1353-1361, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9141515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9141515</a>] [<a href="https://doi.org/10.1210/jcem.82.5.3913" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9141515">Clemente et al. (1997)</a> studied autoantibodies for proteins of the adrenal cortex and the liver in 88 subjects of Sardinian descent, including 6 with autoimmune polyglandular syndrome type I, 22 relatives of APS I patients, 40 controls with other autoimmune diseases, and 20 healthy controls. Indirect immunofluorescence of tissue sections of the adrenal cortex revealed a cytoplasmic staining pattern in 4 of 6 patients with APS I. The autoantigens were identified as P450 scc (CYP11A; see <a href="/entry/118485">118485</a>) and P450 c17 (CYP17A1; <a href="/entry/609300">609300</a>). One of 6 APS I patients suffered from chronic hepatitis. In this patient, immunofluorescence revealed a centrolobular liver and a proximal renal tubule staining pattern. The autoantigen was identified as cytochrome P450 1A2 (<a href="/entry/124060">124060</a>). Since P450 1A2 usually is not detected by sera of patients with isolated autoimmune liver disease, <a href="#15" class="mim-tip-reference" title="Clemente, M. G., Obermayer-Straub, P., Meloni, A., Strassburg, C. P., Arangino, V., Tukey, R. H., de Virgiliis, S., Manns, M. P. <strong>Cytochrome P450 1A2 is a hepatic autoantigen in autoimmune polyglandular syndrome type 1.</strong> J. Clin. Endocr. Metab. 82: 1353-1361, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9141515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9141515</a>] [<a href="https://doi.org/10.1210/jcem.82.5.3913" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9141515">Clemente et al. (1997)</a> suggested that P450 1A2 might be a hepatic marker autoantigen for patients with APS I. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9141515" 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>Using the immunoblotting of E. coli-expressed antigens to analyze humoral immunity to steroidogenic P450 cytochromes in 18 Eastern and Central European APECED patients, <a href="#14" class="mim-tip-reference" title="Cihakova, D., Trebusak, K., Heino, M., Fadeyev, V., Tiulpakov, A., Battelino, T., Tar, A., Halasz, Z., Blumel, P., Tawfik, S., Krohn, K., Lebl, J., Peterson, P., MEWPE-APECED Study Group. <strong>Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED.</strong> Hum. Mutat. 18: 225-232, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11524733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11524733</a>] [<a href="https://doi.org/10.1002/humu.1178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11524733">Cihakova et al. (2001)</a> showed that 67%, 44%, and 61% had autoantibodies to P450 c17, P450 c21 (<a href="/entry/613815">613815</a>), and P450 scc, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11524733" 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="#32" class="mim-tip-reference" title="Hedstrand, H., Ekwall, O., Haavik, J., Landgren, E., Betterle, C., Perheentupa, J., Gustafsson, J., Husebye, E., Rorsman, F., Kampe, O. <strong>Identification of tyrosine hydroxylase as an autoantigen in autoimmune polyendocrine syndrome type I.</strong> Biochem. Biophys. Res. Commun. 267: 456-461, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10623641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10623641</a>] [<a href="https://doi.org/10.1006/bbrc.1999.1945" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10623641">Hedstrand et al. (2000)</a> related a new autoantigen to APS I; they identified autoantibodies against tyrosine hydroxylase (TH; <a href="/entry/191290">191290</a>) in sera from patients with alopecia areata (<a href="/entry/104000">104000</a>) through immunoscreening of a scalp cDNA library. Immunoreactivity against in vitro-expressed TH was found in 41 (44%) of 94 APS I patients studied, and this reactivity correlated with the presence of alopecia areata. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10623641" 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>Another autoantigen in APSI, tryptophan hydroxylase (TPH; <a href="/entry/191060">191060</a>), is associated with intestinal dysfunction. TPH and TH, together with phenylalanine hydroxylase (PAH; <a href="/entry/612349">612349</a>), constitute the group of biopterin-dependent hydroxylases, which all are involved in the biosynthesis of neurotransmitters. Using a clone encoding PAH for in vitro transcription/translation, followed by immunoprecipitation with sera from 94 APS I patients and 70 healthy controls, <a href="#20" class="mim-tip-reference" title="Ekwall, O., Hedstrand, H., Haavik, J., Perheentupa, J., Betterle, C., Gustafsson, J., Husebye, E., Rorsman, F., Kampe, O. <strong>Pteridin-dependent hydroxylases as autoantigens in autoimmune polyendocrine syndrome type I.</strong> J. Clin. Endocr. Metab. 85: 2944-2950, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10946908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10946908</a>] [<a href="https://doi.org/10.1210/jcem.85.8.6736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10946908">Ekwall et al. (2000)</a> investigated whether PAH is an autoantigen in APS I and whether crossreactivity exists between antibodies to these 3 highly homologous enzymes. Of the APS I patients, 25% had PAH antibodies, and no reactivity was detected in the controls. No association with the main clinical components of APS I was found with PAH antibodies. Altogether, 59 sera from the 94 APS I patients reacted with at least 1 of TPH, TH, or PAH, whereas 35 showed no reactivity. Nineteen of the sera contained antibodies towards all enzymes, 12 to TPH only, and 12 to TH only. No sera showed antibodies that reacted to only PAH. An immunocompetition assay demonstrated that the reactivity against PAH represents a crossreactivity with TPH, whereas antibodies against TPH and TH are directed towards epitopes unique for the 2 enzymes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10946908" 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>Individuals with APECED are at high risk of developing IDDM, but the positive predictive value of GAD65 (<a href="/entry/138275">138275</a>) or islet cell antibodies for IDDM is only 27%. Autoantibodies against the IA2 tyrosine phosphatase-like protein (<a href="/entry/601773">601773</a>) or insulin (<a href="/entry/176730">176730</a>) have been suggested to be better markers for active beta cell destruction. <a href="#29" class="mim-tip-reference" title="Gylling, M., Tuomi, T., Bjorses, P., Kontiainen, S., Partanen, J., Christie, M. R., Knip, M., Perheentupa, J., Miettinen, A. <strong>Beta-cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.</strong> J. Clin. Endocr. Metab. 85: 4434-4440, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11134089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11134089</a>] [<a href="https://doi.org/10.1210/jcem.85.12.7120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11134089">Gylling et al. (2000)</a> studied these antibodies in sera from 60 Finnish patients with APECED, 12 of whom subsequently developed IDDM. Four (36%) of the 11 patients for whom prediabetic samples were available had antibodies against IA2, and 4 (36%) had antibodies against insulin. None of the 48 nondiabetics had antibodies against insulin, and only 2 (4%) had antibodies against IA2. Both had the antibodies for years without diabetes. Thus, antibodies against IA2 or insulin have a low sensitivity (36%), but high specificity (96% or 100%), with a positive predictive value of 67% for IDDM in patients with APECED. None of the 11 patients with IDDM, but 15 of the 56 (27%) nondiabetic patients and 24 of 93 (26%) of the control subjects had the DQB1*0602 allele (see <a href="/entry/604305">604305</a>), which is considered protective for IDDM. <a href="#29" class="mim-tip-reference" title="Gylling, M., Tuomi, T., Bjorses, P., Kontiainen, S., Partanen, J., Christie, M. R., Knip, M., Perheentupa, J., Miettinen, A. <strong>Beta-cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.</strong> J. Clin. Endocr. Metab. 85: 4434-4440, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11134089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11134089</a>] [<a href="https://doi.org/10.1210/jcem.85.12.7120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11134089">Gylling et al. (2000)</a> noted that theretofore no positive or negative associations had been reported for any disease components of APECED with human leukocyte II antigens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11134089" 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="#62" class="mim-tip-reference" title="Soderbergh, A., Myhre, A. G., Ekwall, O., Gebre-Medhin, G., Hedstrand, H., Landgren, E., Miettinen, A., Eskelin, P., Halonen, M., Tuomi, T., Gustafsson, J., Husebye, E. S., Perheentupa, J., Gylling, M., Manns, M. P., Rorsman, F., Kampe, O., Nilsson, T. <strong>Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I.</strong> J. Clin. Endocr. Metab. 89: 557-562, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764761</a>] [<a href="https://doi.org/10.1210/jc.2003-030279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14764761">Soderbergh et al. (2004)</a> used multiple logistic regression analysis on a cohort of 90 APS I patients from Finland, Norway, and Sweden to clarify the significance of each of 10 different autoantibodies as markers for the various disease manifestations of APS I. Reactivities against 21-hydroxylase (P450 c21) and side chain cleavage enzyme (P450 scc) were associated with Addison disease with odds ratios of 7.8 and 6.8, respectively. Hypogonadism was exclusively associated with autoantibodies against P450 scc with an odds ratio of 12.5. Autoantibodies against tyrosine phosphatase-like protein IA-2 were associated with IDDM with an odds ratio of 14.9, but with low sensitivity. Reactivities against TPH and, surprisingly, GAD65 were associated with intestinal dysfunction, with odds ratios of 3.9 and 6.7, respectively. TPH reactivity was the best predictor for autoimmune hepatitis, with an odds ratio of 27.0. The authors concluded that analysis of autoantibodies in APS I patients is a useful tool for establishing autoimmune manifestations of the disease as well as providing diagnosis in patients with suspected disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14764761" 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="#28" class="mim-tip-reference" title="Gylling, M., Kaariainen, E., Vaisanen, R., Kerosuo, L., Solin, M.-L., Halme, L., Saari, S., Halonen, M., Kampe, O., Perheentupa, J., Miettinen, A. <strong>The hypoparathyroidism of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protective effect of male sex.</strong> J. Clin. Endocr. Metab. 88: 4602-4608, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557429</a>] [<a href="https://doi.org/10.1210/jc.2003-030700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14557429">Gylling et al. (2003)</a> sought to identify the determinants and mechanism of hypoparathyroidism in APECED, the most common endocrine component of the disorder. For the determinants, they evaluated gender and HLA class II (see <a href="/entry/142857">142857</a>). For the mechanism, they searched for parathyroid autoantibodies, including antibodies against CASR (<a href="/entry/601199">601199</a>) and PTH (<a href="/entry/168450">168450</a>). Also, they studied whether AIRE (<a href="/entry/607358">607358</a>) is expressed in the human parathyroid because its absence could be a pathogenetic factor. <a href="#28" class="mim-tip-reference" title="Gylling, M., Kaariainen, E., Vaisanen, R., Kerosuo, L., Solin, M.-L., Halme, L., Saari, S., Halonen, M., Kampe, O., Perheentupa, J., Miettinen, A. <strong>The hypoparathyroidism of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protective effect of male sex.</strong> J. Clin. Endocr. Metab. 88: 4602-4608, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557429</a>] [<a href="https://doi.org/10.1210/jc.2003-030700" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14557429">Gylling et al. (2003)</a> found a clear gender linkage with lower and later incidence in males. Of the 14 patients who had escaped hypoparathyroidism, 13 were males. This was associated with adrenal failure, which was the first or only endocrinopathy in 47% of males vs 7% of females. In contrast, they found no linkage to the HLA class II. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14557429" 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="Alimohammadi, M., Bjorklund, P., Hallgren, A., Pontynen, N., Szinnai, G., Shikama, N., Keller, M. P., Ekwall, O., Kinkel, S. A., Husebye, E. S., Gustafsson, J., Rorsman, F., Peltonen, L., Betterle, C., Perheentupa, J., Akerstrom, G., Westin, G., Scott, H. S., Hollander, G. A., Kampe, O. <strong>Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen.</strong> New Eng. J. Med. 358: 1018-1028, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18322283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18322283</a>] [<a href="https://doi.org/10.1056/NEJMoa0706487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18322283">Alimohammadi et al. (2008)</a> studied the specific autoimmunity responsible for hypoparathyroidism, a hallmark of APS1 and its most common autoimmune endocrinopathy. They found that autoantibodies specific for NACHT leucine-rich repeat protein-5 (NALP5; <a href="/entry/609658">609658</a>) were demonstrable in 49% of patients who had APS1 and hypoparathyroidism but were absent in all patients with APS1 without hypoparathyroidism, as well as in all patients with other autoimmune endocrine disorders and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells. Thus NALP5 appears to be a tissue-specific autoantibody involved in hypoparathyroidism in patients with APS1. Autoantibodies against NALP5 may be diagnostic for this prominent component of APS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18322283" 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>Using multiplex particle-based flow cytometry and ELISA analysis, <a href="#56" class="mim-tip-reference" title="Puel, A., Doffinger, R., Natividad, A., Chrabieh M., Barcenas-Morales, G., Picard, C., Cobat, A., Ouachee-Chardin, M., Toulon, A., Bustamante, J., Al- Muhsen, S., Al-Owain, M., and 17 others. <strong>Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I.