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<title>
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Entry
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- #300291 - ECTODERMAL DYSPLASIA AND IMMUNODEFICIENCY 1; EDAID1
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- OMIM
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<span class="h4">#300291</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/300291"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS300291"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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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="#pathogenesis">Pathogenesis</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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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=(ECTODERMAL DYSPLASIA IMMUNODEFICIENCY) OR (IKBKG)" 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="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=19266&Typ=Pat" title="Hypohidrotic ectodermal dysplasia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Hypohidrotic ectodermal dy… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=10922&Typ=Pat" title="Anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Anhidrotic ectodermal dysp… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=13830&Typ=Pat" title="Hypohidrotic ectodermal dysplasia with immunodeficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Hypohidrotic ectodermal dy… </a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/3657" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/anhidrotic-ectodermal-dysplasia-with-immune-deficiency" 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=300291[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="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=238468" title="Hypohidrotic ectodermal dysplasia" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Hypohidrotic ectodermal dy…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=69088" title="Anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Anhidrotic ectodermal dysp…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98813" title="Hypohidrotic ectodermal dysplasia with immunodeficiency" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Hypohidrotic ectodermal dy…</a></div>
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</div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/879e87bd-c66f-4107-917a-c8b5dcfdef2a/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 style="display: table-cell;">Animal Models</div>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0081078" 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/300291" 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>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 703525006<br />
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<strong>ORPHA:</strong> 238468, 69088, 98813<br />
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<strong>DO:</strong> 0081078<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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300291
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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ECTODERMAL DYSPLASIA AND IMMUNODEFICIENCY 1; EDAID1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH IMMUNODEFICIENCY, OSTEOPETROSIS, AND LYMPHEDEMA; OLEDAID<br />
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ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH IMMUNE DEFICIENCY<br />
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ECTODERMAL DYSPLASIA, HYPOHIDROTIC, WITH IMMUNE DEFICIENCY; HEDID<br />
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HYPER-IgM IMMUNODEFICIENCY, X-LINKED, WITH HYPOHIDROTIC ECTODERMAL DYSPLASIA; XHMED
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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|
Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
|
|
<span class="mim-font">
|
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<a href="/geneMap/X/871?start=-3&limit=10&highlight=871">
|
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Xq28
|
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</a>
|
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</span>
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Ectodermal dysplasia and immunodeficiency 1
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/300291"> 300291 </a>
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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IKBKG
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/300248"> 300248 </a>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/300291" 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>
|
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</div>
|
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<div class="btn-group">
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|
|
<a href="/phenotypicSeries/PS300291" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
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</div>
|
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/300291" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/300291" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
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</div>
|
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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|
|
<div>
|
|
<span class="mim-font">
|
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|
|
- X-linked recessive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845977</a>, <a href="https://bioportal.bioontology.org/search?q=C1279481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279481</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span><br />
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|
</span>
|
|
</div>
|
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</div>
|
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</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Teeth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Delayed eruption of teeth <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/5639000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">5639000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239174&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239174</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000684" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000684</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000684" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000684</a>]</span><br /> -
|
|
Conical teeth <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/29553002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">29553002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1162597008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1162597008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0266037&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0266037</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006342" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006342</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000698" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000698</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000698" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000698</a>]</span><br /> -
|
|
Hypodontia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64969001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64969001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K00.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K00.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020608&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020608</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000668" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000668</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000668" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000668</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
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</div>
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</div>
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<div>
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Osteopetrosis (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1926006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1926006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/367489004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">367489004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q78.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q78.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/756.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">756.52</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029454&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029454</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011002</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011002</a>]</span><br />
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|
|
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</span>
|
|
</div>
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</div>
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</div>
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<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">
|
|
|
|
- Ectodermal dysplasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254154003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254154003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8654005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8654005</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/757.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">757.31</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013575&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013575</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000968</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000968</a>]</span><br /> -
|
|
Dry skin <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52475004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52475004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E50.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E50.8</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0043345&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0043345</a>, <a href="https://bioportal.bioontology.org/search?q=C0720057&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0720057</a>, <a href="https://bioportal.bioontology.org/search?q=C0151908&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151908</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000958" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000958</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000958" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000958</a>]</span><br /> -
|
|