</strong> J. Exp. Med. 207: 291-297, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20123958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20123958</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20123958[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/10.1084/jem.20091983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20123958">Puel et al. (2010)</a> screened 33 APS1 patients, 37 healthy controls, and 103 patients with other autoimmune conditions and detected high-titers of neutralizing IgG autoantibodies against IL17A (<a href="/entry/603149">603149</a>), IL17F (<a href="/entry/606496">606496</a>) and/or IL22 (<a href="/entry/605330">605330</a>), but not against other cytokines, except for interferon-alpha (IFNA1; <a href="/entry/147660">147660</a>), in APS1 patients only. Twenty-two APS1 patients had a reaction against all 3 cytokines, 6 had reaction against 2 cytokines, and 5 had reaction against 1 cytokine. Chronic mucocutaneous candidiasis (CMC) was observed in 29 of the 33 APS1 patients. <a href="#56" class="mim-tip-reference" title="Puel, A., Doffinger, R., Natividad, A., Chrabieh M., Barcenas-Morales, G., Picard, C., Cobat, A., Ouachee-Chardin, M., Toulon, A., Bustamante, J., Al- Muhsen, S., Al-Owain, M., and 17 others. <strong>Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I.</strong> J. Exp. Med. 207: 291-297, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20123958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20123958</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20123958[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/10.1084/jem.20091983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20123958">Puel et al. (2010)</a> proposed that anti-IL17 autoantibodies may contribute to the development of CMC in APS1 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20123958" 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="#27" class="mim-tip-reference" title="Gruper, Y., Wolff, A. S. B., Glanz, L., Spoutil, F., Marthinussen, M. C., Osickova, A., Herzig, Y., Goldfarb, Y., Aranaz-Novaliches, G., Dobes, J., Kadouri, N., Ben-Nun, O., and 28 others. <strong>Autoimmune amelogenesis imperfecta in patients with APS-1 and coeliac disease.</strong> Nature 624: 653-662, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37993717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37993717</a>] [<a href="https://doi.org/10.1038/s41586-023-06776-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37993717">Gruper et al. (2023)</a> investigated the mechanism of autoimmune amelogenesis imperfecta, which affects individuals with APS1 and children affected with celiac disease (<a href="/entry/212750">212750</a>). The vast majority (70 to 90%) of patients with APS1 develop IgA autoantibodies against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. Normally, AIRE expression in the thymus induces tolerance of ameloblast-specific protein. The lack of AIRE expression in APS1 and in AIRE-null mice results in a breakdown of central tolerance, and subsequent generation of autobodies that interfere with enamel formation. In celiac disease the generation of enamel autoantibodies appears to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel. Twenty to 50% of children affected with celiac disease manifest amelogenesis imperfecta; enamel defects are rarely seen in patients with celiac disease with later onset. Only secondary teeth are affected. <a href="#27" class="mim-tip-reference" title="Gruper, Y., Wolff, A. S. B., Glanz, L., Spoutil, F., Marthinussen, M. C., Osickova, A., Herzig, Y., Goldfarb, Y., Aranaz-Novaliches, G., Dobes, J., Kadouri, N., Ben-Nun, O., and 28 others. <strong>Autoimmune amelogenesis imperfecta in patients with APS-1 and coeliac disease.</strong> Nature 624: 653-662, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37993717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37993717</a>] [<a href="https://doi.org/10.1038/s41586-023-06776-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37993717">Gruper et al. (2023)</a> showed that patients with celiac disease have higher levels of IgA autoantibodies against the enamel proteins LAMB3 (<a href="/entry/150310">150310</a>), ACPT (<a href="/entry/606362">606362</a>), KLK4 (<a href="/entry/603767">603767</a>), AMELX (<a href="/entry/300391">300391</a>), FAM20A (<a href="/entry/611062">611062</a>), and ENAM (<a href="/entry/606585">606585</a>) compared with control individuals without celiac disease. TGM2 (<a href="/entry/190196">190196</a>) and LAMB3 are dental and intestinal antigens, and kappa-casein (CSN3; <a href="/entry/601695">601695</a>) is a dairy-based antigen. All 3 induce antibodies in celiac disease that interfere with enamel formation. The severity of the amelogenesis imperfecta relates to the duration of exposure and severity to autoantibodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37993717" 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>Loss of CD8-Positive T-Cell Homeostasis</em></strong></p><p>
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Although murine studies have linked Aire to thymocyte selection and peripheral deletional tolerance, the pathogenesis of human APECED is unclear. <a href="#41" class="mim-tip-reference" title="Laakso, S. M., Kekalainen, E., Rossi, L. H., Laurinolli, T.-T., Mannerstrom, H., Heikkila, N., Lehtoviita, A., Perheentupa, J., Jarva, H., Arstila, T. P. <strong>IL-7 dysregulation and loss of CD8+ T cell homeostasis in the monogenic human disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.</strong> J. Immun. 187: 2023-2030, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753149</a>] [<a href="https://doi.org/10.4049/jimmunol.1100212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753149">Laakso et al. (2011)</a> demonstrated increased CD8 (see <a href="/entry/186910">186910</a>)-positive/CD45RO (see <a href="/entry/151460">151460</a>)-negative T cells (i.e., CD8RA, or naive, T cells) that also expressed the proliferation marker Ki67 (MKI67; <a href="/entry/176741">176741</a>) in APECED patients with loss-of-function mutations in AIRE. ELISA indicated increased plasma IL7 (<a href="/entry/146660">146660</a>), while FACS analysis showed reduced IL7R (<a href="/entry/146661">146661</a>) on CD8-positive cells and, to a lesser extent, CD4 (<a href="/entry/186940">186940</a>)-positive T cells. Patients also had reduced CD5 (<a href="/entry/153340">153340</a>), CD62L (SELL; <a href="/entry/153240">153240</a>), and CCR7 (<a href="/entry/600242">600242</a>) expression, but somewhat increased perforin (PRF1; <a href="/entry/170280">170280</a>) expression, on CD8RA cells. Likewise, there was reduced expression of CD31 (PECAM1; <a href="/entry/173445">173445</a>), a marker for recent thymic emigrants. <a href="#41" class="mim-tip-reference" title="Laakso, S. M., Kekalainen, E., Rossi, L. H., Laurinolli, T.-T., Mannerstrom, H., Heikkila, N., Lehtoviita, A., Perheentupa, J., Jarva, H., Arstila, T. P. <strong>IL-7 dysregulation and loss of CD8+ T cell homeostasis in the monogenic human disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.</strong> J. Immun. 187: 2023-2030, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753149</a>] [<a href="https://doi.org/10.4049/jimmunol.1100212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753149">Laakso et al. (2011)</a> proposed that loss of CD8-positive T-cell homeostasis is likely to play a significant role in the pathogenesis of APECED. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21753149" 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="#49" class="mim-tip-reference" title="Nagamine, K., Peterson, P., Scott, H. S., Kudoh, J., Minoshima, S., Heino, M., Krohn, K. J. E., Lalioti, M. D., Mullis, P. E., Antonarakis, S. E., Kawasaki, K., Asakawa, S., Ito, F., Shimizu, N. <strong>Positional cloning of the APECED gene.</strong> Nature Genet. 17: 393-398, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398839</a>] [<a href="https://doi.org/10.1038/ng1297-393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398839">Nagamine et al. (1997)</a> found 2 mutations in the AIRE gene in Swiss and Finnish APECED patients: (R257X; <a href="/entry/607358#0001">607358.0001</a>), found in 10 of 12 alleles in the Finnish patients, and (K83E; <a href="/entry/607358#0002">607358.0002</a>). The <a href="#23" class="mim-tip-reference" title="Finnish-German APECED Consortium. <strong>An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains.</strong> Nature Genet. 17: 399-403, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398840</a>] [<a href="https://doi.org/10.1038/ng1297-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398840">Finnish-German APECED Consortium (1997)</a> identified 5 AIRE mutations, 4 in addition to the common Finnish mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9398839+9398840" 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>Using SSCP analysis and direct DNA sequencing, <a href="#52" class="mim-tip-reference" title="Pearce, S. H. S., Cheetham, T., Imrie, H., Vaidya, B., Barnes, N. D., Bilous, R. W., Carr, D., Meeran, K., Shaw, N. J., Smith, C. S., Toft, A. D., Williams, G., Kendall-Taylor, P. <strong>A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1.</strong> Am. J. Hum. Genet. 63: 1675-1684, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9837820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9837820</a>] [<a href="https://doi.org/10.1086/302145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9837820">Pearce et al. (1998)</a> identified a 13-bp deletion (<a href="/entry/607358#0003">607358.0003</a>) in the AIRE gene in 17 of 24 mutant alleles in 12 British families with APS I. This mutation was found to occur de novo in 1 affected subject. A common haplotype spanning the AIRE locus was found in chromosomes that carried the deletion mutation, suggesting a founder effect in this population. One of 576 normal subjects was also a heterozygous carrier of the deletion mutation. Six other point mutations were found, including two 1-bp deletions, 3 missense mutations, and a nonsense mutation. <a href="#60" class="mim-tip-reference" title="Scott, H. S., Heino, M., Peterson, P., Mittaz, L., Lalioti, M. D., Betterle, C., Cohen, A., Seri, M., Lerone, M., Romeo, G., Collin, P., Salo, M., and 9 others. <strong>Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins.</strong> Molec. Endocr. 12: 1112-1119, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9717837/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9717837</a>] [<a href="https://doi.org/10.1210/mend.12.8.0143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9717837">Scott et al. (1998)</a> likewise found common mutations in patients of various ethnic origins with APS I. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9717837+9837820" 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>To understand the complexity of the APECED phenotype, <a href="#30" class="mim-tip-reference" title="Halonen, M., Eskelin, P., Myhre, A.-G., Perheentupa, J., Husebye, E. S., Kampe, O., Rorsman, F., Peltonen, L., Ulmanen, I., Partanen, J. <strong>AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype.</strong> J. Clin. Endocr. Metab. 87: 2568-2574, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050215</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8564" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050215">Halonen et al. (2002)</a> studied the AIRE and HLA class II genotypes in a series of patients with APECED. The only association between the phenotype and the AIRE genotype was the higher prevalence of candidiasis in the patients with the most common mutation, arg257 to ter (<a href="/entry/607358#0001">607358.0001</a>), than in those with other mutations. Addison disease was associated with HLA-DRB1*03 (P = 0.021), alopecia with HLA-DRB1*04/DQB1*0302 (P less than 0.001), whereas type 1 diabetes correlated negatively with HLA-DRB1*15/DQB1*0602 (P = 0.036). The authors concluded that AIRE mutation has little influence on the APECED phenotype, whereas, in contrast to earlier reports, HLA class II is a significant determinant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050215" 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="#31" class="mim-tip-reference" title="Harris, M., Kecha, O., Deal, C., Howlett, C. R., Deiss, D., Tobias, V., Simoneau-Roy, J., Walker, J. <strong>Reversible metaphyseal dysplasia, a novel bone phenotype, in two unrelated children with autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy: clinical and molecular studies.</strong> J. Clin. Endocr. Metab. 88: 4576-4585, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557425</a>] [<a href="https://doi.org/10.1210/jc.2003-030089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14557425">Harris et al. (2003)</a> reported the association of a theretofore undescribed reversible metaphyseal dysplasia with autoimmune APECED in 2 patients, 1 homozygous and the other heterozygous for a 13-bp deletion in exon 8 of the AIRE gene (<a href="/entry/607358#0003">607358.0003</a>). One patient also had a novel deletion in exon 6, resulting in a frameshift mutation and introduction of a stop codon in exon 10 (<a href="/entry/607358#0009">607358.0009</a>). Their APECED phenotypes differed, but both patients developed progressive skeletal deformities and growth failure from early childhood. Radiologic examination suggested a generalized abnormality of endochondral ossification, with irregular, flared, radioopaque regions in the metaphyses, subjacent to the growth plates. Histopathology in patient 1 showed islands of calcified cartilage within bone, consistent with impaired coupling of cartilage resorption with vascular invasion and ossification. Despite discordance for puberty, both patients experienced radiologic resolution of their bone disease in their mid-teens, with improvement in histopathology in patient 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14557425" 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>Among 14 unrelated Polish patients with APECED, <a href="#64" class="mim-tip-reference" title="Stolarski, B., Pronicka, E., Korniszewski, L., Pollak, A., Kostrzewa, G., Rowinska, E., Wlodarski, P., Skorka, A., Gremida, M., Krajewski, P., Ploski, R. <strong>Molecular background of polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence.</strong> Clin. Genet. 70: 348-354, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16965330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16965330</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00690.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16965330">Stolarski et al. (2006)</a> identified 6 different mutations in the AIRE gene, including 3 novel mutations (see, e.g., <a href="/entry/607358#0008">607358.0008</a>). R257X was the most common mutation, accounting for 71% of mutant alleles. The authors stated that 57 pathogenic mutations in the AIRE gene had been described. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16965330" 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="#18" class="mim-tip-reference" title="Eggermann, T., Elbracht, M., Haverkamp, F., Schmidt, C., Zerres, K. <strong>Isolated cystinuria (OMIM 238200) is not a separate entity but is caused by a mutation in the cystinuria gene SLC7A9. (Letter)</strong> Clin. Genet. 71: 597-598, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17539912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17539912</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00797.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17539912">Eggermann et al. (2007)</a> followed a patient previously diagnosed by <a href="#11" class="mim-tip-reference" title="Brodehl, J., Gellissen, K., Kowalewski, S. <strong>Isolierter Defekt der tubulaeren Cystin-Rueckresorption in einer Familie mit idiopathischem Hypoparathyroidismus.</strong> Klin. Wschr. 45: 38-40, 1967.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6031738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6031738</a>] [<a href="https://doi.org/10.1007/BF01745737" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6031738">Brodehl et al. (1967)</a> with idiopathic hypoparathyroidism and isolated hypercystinuria (see <a href="/entry/220100">220100</a>) discovered during an episode of candidiasis at 2 years of age, who subsequently developed Addison disease at 26 years of age, leading to the diagnosis of APS1. Two older sibs had died from hypocalcemic tetany. Direct sequencing of the AIRE gene revealed compound heterozygosity for the common R257X (<a href="/entry/607358#0001">607358.0001</a>) and 964del13 (<a href="/entry/607358#0003">607358.0003</a>) mutations; the patient was also found to carry a mutation in the SLC7A9 gene (<a href="/entry/604144#0014">604144.0014</a>) believed to be responsible for the cystinuria phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6031738+17539912" 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="#21" class="mim-tip-reference" title="Faiyaz-Ul-Haque, M., Bin-Abbas, B., Al-Abdullatif, A., Abdullah Abalkhail, H., Toulimat, M., Al-Gazlan, S., Almutawa, A. M., Al-Sagheir, A., Peltekova, I., Al-Dayel, F., Zaidi, S. H. E. <strong>Novel and recurrent mutations in the AIRE gene of autoimmune polyendocrinopathy syndrome type 1 (APS1) patients.</strong> Clin. Genet. 76: 431-440, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19758376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19758376</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01278.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19758376">Faiyaz-Ul-Haque et al. (2009)</a> reported 18 patients with APS1 from 7 consanguineous Arab families. One recurrent (<a href="/entry/607358#0010">607358.0010</a>) and 4 novel mutations in the AIRE gene were identified in 6 of the families; in 1 family no mutation was present in the coding region or exon/intron boundaries of the AIRE gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19758376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 9 Indian patients with APS1 from 8 families, <a href="#69" class="mim-tip-reference" title="Zaidi, G., Sahu, R. P., Zhang, L., George, G., Bhavani, N., Shah, N., Bhatia, V., Bhansali, A., Jevalikar, G., Jayakumar, R. V., Eisenbarth, G. S., Bhatia, E. <strong>Two novel AIRE mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) among Indians.</strong> Clin. Genet. 76: 441-448, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19807739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19807739</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01280.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19807739">Zaidi et al. (2009)</a> identified homozygosity for 3 mutations previously reported in Caucasian individuals (<a href="/entry/607358#0001">607358.0001</a>, <a href="/entry/607358#0003">607358.0003</a>, <a href="/entry/607358#0004">607358.0004</a>) and 2 novel mutations, 1 of which appeared to be an ancestral mutation (<a href="/entry/607358#0011">607358.0011</a>), in the AIRE gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19807739" 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 3 sibs with hypoparathyroidism, including a sister who had premature ovarian failure, who were negative for mutation in 6 hypoparathyroidism- and calcium metabolism-associated genes, <a href="#42" class="mim-tip-reference" title="Li, D., Streeten, E. A., Chan, A., Lwin, W., Tian, L., Pellegrino da Silva, R., Kim, C. E., Anderson, M. S., Hakonarson, H., Levine, M. A. <strong>Exome sequencing reveals mutations in AIRE as a cause of isolated hypoparathyroidism.</strong> J. Clin. Endocr. Metab. 102: 1726-1733, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28323927/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28323927</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28323927[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/10.1210/jc.2016-3836" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28323927">Li et al. (2017)</a> identified compound heterozygosity for the recurrent 13-bp deletion in the AIRE gene (<a href="/entry/607358#0003">607358.0003</a>) and a splicing mutation (<a href="/entry/607358#0012">607358.0012</a>). The unaffected parents were each heterozygous for 1 of the mutations, and unaffected offspring were either heterozygous or wildtype. Noting that the patients were in the sixth and seventh decades of life, and that multiple manifestations of APS1 usually develop by the fifth decade of life, the authors stated that it was unclear why 2 of the 3 patients had such a limited APS1 phenotype. However, the near-constant development of hypoparathyroidism in APS1 suggested that parathyroid involvement occurs at a very low threshold and represents a very mild expression of the disease. The authors also noted that antibodies to NALP5, previously proposed as a useful indicator of parathyroid autoimmunity in APS1, were absent in their patients, suggesting that the NALP5 autoantibody is not a very sensitive marker for hypoparathyroidism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28323927" 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>Autoimmune Polyendocrinopathy Syndrome, Type I, Autosomal Dominant</em></strong></p><p>
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<a href="#13" class="mim-tip-reference" title="Cetani, F., Barbesino, G., Borsari, S., Pardi, E., Cianferotti, L., Pinchera, A., Marcocci, C. <strong>A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis.</strong> J. Clin. Endocr. Metab. 86: 4747-4752, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11600535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11600535</a>] [<a href="https://doi.org/10.1210/jcem.86.10.7884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11600535">Cetani et al. (2001)</a> identified an Italian family with autoimmune polyendocrinopathy syndrome and a pattern of inheritance suggestive of a dominant mechanism. Serologic and clinical studies showed a high prevalence of hypothyroid autoimmune thyroiditis in affected members with classic autoimmune polyendocrinopathy. Direct sequencing of the entire coding region of the AIRE gene revealed the presence in the proband of a novel missense mutation in exon 6, gly228 to trp, in heterozygous state (G228W; <a href="/entry/607358#0007">607358.0007</a>). In contrast with all other autoimmune regulator mutations reported in families, the novel G228W mutation acts in a dominant fashion in this family, as only one heterozygous mutation was found in the entire coding sequence of the autoimmune regulator gene in the proband. Moreover, analysis of the family tree showed direct transmission of the APECED phenotype to the offspring in each generation in the absence of consanguinity. The G228W mutation closely cosegregated with hypothyroid autoimmune thyroiditis in this family, whereas a low penetrance of the full autoimmune polyendocrinopathy phenotype was observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11600535" 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="#37" class="mim-tip-reference" title="Ilmarinen, T., Eskelin, P., Halonen, M., Ruppell, T., Kilpikari, R., Duran Torres, G., Kangas, H., Ulmanen, I. <strong>Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation.</strong> Hum. Mutat. 26: 322-331, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16114041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16114041</a>] [<a href="https://doi.org/10.1002/humu.20224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16114041">Ilmarinen et al. (2005)</a> analyzed the effect of AIRE proteins with mutations in the SAND domain on wildtype AIRE in a simulated heterozygous situation in vitro. Only the G228W mutant changed the subcellular localization and severely disrupted the transactivating capacity of wildtype AIRE. <a href="#37" class="mim-tip-reference" title="Ilmarinen, T., Eskelin, P., Halonen, M., Ruppell, T., Kilpikari, R., Duran Torres, G., Kangas, H., Ulmanen, I. <strong>Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation.</strong> Hum. Mutat. 26: 322-331, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16114041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16114041</a>] [<a href="https://doi.org/10.1002/humu.20224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16114041">Ilmarinen et al. (2005)</a> concluded that the G228W protein acts with a dominant-negative effect by binding to wildtype AIRE, preventing the protein from forming the complexes needed for transactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16114041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a cohort of 305 index patients, including 144 probands with suspected APS1 and 161 with suspected familial hypoparathyroidism, <a href="#17" class="mim-tip-reference" title="Cranston, T., Boon, H., Olesen, M. K., Ryan, F. J., Shears, D., London, R., Rostom, H., Elajnaf, T., Thakker, R. V., Hannan, F. M. <strong>Spectrum of germline AIRE mutations causing APS-1 and familial hypoparathyroidism.</strong> Europ. J. Endocr. 187: 111-122, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35521792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35521792</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35521792[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/10.1530/EJE-21-0730" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35521792">Cranston et al. (2022)</a> sequenced the AIRE gene and identified germline mutations in 40 probands. The authors compared clinical features of probands with suspected APS1 who had AIRE mutations to those without, and observed that more than 45% of probands with AIRE mutations had at least 2 diseases out of the triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency, whereas significantly fewer AIRE mutation-negative probands with suspected APS1 (approximately 16%; p less than 0.01) had developed 2 out of 3 components of the classic disease triad. In addition, hypoparathyroidism occurred significantly more frequently (p less than 0.0001) in probands with AIRE mutations, whereas type 1 diabetes and hypothyroidism occurred significantly more frequently (p less than 0.01) in AIRE mutation-negative probands. Among the probands with suspected familial hypoparathyroidism, 5 children with apparent isolated hypoparathyroidism were homozygous for mutations in the AIRE gene (see, e.g., <a href="/entry/607358#0003">607358.0003</a>). However, the authors noted that autoimmune parathyroid gland destruction represents an early manifestation of APS1, with a peak incidence at around 5 years of age, and thus it remained to be established whether those 5 probands would subsequently develop additional features of APS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35521792" 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="#53" class="mim-tip-reference" title="Perheentupa, J. <strong>Autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED). In: Eriksson, A. W.; Forsius, H. R.; Nevanlinna, H. R.; Workman, P. L.; Norio, R. K.: Population Structure and Genetic Disorders.</strong> New York: Academic Press (pub.) 1980. Pp. 583-587."None>Perheentupa (1980)</a> stated that 40 cases of APECED in 28 families had been identified in Finland as compared to less than 100 cases elsewhere in the world. <a href="#3" class="mim-tip-reference" title="Ahonen, P. <strong>Autoimmune polyendocrinopathy--candidosis--ectodermal dystrophy (APECED): autosomal recessive inheritance.</strong> Clin. Genet. 27: 535-542, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4017274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4017274</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1985.tb02037.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4017274">Ahonen (1985)</a> also demonstrated that APECED is part of the 'Finnish heritage of disease.' The disorder is unusually frequent in some Finnish subpopulations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4017274" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Bjorses, P., Halonen, M., Palvimo, J. J., Kolmer, M., Aaltonen, J., Ellonen, P., Perheentupa, J., Ulmanen, I., Peltonen, L. <strong>Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein.</strong> Am. J. Hum. Genet. 66: 378-392, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677297</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677297[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/10.1086/302765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677297">Bjorses et al. (2000)</a> stated that APECED is enriched in 3 genetically isolated populations: the Finnish, Iranian Jews, and Sardinians. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677297" 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="#22" class="mim-tip-reference" title="Falorni, A., Laureti, S., De Bellis, A., Zanchetta, R., Tiberti, C., Arnaldi, G., Bini, V., Beck-Peccoz, P., Bizzarro, A., Dotta, F., Mantero, F., Bellastella, A., Betterle, C., Santeusanio, F., SIE Addison Study Group. <strong>Italian Addison Network Study: update of diagnostic criteria for the etiological classification of primary adrenal insufficiency.</strong> J. Clin. Endocr. Metab. 89: 1598-1604, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15070918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15070918</a>] [<a href="https://doi.org/10.1210/jc.2003-030954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15070918">Falorni et al. (2004)</a> studied 222 Italian patients with primary adrenal insufficiency (PAI) and found APS1 in 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15070918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The prevalence of APECED is increased in Finland and Sardinia, where it occurs in 1 in 25,000 (<a href="#2" class="mim-tip-reference" title="Ahonen, P., Myllarniemi, S., Sipila, I., Perheentupa, J. <strong>Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients.</strong> New Eng. J. Med. 322: 1829-1836, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2348835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2348835</a>] [<a href="https://doi.org/10.1056/NEJM199006283222601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2348835">Ahonen et al., 1990</a>) and 1 in 14,000 (<a href="#57" class="mim-tip-reference" title="Rosatelli, M. C., Meloni, A., Meloni, A., Devoto, M., Cao, A., Scott, H. S., Peterson, P., Heino, M., Krohn, K. J. E., Nagamine, K., Kudoh, J., Shimizu, N., Antonarakis, S. E. <strong>A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients.</strong> Hum. Genet. 103: 428-434, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9856486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9856486</a>] [<a href="https://doi.org/10.1007/s004390050846" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9856486">Rosatelli et al., 1998</a>) individuals, respectively. Estimates in other populations include 1 in 80,000 in Norway (<a href="#48" class="mim-tip-reference" title="Myhre, A. G., Halonen, M., Eskelin, P., Ekwall, O., Hedstrand, H., Rorsman, F., Kampe, O., Husebye, E. S. <strong>Autoimmune polyendocrine syndrome type 1 (APS I) in Norway.</strong> Clin. Endocr. 54: 211-217, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11207636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11207636</a>] [<a href="https://doi.org/10.1046/j.1365-2265.2001.01201.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11207636">Myhre et al., 2001</a>), 1 in 43,000 in Slovenia (<a href="#54" class="mim-tip-reference" title="Podkrajsek, K. T., Bratanic, N., Krzisnik, C., Battelino, T. <strong>Autoimmune regulator-1 messenger ribonucleic acid analysis in a novel intronic mutation and two additional novel AIRE gene mutations in a cohort of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients.</strong> J. Clin. Endocr. Metab. 90: 4930-4935, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15886230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15886230</a>] [<a href="https://doi.org/10.1210/jc.2005-0418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15886230">Podkrajsek et al., 2005</a>), and 1 in 129,000 in Poland (<a href="#64" class="mim-tip-reference" title="Stolarski, B., Pronicka, E., Korniszewski, L., Pollak, A., Kostrzewa, G., Rowinska, E., Wlodarski, P., Skorka, A., Gremida, M., Krajewski, P., Ploski, R. <strong>Molecular background of polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence.</strong> Clin. Genet. 70: 348-354, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16965330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16965330</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00690.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16965330">Stolarski et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9856486+2348835+11207636+15886230+16965330" 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="#68" class="mim-tip-reference" title="Wolff, A. S. B., Erichsen, M. M., Meager, A., Magitta, N. F., Myhre, A. G., Bollerslev, J., Fougner, K. J., Lima, K., Knappskog, P. M., Husebye, E. S. <strong>Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene.</strong> J. Clin. Endocr. Metab. 92: 595-603, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17118990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17118990</a>] [<a href="https://doi.org/10.1210/jc.2006-1873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17118990">Wolff et al. (2007)</a> estimated the prevalence of APS1 in Norway to be 1 in 90,000. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17118990" 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="#26" class="mim-tip-reference" title="Goldfarb, Y., Givony, T., Kadouri, N., Dobes, J., Peligero-Cruz, C., Zalayat, I., Damari, G., Dassa, B., Ben-Dor, S., Gruper, Y., Oftedal, B. E., Bratland, E., and 13 others. <strong>Mechanistic dissection of dominant AIRE mutations in mouse models reveals AIRE autoregulation.</strong> J. Exp. Med. 218: e20201076, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34477806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34477806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34477806[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/10.1084/jem.20201076" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34477806">Goldfarb et al. (2021)</a> developed mouse models to recapitulate dominant and recessive mutations in the AIRE gene that were identified in patients with APS1. The mouse Aire mutations C313X and Y86C were modeled after the human autosomal recessive mutations C311X and Y85C, respectively, and the mouse Aire mutations V303M, C313Y, and C442G were modeled after the human autosomal dominant mutations V301M, C311Y, and C446G, respectively. The Aire C313Y heterozygous mice had lymphocytic infiltrates in the liver, prostate, and salivary glands and developed autoantibodies against eye, stomach, and liver. Ultimately, they died from a fatal wasting disease. The Aire C442G heterozygous mutant mice had a milder phenotype with incomplete penetrance of retinal degeneration and prostatitis. The Aire V303M mutation was found to be functionally nonpathologic. Mice that were homozygous for the C313X or Y86C mutations had absent Aire protein expression in EpCAM-enriched stroma. The C313X lack of protein expression was determined to be due to mRNA nonsense-mediated decay, whereas the lack of Y86C protein expression was determined to be due to proteolytic degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34477806" 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>An infectious etiology was suggested by <a href="#40" class="mim-tip-reference" title="Kunin, A. S., MacKay, B. R., Burns, S. L., Halberstam, M. J. <strong>The syndrome of hypoparathyroidism and adrenocortical insufficiency, a possible sequel of hepatitis: case report and review of the literature.</strong> Am. J. Med. 34: 856-866, 1963."None>Kunin et al. (1963)</a> who pointed out that hepatitis had occurred in a number of these cases before the development of endocrinopathy.</p><p>Heterogeneity in Addison disease and hypoparathyroidism was suggested by the analysis of <a href="#63" class="mim-tip-reference" title="Spinner, M. W., Blizzard, R. M., Childs, B. <strong>Clinical and genetical heterogeneity in idiopathic Addison's disease and hypoparathyroidism.</strong> J. Clin. Endocr. 28: 795-804, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5656437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5656437</a>] [<a href="https://doi.org/10.1210/jcem-28-6-795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5656437">Spinner et al. (1968)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5656437" 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="#44" class="mim-tip-reference" title="Maclaren, N. K., Riley, W. J. <strong>Inherited susceptibility to autoimmune Addison's disease is linked to human leukocyte antigens-DR3 and/or DR4, except when associated with type I autoimmune polyglandular syndrome.</strong> J. Clin. Endocr. Metab. 62: 455-459, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3484749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3484749</a>] [<a href="https://doi.org/10.1210/jcem-62-3-455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3484749">Maclaren and Riley (1986)</a> found that autoimmune Addison disease was strongly associated with HLA-DR3 and HLA-DR4; relative risks were 6.0, 4.6, and 26.5 for DR3, DR4, and DR3/DR4, respectively. This is similar to the findings for insulin-dependent diabetes. Patients with type I autoimmune polyglandular syndrome did not show the association. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3484749" 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="#Arulanantham1979" class="mim-tip-reference" title="Arulanantham, K., Dwyer, J. M., Genel, M. <strong>Evidence for defective immunoregulation in the syndrome of familial candidiasis endocrinopathy.</strong> New Eng. J. Med. 300: 164-168, 1979.">Arulanantham et al. (1979)</a>; <a href="#Castells1971" class="mim-tip-reference" title="Castells, S., Fikrig, S., Inamdar, S., Orti, E. <strong>Familial moniliasis, defective delayed hypersensitivity, and adrenocorticotropic hormone deficiency.</strong> J. Pediat. 79: 72-79, 1971.">Castells et al. (1971)</a>; <a href="#Craig1955" class="mim-tip-reference" title="Craig, J. M., Schiff, L. H., Boone, J. E. <strong>Chronic moniliasis associated with Addison's disease.</strong> AMA Am. J. Dis. Child. 89: 669-684, 1955.">Craig et al.
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(1955)</a>; <a href="#Gass1962" class="mim-tip-reference" title="Gass, J. D. M. <strong>The syndrome of keratoconjunctivitis, superficial moniliasis, idiopathic hypoparathyroidism and Addison's disease.</strong> Am. J. Ophthal. 54: 660-674, 1962.">Gass (1962)</a>; <a href="#Hiekkala1964" class="mim-tip-reference" title="Hiekkala, H. <strong>Idiopathic hypoparathyroidism, adrenal insufficiency and moniliasis in children.</strong> Ann. Paediat. Fenn. 10: 213-222, 1964.">Hiekkala (1964)</a>; <a href="#Kenny1964" class="mim-tip-reference" title="Kenny, F. M., Holliday, M. D. <strong>Hypoparathyroidism, moniliasis, Addison's and Hashimoto's disease. Hypercalcemia treated with intravenously administered sodium sulfate.</strong> New Eng. J. Med. 271: 708-713, 1964.">Kenny and Holliday (1964)</a>; <a href="#Louria1967" class="mim-tip-reference" title="Louria, D. B., Shannon, D. C., Johnson, G., Caroline, L., Okas, A., Taschdjian, C. <strong>The susceptibility to moniliasis in children with endocrine hypofunction.</strong> Trans. Assoc. Am. Phys. 80: 236-249, 1967.">Louria et al. (1967)</a>; <a href="#Sweetnam1966" class="mim-tip-reference" title="Sweetnam, W. P. <strong>Juvenile familial endocrinopathy.</strong> Lancet 287: 463-465, 1966. Note: Originally Volume I.">Sweetnam (1966)</a>; <a href="#Whitaker1956" class="mim-tip-reference" title="Whitaker, J. A., Landing, B. H., Esselborn, V. M., Williams, R. R. <strong>Syndrome of familial juvenile hypoadrenocorticism, hypoparathyroidism and superficial moniliasis.</strong> J. Clin. Endocr. 16: 1374-1387, 1956.">Whitaker et al. (1956)</a>; <a href="#Wirfalt1981" class="mim-tip-reference" title="Wirfalt, A. <strong>Genetic heterogeneity in autoimmune polyglandular failure.</strong> Acta Med. Scand. 210: 7-13, 1981.">Wirfalt (1981)</a>
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[<a href="https://doi.org/10.1056/NEJMoa0706487" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMra030158" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM196309262691303" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.82.1.3647" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM196410012711404" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19807739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19807739</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19807739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2009.01280.x" target="_blank">Full Text</a>]
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<a id="70" class="mim-anchor"></a>
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<a id="Zlotogora1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zlotogora, J., Shapiro, M. S.
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<strong>Polyglandular autoimmune syndrome type I among Iranian Jews.</strong>
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J. Med. Genet. 29: 824-826, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1453436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1453436</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1453436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.29.11.824" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Ada Hamosh - updated : 01/23/2024
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Marla J. F. O'Neill - updated : 07/05/2022<br>Hilary J. Vernon - updated : 01/21/2022<br>Jane Kelly - updated : 03/29/2016<br>Paul J. Converse - updated : 1/6/2012<br>Paul J. Converse - updated : 5/25/2010<br>Marla J. F. O'Neill - updated : 1/13/2010<br>John A. Phillips, III - updated : 3/3/2009<br>Victor A. McKusick - updated : 3/26/2008<br>John A. Phillips, III - updated : 12/17/2007<br>Marla J. F. O'Neill - updated : 7/17/2007<br>John A. Phillips, III - updated : 11/16/2006<br>Cassandra L. Kniffin - updated : 11/2/2006<br>Marla J. F. O'Neill - updated : 11/4/2005<br>John A. Phillips, III - updated : 7/22/2005<br>John A. Phillips, III - updated : 4/28/2005<br>Victor A. McKusick - updated : 5/19/2004<br>John A. Phillips, III - updated : 2/3/2003<br>Cassandra L. Kniffin - reorganized : 11/19/2002<br>George E. Tiller - updated : 9/26/2002<br>John A. Phillips, III - updated : 8/7/2002<br>John A. Phillips, III - updated : 3/22/2002<br>Victor A. McKusick - updated : 9/26/2001<br>John A. Phillips, III - updated : 7/11/2001<br>John A. Phillips, III - updated : 3/8/2001<br>Victor A. McKusick - updated : 10/23/2000<br>Victor A. McKusick - updated : 3/31/2000<br>Victor A. McKusick - updated : 1/13/2000<br>Ada Hamosh - updated : 4/8/1999<br>Victor A. McKusick - updated : 1/21/1999<br>Victor A. McKusick - updated : 1/14/1999<br>Victor A. McKusick - updated : 1/11/1999<br>John A. Phillips, III - updated : 9/29/1998<br>Victor A. McKusick - updated : 12/2/1997<br>Victor A. McKusick - updated : 9/23/1997<br>John A. Phillips, III - updated : 5/29/1997<br>John A. Phillips, III - updated : 1/18/1997
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 6/3/1986
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alopez : 05/07/2024
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alopez : 01/23/2024<br>carol : 07/06/2022<br>alopez : 07/05/2022<br>carol : 01/24/2022<br>carol : 01/24/2022<br>carol : 01/21/2022<br>alopez : 09/15/2016<br>carol : 03/29/2016<br>carol : 5/12/2014<br>carol : 1/2/2014<br>carol : 12/30/2013<br>mgross : 1/19/2012<br>terry : 1/6/2012<br>wwang : 6/10/2011<br>alopez : 3/24/2011<br>wwang : 5/25/2010<br>wwang : 3/22/2010<br>wwang : 1/25/2010<br>terry : 1/13/2010<br>terry : 3/4/2009<br>alopez : 3/3/2009<br>alopez : 3/3/2009<br>terry : 3/3/2009<br>mgross : 10/21/2008<br>alopez : 3/26/2008<br>terry : 3/26/2008<br>carol : 12/17/2007<br>terry : 9/19/2007<br>wwang : 7/18/2007<br>terry : 7/17/2007<br>alopez : 4/12/2007<br>carol : 12/13/2006<br>carol : 12/13/2006<br>alopez : 11/16/2006<br>carol : 11/6/2006<br>carol : 11/3/2006<br>ckniffin : 11/2/2006<br>wwang : 6/22/2006<br>wwang : 11/4/2005<br>alopez : 7/22/2005<br>alopez : 4/28/2005<br>tkritzer : 5/19/2004<br>cwells : 2/3/2003<br>ckniffin : 11/19/2002<br>carol : 11/19/2002<br>ckniffin : 11/18/2002<br>ckniffin : 11/18/2002<br>cwells : 9/26/2002<br>cwells : 8/7/2002<br>carol : 6/4/2002<br>alopez : 3/22/2002<br>carol : 10/4/2001<br>mcapotos : 10/2/2001<br>terry : 9/26/2001<br>alopez : 7/11/2001<br>alopez : 3/8/2001<br>alopez : 3/8/2001<br>mcapotos : 11/6/2000<br>mcapotos : 11/2/2000<br>terry : 10/23/2000<br>alopez : 6/20/2000<br>mgross : 4/11/2000<br>terry : 3/31/2000<br>mcapotos : 1/14/2000<br>mcapotos : 1/14/2000<br>terry : 1/13/2000<br>carol : 5/18/1999<br>carol : 5/18/1999<br>alopez : 4/8/1999<br>alopez : 4/8/1999<br>alopez : 4/8/1999<br>mgross : 3/17/1999<br>mgross : 3/10/1999<br>alopez : 3/9/1999<br>carol : 2/1/1999<br>terry : 1/21/1999<br>carol : 1/15/1999<br>carol : 1/14/1999<br>terry : 1/11/1999<br>carol : 12/17/1998<br>carol : 9/29/1998<br>carol : 6/29/1998<br>jenny : 12/2/1997<br>terry : 11/25/1997<br>terry : 9/26/1997<br>terry : 9/23/1997<br>alopez : 7/29/1997<br>alopez : 7/8/1997<br>jenny : 6/20/1997<br>jenny : 5/29/1997<br>jenny : 5/29/1997<br>jenny : 5/28/1997<br>jenny : 5/28/1997<br>mark : 11/21/1996<br>mark : 11/21/1996<br>terry : 11/19/1996<br>mark : 10/25/1996<br>terry : 10/17/1996<br>mark : 8/21/1995<br>carol : 2/6/1995<br>warfield : 4/15/1994<br>mimadm : 2/19/1994<br>carol : 1/7/1993<br>carol : 12/3/1992
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<span class="mim-font">
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<strong>#</strong> 240300
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<h3>
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AUTOIMMUNE POLYENDOCRINE SYNDROME, TYPE I, WITH OR WITHOUT REVERSIBLE METAPHYSEAL DYSPLASIA; APS1
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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APS I<br />
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AUTOIMMUNE POLYENDOCRINOPATHY-CANDIDIASIS-ECTODERMAL DYSTROPHY; APECED<br />
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AUTOIMMUNE POLYGLANDULAR SYNDROME, TYPE I<br />
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POLYGLANDULAR AUTOIMMUNE SYNDROME, TYPE I<br />
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PGA I<br />
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HYPOADRENOCORTICISM WITH HYPOPARATHYROIDISM AND SUPERFICIAL MONILIASIS
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Other entities represented in this entry:
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<span class="h3 mim-font">
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AUTOIMMUNE POLYENDOCRINOPATHY SYNDROME, TYPE I, AUTOSOMAL DOMINANT, INCLUDED
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<span class="h4 mim-font">
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POLYGLANDULAR DEFICIENCY SYNDROME, PERSIAN-JEWISH TYPE, INCLUDED
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<strong>SNOMEDCT:</strong> 11244009;
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<strong>ORPHA:</strong> 3453;
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<strong>DO:</strong> 0050167;
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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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21q22.3
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<span class="mim-font">
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Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia
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<span class="mim-font">
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240300
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<td>
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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<td>
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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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AIRE
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<span class="mim-font">
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607358
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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 of evidence that autoimmune polyendocrinopathy syndrome type I (APS1) is caused by homozygous, compound heterozygous, or heterozygous mutation in the autoimmune regulator gene (AIRE; 607358) on chromosome 21q22.</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>Autoimmune polyglandular syndrome type I (APS1) is characterized by the presence of 2 of 3 major clinical symptoms: Addison disease, and/or hypoparathyroidism, and/or chronic mucocutaneous candidiasis (Neufeld et al., 1981). However, variable APS1 phenotypes have been observed, even among sibs. In addition, some patients may exhibit apparent isolated hypoparathyroidism, an early manifestation of APS1 with peak incidence at around age 5 years; over long-term follow-up, the development of additional features of APS1 may be observed (Cranston et al., 2022). </p>
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<strong>Clinical Features</strong>
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<p>Malabsorption and diarrhea can be very striking and even dominate the clinical picture (Prader, 1972).</p><p>Neufeld et al. (1980) recognized 3 types of the polyglandular autoimmune syndrome. Neufeld et al. (1981) collated information on 295 patients with autoimmune Addison disease as part of a polyglandular autoimmune syndrome. The information was supplied to them by members of the Lawson Wilkins Pediatric Endocrine Society and obtained from the literature. PGA I is represented by patients who have at least 2 of the triad of Addison disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. Associated immune disorders may be present. The Addison disease of PGA I has its predominant age of onset in childhood or early adulthood. It is also frequently associated with chronic active hepatitis, malabsorption, juvenile-onset pernicious anemia, alopecia, and primary hypogonadism. Insulin-dependent diabetes mellitus (IDDM; see 222100) and/or autoimmune thyroid disease are infrequent. PGA II (Schmidt syndrome; 269200) is represented by patients who have Addison disease with autoimmune thyroid disease and/or insulin-dependent diabetes mellitus, but do not have hypoparathyroidism or candidiasis, although other autoimmune disorders may be present. Although not confined to one age group or sex, PGA II is predominantly a disease of middle-aged females. The autoimmune disorders that occur with PGA I (e.g., chronic active hepatitis) are rare in PGA II, except for a low frequency of gonadal failure. Addison disease probably has a different genetic basis in PGA I than in PGA II. PGA III is represented by patients who have autoimmune thyroid disease and one or more other autoimmune disorders but do not have Addison disease. </p><p>In autoimmune adrenal insufficiency, isolated hypoaldosteronism may occur as a transient state on the way to Addison disease (Saenger, 1984). In a patient reported by Saenger et al. (1982) and in one reported by Marieb et al. (1974), impairment of fasciculata function or Addison disease developed over a period of several years after initial presentation with isolated hypoaldosteronism due to an early selective damage to the zona glomerulosa. At an early stage, primary hypoaldosteronism (203400, 610600) might be incorrectly diagnosed. Selective testing for antibodies against the 3 layers of the adrenal cortex is possible (Saenger, 1984). </p><p>McKusick (1985) observed achalasia in this syndrome. The association is observed also in the achalasia-addisonianism-alacrima syndrome (231550). Hendrix (1985) pointed out that although achalasia predisposes to esophageal candidiasis through lack of the normal cleansing effect of peristalsis, it is doubtful that invasive candidiasis can produce true achalasia, nor in ordinary achalasia is there evidence, it seems, of an autoimmune basis. Association of achalasia with autoimmune thyroiditis has not been observed, for example.</p><p>Ahonen et al. (1990) reported data from a 10-month to 31-year follow-up of 68 patients from 54 families, aged 10 months to 53 years at the time of report. The largest previous reported series, aside from earlier studies in Finnish patients, involved 9 patients. Ahonen et al. (1990) emphasized the broad clinical spectrum. Hypoplasia of the dental enamel and keratopathy were frequent and were not attributable to hypoparathyroidism. Some of the manifestations of the disorder did not appear until the fifth decade. Thus, all patients need lifelong follow-up for the detection of new components of the disease. Candidiasis was the initial manifestation in 60% of the patients and was present in all patients at some time. Hypoparathyroidism was present in 79%, adrenocortical failure in 72%, and gonadal failure in 60% of female patients over 13 years of age, and in 14% of male patients over 16 years of age. Half of the patients had multiple endocrine deficiencies. Two affected women had given birth, and 3 men reported having fathered healthy children. No genetic data were presented. </p><p>Betterle et al. (1998) reviewed the clinical findings of APECED. They found that the spectrum of associated minor clinical diseases includes other autoimmune endocrinopathies (hypergonadotropic hypogonadism, insulin-dependent diabetes mellitus, autoimmune thyroid diseases, and pituitary defects), autoimmune or immuno-mediated gastrointestinal diseases (chronic atrophic gastritis, pernicious anemia, and malabsorption), chronic active hepatitis, autoimmune skin diseases (vitiligo and alopecia), ectodermal dystrophy, keratoconjunctivitis, immunologic defects (cellular and humoral), asplenia, and cholelithiasis. The first manifestations usually occur in childhood with the 3 main diseases developing in the first 20 years of life, and other accompanying diseases continue to appear until at least the fifth decade. In a majority of cases, candidiasis is the first clinical manifestation to appear, usually before the age of 5 years, followed by hypoparathyroidism (usually before the age of 10 years), and later by Addison disease (usually before the age of 15 years). Overall, the 3 main components of APECED occur in chronologic order, but they are present together in only about one-third to one-half of the cases. Generally, the earlier the first components appear, the more likely it is that multiple components will develop; conversely, patients who have late manifestations of the disease are likely to have fewer components. </p><p>Among 79 patients with central diabetes insipidus, Maghnie et al. (2000) identified 1 patient with autoimmune polyendocrinopathy. The patient was almost 25 years old at the time of presentation. </p><p>Faiyaz-Ul-Haque et al. (2009) studied 18 patients with APS1 from 7 consanguineous Arab families and noted that although the patients displayed characteristic features of APS1, there was unusually early expression of hypoparathyroidism and mucocutaneous candidiasis, with onset during the neonatal period in 3 of 14 and 7 of 14 patients, respectively. Seven APS1 patients from 4 of the families had alopecia universalis, and scalp biopsies from 2 unrelated patients showed peribulbar lymphocytic inflammation of hair follicles associated with reduced follicle density, decreased presence of the anagen phase, increased presence of the catagen/telogen phase, and predominance of vellus hair. </p><p>Zaidi et al. (2009) reported 9 Indian patients with APS1 from 8 families, 3 of whom had unusual manifestations, including presentation with type 1 diabetes, chronic sinusitis and otitis media, and facial dysmorphism. Two patients died of septicemia. </p><p>Bourgault et al. (2015) reported the ocular features and characterized the retinal phenotype in a retrospective study of 5 patients with molecularly confirmed APS1. Age at presentation ranged from 19 months to 44 years, and follow-up ranged from 4 to 13 years (average, 8 years). All but 1 patient, aged 11 years, had decreased vision on presentation, and acuity did not correlate with age. The youngest patient at presentation had no light perception acuity. All cases had peripheral pigmentary retinal changes ranging from isolated patchy atrophy of the retinal pigment epithelium to a retinitis pigmentosa-like fundus with bone spicules, waxy pallor of the optic disc, and attenuated vasculature. Macular atrophy was noted in 4 patients. The most common feature on spectral-domain optical coherence tomography, which was found in 3 patients, was a disruption of the external limiting membrane and the inner segment ellipsoid band. The 4 patients who were tested for antiretinal antibodies were found to be positive by immunohistochemistry and/or Western blot analysis. Visual fields were constricted in all 3 patients tested. The rod ERG was abnormal in all of the patients, but the relative involvement of rods and cones differed. Bourgault et al. (2015) concluded that photoreceptor degeneration is part of the APS1 phenotype and that the presence of antiretinal antibodies strongly supports an etiology similar to that of nonparaneoplastic autoimmune retinopathy. </p><p>Li et al. (2017) reported 2 brothers and a sister with AIPS1 and mutation in the AIRE gene. The sibs, aged 63, 57, and 53 years, were diagnosed with hypoparathyroidism at ages 2, 5, and 7 years, respectively. In addition, the sister developed premature ovarian failure at age 33 years. The patients lacked clinical or biochemical signs of thyroid or adrenal insufficiency, mucocutaneous candidiasis, or ectodermal dysplasia, and conventional autoantibodies against thyroid and intestinal antigens were negative in all 3. Further testing in the brothers revealed that the proband had positive autoantibodies to GAD65 (GAD2; 138275) and islet cells, whereas his brother was negative; both showed IFN-alpha (IFNA1; 147660) antibodies but were negative for the NALP5 (NLRP5; 609658) antibody. </p><p><strong><em>Polyglandular Deficiency Syndrome, Persian-Jewish Type</em></strong></p><p>
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Shapiro et al. (1987) detected a seemingly new variant of the polyglandular deficiency syndrome in 5 Persian Jews. All 5 had primary hypoparathyroidism and hypogonadism, 2 had adrenal insufficiency, 1 had insulin-dependent diabetes mellitus, and 1 had latent hypothyroidism. The last patient also had antithyroid and antinuclear antibodies. Two of the 5 patients were cousins, and 2 had first-cousin parents. Isolated primary hypoparathyroidism was found in the 16-year-old sister of 1 of the 5. One of the patients had alopecia totalis. Primary sertoli cell insufficiency was detected by laboratory evaluation. Pernicious anemia was documented in 1 patient. One patient had mild hypogammaglobulinemia and a low T4/T8 cell ratio. A high frequency of hypogonadism was considered a distinctive feature in this group of patients. Hypoparathyroidism was the most common initial presenting disorder, occurring before the age of 10 in 4 of the 5 subjects. </p><p>Although the accepted criterion for diagnosis of type I polyglandular autoimmune syndrome is the presence of at least 2 of the 3 components (hypoparathyroidism, candidiasis, and adrenal insufficiency), hypoparathyroidism may be the only manifestation. Zlotogora and Shapiro (1992) reported on 19 families of patients with hypoparathyroidism from the Iranian Jewish community in which 23 persons (11 males and 12 females) were affected with what these workers considered to be PGA I. All but 1 had hypoparathyroidism (96%), and most were diagnosed by the age of 20 years (91%). Adrenal insufficiency was diagnosed in 5 of the patients; in all cases but 1, it appeared after hypoparathyroidism. Mild oral candidiasis was present in 4 patients, and 6 of the patients (3 males and 3 females) had hypogonadism. Other features of the syndrome found in some patients were pernicious anemia, hypothyroidism, and alopecia. The inheritance was clearly autosomal recessive. The prevalence among Iranian Jews was estimated to be between 1:6,500 and 1:9,000. This is comparable to the high incidence among Finns. Compared with the Finns, the disorder showed relative rarity of candidiasis and absence of keratopathy among the Iranian Jews. </p><p>To investigate the question of locus heterogeneity in this disorder. Bjorses et al. (1996) performed linkage and haplotype analyses on APECED families from these 2 isolated populations and in other population groups. Six microsatellite markers on the critical chromosomal region of 2.6 cM on 21q22.3 were analyzed. Pairwise linkage analyses revealed significant lod scores for all these markers (maximum lod = 10.23). The haplotype data and the geographic distribution of the great-grandparents of the Finnish APECED patients suggested the existence of 1 major, relatively old mutation responsible for approximately 90% of the Finnish cases. Similar evidence for one founder mutation was also found in analyses of Iranian Jewish APECED haplotypes. These haplotypes, however, differed totally from the Finnish ones. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for linkage to the same chromosomal region on 21q22.3 and revealed no evidence of locus heterogeneity. The haplotype analyses suggested to Bjorses et al. (1996) that in different populations APECED is due to a number of different mutations in a gene on chromosome 21. Thus, linkage studies demonstrated that the condition previously called polyglandular deficiency syndrome, Persian-Jewish type, is the same as APECED. </p><p>Eisenbarth and Gottlieb (2004) compared the features of 3 autoimmune polyendocrine syndromes: autoimmune polyendocrine syndrome type I, autoimmune polyendocrine syndrome type II, and X-linked polyendocrinopathy with immune dysfunction and diarrhea (304790). </p>
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<strong>Inheritance</strong>
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<p>Fox et al. (1970) made a brief note of a sibship, offspring of first-cousin parents, containing 2 female sibs with idiopathic Addison disease. One also had primary hypoparathyroidism and one had oral candidiasis. Ahonen (1985) provided a genetic analysis of 58 patients in 42 families and corroborated autosomal recessive inheritance. </p><p>Cetani et al. (2001) identified an Italian family with autoimmune polyendocrinopathy syndrome and a pattern of inheritance suggestive of a dominant mechanism (see MOLECULAR GENETICS). </p>
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<strong>Mapping</strong>
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<p>Taking advantage of the high frequency of APECED in Finland, Aaltonen et al. (1994) did linkage studies and mapped the locus to 21q22.3 with DNA markers. Studies of linkage disequilibrium increased the informativeness of the analyses and helped to locate the gene to a 500-kb segment. This was perhaps the first gene involving an autoimmune disorder that had been located outside the major histocompatibility complex (MHC) region on chromosome 6. </p>
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<strong>Pathogenesis</strong>
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<p><strong><em>Autoantibodies</em></strong></p><p>
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Blizzard and Kyle (1963) offered the first substantial evidence for the autoimmune concept. They found antiadrenal antibodies in 36 of 71 patients with Addison disease and antithyroid antibodies in 22. Hung et al. (1963) found circulating adrenal antibodies in 2 sibs with Addison disease. A third sib had died from Addison disease. One of the affected sibs also had hypoparathyroidism, pernicious anemia, and superficial moniliasis. The authors suggested the disorder may not be inherited as a simple mendelian recessive but may be autoimmune in nature. </p><p>In studies performed in Finland and Estonia, Krohn et al. (1992) screened serum samples from patients with Addison disease as part of the type I polyendocrine autoimmunity syndrome. In 3 patients they demonstrated precipitating antibodies against adrenal proteins. They cloned these proteins and found that one of them was 17-alpha-hydroxylase, the steroid hormone that is deficient or defective in one form of congenital adrenal hypoplasia (202110). Patients with idiopathic Addison disease likewise showed antibodies to this protein. </p><p>Husebye et al. (1997) investigated the presence of autoantibodies against the enzyme aromatic L-amino acid decarboxylase (AADC) of pancreatic beta-cells in a cohort of PGA I and isolated IDDM patients. They found AADC autoantibodies in 35 of 69 (51%) PGA I patients but in none of 138 isolated IDDM patients or 91 controls. Among PGA I patients, anti-AADC antibodies were found more often in those with hepatitis (11 of 12, 92%) than in those without hepatitis (24 of 57, 42%) (P = 0.003). Similarly, 12 of 15 (80%) patients with vitiligo had antibodies, compared with 23 of 54 (43%) without vitiligo (P = 0.021). Of the 9 PGA I patients with IDDM, 5 had antibodies against both AADC and glutamate decarboxylase, 2 against AADC only, and 2 against glutamate decarboxylase only. Thus, an autoimmune reactivity against AADC may be involved in the pathogenesis of autoimmune chronic active hepatitis and vitiligo in PGA I patients, but the role of AADC in the development of IDDM in these patients remains to be determined. </p><p>Clemente et al. (1997) studied autoantibodies for proteins of the adrenal cortex and the liver in 88 subjects of Sardinian descent, including 6 with autoimmune polyglandular syndrome type I, 22 relatives of APS I patients, 40 controls with other autoimmune diseases, and 20 healthy controls. Indirect immunofluorescence of tissue sections of the adrenal cortex revealed a cytoplasmic staining pattern in 4 of 6 patients with APS I. The autoantigens were identified as P450 scc (CYP11A; see 118485) and P450 c17 (CYP17A1; 609300). One of 6 APS I patients suffered from chronic hepatitis. In this patient, immunofluorescence revealed a centrolobular liver and a proximal renal tubule staining pattern. The autoantigen was identified as cytochrome P450 1A2 (124060). Since P450 1A2 usually is not detected by sera of patients with isolated autoimmune liver disease, Clemente et al. (1997) suggested that P450 1A2 might be a hepatic marker autoantigen for patients with APS I. </p><p>Using the immunoblotting of E. coli-expressed antigens to analyze humoral immunity to steroidogenic P450 cytochromes in 18 Eastern and Central European APECED patients, Cihakova et al. (2001) showed that 67%, 44%, and 61% had autoantibodies to P450 c17, P450 c21 (613815), and P450 scc, respectively. </p><p>Hedstrand et al. (2000) related a new autoantigen to APS I; they identified autoantibodies against tyrosine hydroxylase (TH; 191290) in sera from patients with alopecia areata (104000) through immunoscreening of a scalp cDNA library. Immunoreactivity against in vitro-expressed TH was found in 41 (44%) of 94 APS I patients studied, and this reactivity correlated with the presence of alopecia areata. </p><p>Another autoantigen in APSI, tryptophan hydroxylase (TPH; 191060), is associated with intestinal dysfunction. TPH and TH, together with phenylalanine hydroxylase (PAH; 612349), constitute the group of biopterin-dependent hydroxylases, which all are involved in the biosynthesis of neurotransmitters. Using a clone encoding PAH for in vitro transcription/translation, followed by immunoprecipitation with sera from 94 APS I patients and 70 healthy controls, Ekwall et al. (2000) investigated whether PAH is an autoantigen in APS I and whether crossreactivity exists between antibodies to these 3 highly homologous enzymes. Of the APS I patients, 25% had PAH antibodies, and no reactivity was detected in the controls. No association with the main clinical components of APS I was found with PAH antibodies. Altogether, 59 sera from the 94 APS I patients reacted with at least 1 of TPH, TH, or PAH, whereas 35 showed no reactivity. Nineteen of the sera contained antibodies towards all enzymes, 12 to TPH only, and 12 to TH only. No sera showed antibodies that reacted to only PAH. An immunocompetition assay demonstrated that the reactivity against PAH represents a crossreactivity with TPH, whereas antibodies against TPH and TH are directed towards epitopes unique for the 2 enzymes. </p><p>Individuals with APECED are at high risk of developing IDDM, but the positive predictive value of GAD65 (138275) or islet cell antibodies for IDDM is only 27%. Autoantibodies against the IA2 tyrosine phosphatase-like protein (601773) or insulin (176730) have been suggested to be better markers for active beta cell destruction. Gylling et al. (2000) studied these antibodies in sera from 60 Finnish patients with APECED, 12 of whom subsequently developed IDDM. Four (36%) of the 11 patients for whom prediabetic samples were available had antibodies against IA2, and 4 (36%) had antibodies against insulin. None of the 48 nondiabetics had antibodies against insulin, and only 2 (4%) had antibodies against IA2. Both had the antibodies for years without diabetes. Thus, antibodies against IA2 or insulin have a low sensitivity (36%), but high specificity (96% or 100%), with a positive predictive value of 67% for IDDM in patients with APECED. None of the 11 patients with IDDM, but 15 of the 56 (27%) nondiabetic patients and 24 of 93 (26%) of the control subjects had the DQB1*0602 allele (see 604305), which is considered protective for IDDM. Gylling et al. (2000) noted that theretofore no positive or negative associations had been reported for any disease components of APECED with human leukocyte II antigens. </p><p>Soderbergh et al. (2004) used multiple logistic regression analysis on a cohort of 90 APS I patients from Finland, Norway, and Sweden to clarify the significance of each of 10 different autoantibodies as markers for the various disease manifestations of APS I. Reactivities against 21-hydroxylase (P450 c21) and side chain cleavage enzyme (P450 scc) were associated with Addison disease with odds ratios of 7.8 and 6.8, respectively. Hypogonadism was exclusively associated with autoantibodies against P450 scc with an odds ratio of 12.5. Autoantibodies against tyrosine phosphatase-like protein IA-2 were associated with IDDM with an odds ratio of 14.9, but with low sensitivity. Reactivities against TPH and, surprisingly, GAD65 were associated with intestinal dysfunction, with odds ratios of 3.9 and 6.7, respectively. TPH reactivity was the best predictor for autoimmune hepatitis, with an odds ratio of 27.0. The authors concluded that analysis of autoantibodies in APS I patients is a useful tool for establishing autoimmune manifestations of the disease as well as providing diagnosis in patients with suspected disease. </p><p>Gylling et al. (2003) sought to identify the determinants and mechanism of hypoparathyroidism in APECED, the most common endocrine component of the disorder. For the determinants, they evaluated gender and HLA class II (see 142857). For the mechanism, they searched for parathyroid autoantibodies, including antibodies against CASR (601199) and PTH (168450). Also, they studied whether AIRE (607358) is expressed in the human parathyroid because its absence could be a pathogenetic factor. Gylling et al. (2003) found a clear gender linkage with lower and later incidence in males. Of the 14 patients who had escaped hypoparathyroidism, 13 were males. This was associated with adrenal failure, which was the first or only endocrinopathy in 47% of males vs 7% of females. In contrast, they found no linkage to the HLA class II. </p><p>Alimohammadi et al. (2008) studied the specific autoimmunity responsible for hypoparathyroidism, a hallmark of APS1 and its most common autoimmune endocrinopathy. They found that autoantibodies specific for NACHT leucine-rich repeat protein-5 (NALP5; 609658) were demonstrable in 49% of patients who had APS1 and hypoparathyroidism but were absent in all patients with APS1 without hypoparathyroidism, as well as in all patients with other autoimmune endocrine disorders and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells. Thus NALP5 appears to be a tissue-specific autoantibody involved in hypoparathyroidism in patients with APS1. Autoantibodies against NALP5 may be diagnostic for this prominent component of APS1. </p><p>Using multiplex particle-based flow cytometry and ELISA analysis, Puel et al. (2010) screened 33 APS1 patients, 37 healthy controls, and 103 patients with other autoimmune conditions and detected high-titers of neutralizing IgG autoantibodies against IL17A (603149), IL17F (606496) and/or IL22 (605330), but not against other cytokines, except for interferon-alpha (IFNA1; 147660), in APS1 patients only. Twenty-two APS1 patients had a reaction against all 3 cytokines, 6 had reaction against 2 cytokines, and 5 had reaction against 1 cytokine. Chronic mucocutaneous candidiasis (CMC) was observed in 29 of the 33 APS1 patients. Puel et al. (2010) proposed that anti-IL17 autoantibodies may contribute to the development of CMC in APS1 patients. </p><p>Gruper et al. (2023) investigated the mechanism of autoimmune amelogenesis imperfecta, which affects individuals with APS1 and children affected with celiac disease (212750). The vast majority (70 to 90%) of patients with APS1 develop IgA autoantibodies against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. Normally, AIRE expression in the thymus induces tolerance of ameloblast-specific protein. The lack of AIRE expression in APS1 and in AIRE-null mice results in a breakdown of central tolerance, and subsequent generation of autobodies that interfere with enamel formation. In celiac disease the generation of enamel autoantibodies appears to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel. Twenty to 50% of children affected with celiac disease manifest amelogenesis imperfecta; enamel defects are rarely seen in patients with celiac disease with later onset. Only secondary teeth are affected. Gruper et al. (2023) showed that patients with celiac disease have higher levels of IgA autoantibodies against the enamel proteins LAMB3 (150310), ACPT (606362), KLK4 (603767), AMELX (300391), FAM20A (611062), and ENAM (606585) compared with control individuals without celiac disease. TGM2 (190196) and LAMB3 are dental and intestinal antigens, and kappa-casein (CSN3; 601695) is a dairy-based antigen. All 3 induce antibodies in celiac disease that interfere with enamel formation. The severity of the amelogenesis imperfecta relates to the duration of exposure and severity to autoantibodies. </p><p><strong><em>Loss of CD8-Positive T-Cell Homeostasis</em></strong></p><p>
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Although murine studies have linked Aire to thymocyte selection and peripheral deletional tolerance, the pathogenesis of human APECED is unclear. Laakso et al. (2011) demonstrated increased CD8 (see 186910)-positive/CD45RO (see 151460)-negative T cells (i.e., CD8RA, or naive, T cells) that also expressed the proliferation marker Ki67 (MKI67; 176741) in APECED patients with loss-of-function mutations in AIRE. ELISA indicated increased plasma IL7 (146660), while FACS analysis showed reduced IL7R (146661) on CD8-positive cells and, to a lesser extent, CD4 (186940)-positive T cells. Patients also had reduced CD5 (153340), CD62L (SELL; 153240), and CCR7 (600242) expression, but somewhat increased perforin (PRF1; 170280) expression, on CD8RA cells. Likewise, there was reduced expression of CD31 (PECAM1; 173445), a marker for recent thymic emigrants. Laakso et al. (2011) proposed that loss of CD8-positive T-cell homeostasis is likely to play a significant role in the pathogenesis of APECED. </p>
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<p>Nagamine et al. (1997) found 2 mutations in the AIRE gene in Swiss and Finnish APECED patients: (R257X; 607358.0001), found in 10 of 12 alleles in the Finnish patients, and (K83E; 607358.0002). The Finnish-German APECED Consortium (1997) identified 5 AIRE mutations, 4 in addition to the common Finnish mutation. </p><p>Using SSCP analysis and direct DNA sequencing, Pearce et al. (1998) identified a 13-bp deletion (607358.0003) in the AIRE gene in 17 of 24 mutant alleles in 12 British families with APS I. This mutation was found to occur de novo in 1 affected subject. A common haplotype spanning the AIRE locus was found in chromosomes that carried the deletion mutation, suggesting a founder effect in this population. One of 576 normal subjects was also a heterozygous carrier of the deletion mutation. Six other point mutations were found, including two 1-bp deletions, 3 missense mutations, and a nonsense mutation. Scott et al. (1998) likewise found common mutations in patients of various ethnic origins with APS I. </p><p>To understand the complexity of the APECED phenotype, Halonen et al. (2002) studied the AIRE and HLA class II genotypes in a series of patients with APECED. The only association between the phenotype and the AIRE genotype was the higher prevalence of candidiasis in the patients with the most common mutation, arg257 to ter (607358.0001), than in those with other mutations. Addison disease was associated with HLA-DRB1*03 (P = 0.021), alopecia with HLA-DRB1*04/DQB1*0302 (P less than 0.001), whereas type 1 diabetes correlated negatively with HLA-DRB1*15/DQB1*0602 (P = 0.036). The authors concluded that AIRE mutation has little influence on the APECED phenotype, whereas, in contrast to earlier reports, HLA class II is a significant determinant. </p><p>Harris et al. (2003) reported the association of a theretofore undescribed reversible metaphyseal dysplasia with autoimmune APECED in 2 patients, 1 homozygous and the other heterozygous for a 13-bp deletion in exon 8 of the AIRE gene (607358.0003). One patient also had a novel deletion in exon 6, resulting in a frameshift mutation and introduction of a stop codon in exon 10 (607358.0009). Their APECED phenotypes differed, but both patients developed progressive skeletal deformities and growth failure from early childhood. Radiologic examination suggested a generalized abnormality of endochondral ossification, with irregular, flared, radioopaque regions in the metaphyses, subjacent to the growth plates. Histopathology in patient 1 showed islands of calcified cartilage within bone, consistent with impaired coupling of cartilage resorption with vascular invasion and ossification. Despite discordance for puberty, both patients experienced radiologic resolution of their bone disease in their mid-teens, with improvement in histopathology in patient 1. </p><p>Among 14 unrelated Polish patients with APECED, Stolarski et al. (2006) identified 6 different mutations in the AIRE gene, including 3 novel mutations (see, e.g., 607358.0008). R257X was the most common mutation, accounting for 71% of mutant alleles. The authors stated that 57 pathogenic mutations in the AIRE gene had been described. </p><p>Eggermann et al. (2007) followed a patient previously diagnosed by Brodehl et al. (1967) with idiopathic hypoparathyroidism and isolated hypercystinuria (see 220100) discovered during an episode of candidiasis at 2 years of age, who subsequently developed Addison disease at 26 years of age, leading to the diagnosis of APS1. Two older sibs had died from hypocalcemic tetany. Direct sequencing of the AIRE gene revealed compound heterozygosity for the common R257X (607358.0001) and 964del13 (607358.0003) mutations; the patient was also found to carry a mutation in the SLC7A9 gene (604144.0014) believed to be responsible for the cystinuria phenotype. </p><p>Faiyaz-Ul-Haque et al. (2009) reported 18 patients with APS1 from 7 consanguineous Arab families. One recurrent (607358.0010) and 4 novel mutations in the AIRE gene were identified in 6 of the families; in 1 family no mutation was present in the coding region or exon/intron boundaries of the AIRE gene. </p><p>In 9 Indian patients with APS1 from 8 families, Zaidi et al. (2009) identified homozygosity for 3 mutations previously reported in Caucasian individuals (607358.0001, 607358.0003, 607358.0004) and 2 novel mutations, 1 of which appeared to be an ancestral mutation (607358.0011), in the AIRE gene. </p><p>In 3 sibs with hypoparathyroidism, including a sister who had premature ovarian failure, who were negative for mutation in 6 hypoparathyroidism- and calcium metabolism-associated genes, Li et al. (2017) identified compound heterozygosity for the recurrent 13-bp deletion in the AIRE gene (607358.0003) and a splicing mutation (607358.0012). The unaffected parents were each heterozygous for 1 of the mutations, and unaffected offspring were either heterozygous or wildtype. Noting that the patients were in the sixth and seventh decades of life, and that multiple manifestations of APS1 usually develop by the fifth decade of life, the authors stated that it was unclear why 2 of the 3 patients had such a limited APS1 phenotype. However, the near-constant development of hypoparathyroidism in APS1 suggested that parathyroid involvement occurs at a very low threshold and represents a very mild expression of the disease. The authors also noted that antibodies to NALP5, previously proposed as a useful indicator of parathyroid autoimmunity in APS1, were absent in their patients, suggesting that the NALP5 autoantibody is not a very sensitive marker for hypoparathyroidism. </p><p><strong><em>Autoimmune Polyendocrinopathy Syndrome, Type I, Autosomal Dominant</em></strong></p><p>
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Cetani et al. (2001) identified an Italian family with autoimmune polyendocrinopathy syndrome and a pattern of inheritance suggestive of a dominant mechanism. Serologic and clinical studies showed a high prevalence of hypothyroid autoimmune thyroiditis in affected members with classic autoimmune polyendocrinopathy. Direct sequencing of the entire coding region of the AIRE gene revealed the presence in the proband of a novel missense mutation in exon 6, gly228 to trp, in heterozygous state (G228W; 607358.0007). In contrast with all other autoimmune regulator mutations reported in families, the novel G228W mutation acts in a dominant fashion in this family, as only one heterozygous mutation was found in the entire coding sequence of the autoimmune regulator gene in the proband. Moreover, analysis of the family tree showed direct transmission of the APECED phenotype to the offspring in each generation in the absence of consanguinity. The G228W mutation closely cosegregated with hypothyroid autoimmune thyroiditis in this family, whereas a low penetrance of the full autoimmune polyendocrinopathy phenotype was observed. </p><p>Ilmarinen et al. (2005) analyzed the effect of AIRE proteins with mutations in the SAND domain on wildtype AIRE in a simulated heterozygous situation in vitro. Only the G228W mutant changed the subcellular localization and severely disrupted the transactivating capacity of wildtype AIRE. Ilmarinen et al. (2005) concluded that the G228W protein acts with a dominant-negative effect by binding to wildtype AIRE, preventing the protein from forming the complexes needed for transactivation. </p>
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<p>In a cohort of 305 index patients, including 144 probands with suspected APS1 and 161 with suspected familial hypoparathyroidism, Cranston et al. (2022) sequenced the AIRE gene and identified germline mutations in 40 probands. The authors compared clinical features of probands with suspected APS1 who had AIRE mutations to those without, and observed that more than 45% of probands with AIRE mutations had at least 2 diseases out of the triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency, whereas significantly fewer AIRE mutation-negative probands with suspected APS1 (approximately 16%; p less than 0.01) had developed 2 out of 3 components of the classic disease triad. In addition, hypoparathyroidism occurred significantly more frequently (p less than 0.0001) in probands with AIRE mutations, whereas type 1 diabetes and hypothyroidism occurred significantly more frequently (p less than 0.01) in AIRE mutation-negative probands. Among the probands with suspected familial hypoparathyroidism, 5 children with apparent isolated hypoparathyroidism were homozygous for mutations in the AIRE gene (see, e.g., 607358.0003). However, the authors noted that autoimmune parathyroid gland destruction represents an early manifestation of APS1, with a peak incidence at around 5 years of age, and thus it remained to be established whether those 5 probands would subsequently develop additional features of APS1. </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>Population Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Perheentupa (1980) stated that 40 cases of APECED in 28 families had been identified in Finland as compared to less than 100 cases elsewhere in the world. Ahonen (1985) also demonstrated that APECED is part of the 'Finnish heritage of disease.' The disorder is unusually frequent in some Finnish subpopulations. </p><p>Bjorses et al. (2000) stated that APECED is enriched in 3 genetically isolated populations: the Finnish, Iranian Jews, and Sardinians. </p><p>Falorni et al. (2004) studied 222 Italian patients with primary adrenal insufficiency (PAI) and found APS1 in 11. </p><p>The prevalence of APECED is increased in Finland and Sardinia, where it occurs in 1 in 25,000 (Ahonen et al., 1990) and 1 in 14,000 (Rosatelli et al., 1998) individuals, respectively. Estimates in other populations include 1 in 80,000 in Norway (Myhre et al., 2001), 1 in 43,000 in Slovenia (Podkrajsek et al., 2005), and 1 in 129,000 in Poland (Stolarski et al., 2006). </p><p>Wolff et al. (2007) estimated the prevalence of APS1 in Norway to be 1 in 90,000. </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>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Goldfarb et al. (2021) developed mouse models to recapitulate dominant and recessive mutations in the AIRE gene that were identified in patients with APS1. The mouse Aire mutations C313X and Y86C were modeled after the human autosomal recessive mutations C311X and Y85C, respectively, and the mouse Aire mutations V303M, C313Y, and C442G were modeled after the human autosomal dominant mutations V301M, C311Y, and C446G, respectively. The Aire C313Y heterozygous mice had lymphocytic infiltrates in the liver, prostate, and salivary glands and developed autoantibodies against eye, stomach, and liver. Ultimately, they died from a fatal wasting disease. The Aire C442G heterozygous mutant mice had a milder phenotype with incomplete penetrance of retinal degeneration and prostatitis. The Aire V303M mutation was found to be functionally nonpathologic. Mice that were homozygous for the C313X or Y86C mutations had absent Aire protein expression in EpCAM-enriched stroma. The C313X lack of protein expression was determined to be due to mRNA nonsense-mediated decay, whereas the lack of Y86C protein expression was determined to be due to proteolytic degradation. </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>History</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>An infectious etiology was suggested by Kunin et al. (1963) who pointed out that hepatitis had occurred in a number of these cases before the development of endocrinopathy.</p><p>Heterogeneity in Addison disease and hypoparathyroidism was suggested by the analysis of Spinner et al. (1968). </p><p>Maclaren and Riley (1986) found that autoimmune Addison disease was strongly associated with HLA-DR3 and HLA-DR4; relative risks were 6.0, 4.6, and 26.5 for DR3, DR4, and DR3/DR4, respectively. This is similar to the findings for insulin-dependent diabetes. Patients with type I autoimmune polyglandular syndrome did not show the association. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Arulanantham et al. (1979); Castells et al. (1971); Craig et al.
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(1955); Gass (1962); Hiekkala (1964); Kenny and Holliday (1964);
|
|
Louria et al. (1967); Sweetnam (1966); Whitaker et al. (1956);
|
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Wirfalt (1981)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<strong>Isolierter Defekt der tubulaeren Cystin-Rueckresorption in einer Familie mit idiopathischem Hypoparathyroidismus.</strong>
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<strong>A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis.</strong>
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Cranston, T., Boon, H., Olesen, M. K., Ryan, F. J., Shears, D., London, R., Rostom, H., Elajnaf, T., Thakker, R. V., Hannan, F. M.
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Eggermann, T., Elbracht, M., Haverkamp, F., Schmidt, C., Zerres, K.
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<strong>Isolated cystinuria (OMIM 238200) is not a separate entity but is caused by a mutation in the cystinuria gene SLC7A9. (Letter)</strong>
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Eisenbarth, G. S., Gottlieb, P. A.
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<strong>Autoimmune polyendocrine syndromes.</strong>
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New Eng. J. Med. 350: 2068-2079, 2004.
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<p class="mim-text-font">
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Ekwall, O., Hedstrand, H., Haavik, J., Perheentupa, J., Betterle, C., Gustafsson, J., Husebye, E., Rorsman, F., Kampe, O.
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<strong>Pteridin-dependent hydroxylases as autoantigens in autoimmune polyendocrine syndrome type I.</strong>
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J. Clin. Endocr. Metab. 85: 2944-2950, 2000.
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[PubMed: 10946908]
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[Full Text: https://doi.org/10.1210/jcem.85.8.6736]
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<p class="mim-text-font">
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Faiyaz-Ul-Haque, M., Bin-Abbas, B., Al-Abdullatif, A., Abdullah Abalkhail, H., Toulimat, M., Al-Gazlan, S., Almutawa, A. M., Al-Sagheir, A., Peltekova, I., Al-Dayel, F., Zaidi, S. H. E.
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<strong>Novel and recurrent mutations in the AIRE gene of autoimmune polyendocrinopathy syndrome type 1 (APS1) patients.</strong>
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Clin. Genet. 76: 431-440, 2009.
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[PubMed: 19758376]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2009.01278.x]
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<p class="mim-text-font">
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Falorni, A., Laureti, S., De Bellis, A., Zanchetta, R., Tiberti, C., Arnaldi, G., Bini, V., Beck-Peccoz, P., Bizzarro, A., Dotta, F., Mantero, F., Bellastella, A., Betterle, C., Santeusanio, F., SIE Addison Study Group.
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<strong>Italian Addison Network Study: update of diagnostic criteria for the etiological classification of primary adrenal insufficiency.</strong>
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J. Clin. Endocr. Metab. 89: 1598-1604, 2004.
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<li>
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<p class="mim-text-font">
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|
Finnish-German APECED Consortium.
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<strong>An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains.</strong>
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Nature Genet. 17: 399-403, 1997.
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[PubMed: 9398840]
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[Full Text: https://doi.org/10.1038/ng1297-399]
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<p class="mim-text-font">
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Fox, M., Mirada, A., Guardia, J.
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<strong>Endocrine disorders in a family. (Letter)</strong>
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Lancet 296: 269 only, 1970. Note: Originally Volume II.
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</p>
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Wolff, A. S. B., Erichsen, M. M., Meager, A., Magitta, N. F., Myhre, A. G., Bollerslev, J., Fougner, K. J., Lima, K., Knappskog, P. M., Husebye, E. S.
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Zaidi, G., Sahu, R. P., Zhang, L., George, G., Bhavani, N., Shah, N., Bhatia, V., Bhansali, A., Jevalikar, G., Jayakumar, R. V., Eisenbarth, G. S., Bhatia, E.
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Ada Hamosh - updated : 01/23/2024<br>Marla J. F. O'Neill - updated : 07/05/2022<br>Hilary J. Vernon - updated : 01/21/2022<br>Jane Kelly - updated : 03/29/2016<br>Paul J. Converse - updated : 1/6/2012<br>Paul J. Converse - updated : 5/25/2010<br>Marla J. F. O'Neill - updated : 1/13/2010<br>John A. Phillips, III - updated : 3/3/2009<br>Victor A. McKusick - updated : 3/26/2008<br>John A. Phillips, III - updated : 12/17/2007<br>Marla J. F. O'Neill - updated : 7/17/2007<br>John A. Phillips, III - updated : 11/16/2006<br>Cassandra L. Kniffin - updated : 11/2/2006<br>Marla J. F. O'Neill - updated : 11/4/2005<br>John A. Phillips, III - updated : 7/22/2005<br>John A. Phillips, III - updated : 4/28/2005<br>Victor A. McKusick - updated : 5/19/2004<br>John A. Phillips, III - updated : 2/3/2003<br>Cassandra L. Kniffin - reorganized : 11/19/2002<br>George E. Tiller - updated : 9/26/2002<br>John A. Phillips, III - updated : 8/7/2002<br>John A. Phillips, III - updated : 3/22/2002<br>Victor A. McKusick - updated : 9/26/2001<br>John A. Phillips, III - updated : 7/11/2001<br>John A. Phillips, III - updated : 3/8/2001<br>Victor A. McKusick - updated : 10/23/2000<br>Victor A. McKusick - updated : 3/31/2000<br>Victor A. McKusick - updated : 1/13/2000<br>Ada Hamosh - updated : 4/8/1999<br>Victor A. McKusick - updated : 1/21/1999<br>Victor A. McKusick - updated : 1/14/1999<br>Victor A. McKusick - updated : 1/11/1999<br>John A. Phillips, III - updated : 9/29/1998<br>Victor A. McKusick - updated : 12/2/1997<br>Victor A. McKusick - updated : 9/23/1997<br>John A. Phillips, III - updated : 5/29/1997<br>John A. Phillips, III - updated : 1/18/1997
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