Thin skin <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/277797007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">277797007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423757&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423757</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000963" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000963</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000963" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000963</a>]</span><br /> -
|
|
Hypohidrosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45004005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45004005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L74.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L74.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020620&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020620</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000966" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000966</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000966" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000966</a>]</span><br /> -
|
|
Anhidrosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14662005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14662005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39659002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39659002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L74.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L74.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/705.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">705.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003028&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003028</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000970" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000970</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000970" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000970</a>]</span><br /> -
|
|
Pigmentary abnormalities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3552307&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3552307</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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<span class="h5 mim-font">
|
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<em> Hair </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
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|
- Sparse hair <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1162675003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1162675003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5551005&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5551005</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008070" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008070</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008070" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008070</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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<div>
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<span class="h5 mim-font">
|
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<strong> MUSCLE, SOFT TISSUES </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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|
- Edema (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/79654002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">79654002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267038008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267038008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20741006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20741006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R60.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R60.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/782.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">782.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013604&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013604</a>, <a href="https://bioportal.bioontology.org/search?q=C1717255&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1717255</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000969" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000969</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000969" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000969</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">
|
|
<strong> IMMUNOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
|
<span class="mim-font">
|
|
|
|
- Recurrent infections <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/451991000124106" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">451991000124106</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239998&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239998</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002719" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002719</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002719" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002719</a>]</span><br /> -
|
|
Variably impaired immunologic function <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5394638&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5394638</a>]</span><br /> -
|
|
Dysgammaglobulinemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/123782009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">123782009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013374&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013374</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002961" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002961</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002961" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002961</a>]</span><br /> -
|
|
Increased IgM (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239990&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239990</a>]</span><br /> -
|
|
Hypogammaglobulinemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/119250001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">119250001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D80.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D80.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/279.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">279.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0086438&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0086438</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004313" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004313</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004313" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004313</a>]</span><br /> -
|
|
Aberrant IgG and IgA <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393255&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393255</a>]</span><br /> -
|
|
Poor class-switching in B cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393256&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393256</a>]</span><br /> -
|
|
Poor response to vaccination, particularly to pneumococcus <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393257&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393257</a>]</span><br /> -
|
|
T-cell dysfunction (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860127&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860127</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005435" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005435</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005435" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005435</a>]</span><br /> -
|
|
Normal immunologic parameters (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393258&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393258</a>]</span><br /> -
|
|
Susceptibility to disseminated mycobacterial infections <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4315619&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4315619</a>]</span><br /> -
|
|
Susceptibility to pneumococcus <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393259&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393259</a>]</span><br /> -
|
|
Susceptibility to H. influenza <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393260</a>]</span><br /> -
|
|
Impaired cytokine production, including IL6, IL12, and gamma-interferon <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393261&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393261</a>]</span><br /> -
|
|
Impaired response to IL1B and TNFA <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393262&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393262</a>]</span><br /> -
|
|
Impaired NK cytotoxic function <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393263&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393263</a>]</span><br /> -
|
|
Impaired CD40 signaling <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393264&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393264</a>]</span><br /> -
|
|
Decreased activation of the NFKB signaling pathway <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5393265&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5393265</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">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</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 usually in infancy or early childhood<br /> -
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Highly variable severity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866862&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866862</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span><br /> -
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- Caused by mutation in the inhibitor of nuclear factor kappa B kinase, regulatory subunit gamma gene (IKBKG, <a href="/entry/300248#0002">300248.0002</a>)<br />
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Ectodermal dysplasia and immune deficiency
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- <a href="/phenotypicSeries/PS300291">PS300291</a>
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- 2 Entries
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<a href="/entry/612132"> Ectodermal dysplasia and immunodeficiency 2 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/164008"> NFKBIA </a>
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<a href="/entry/164008"> 164008 </a>
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<a href="/entry/300291"> Ectodermal dysplasia and immunodeficiency 1 </a>
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<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/300291"> 300291 </a>
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<a href="/entry/300248"> IKBKG </a>
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<a href="/entry/300248"> 300248 </a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that ectodermal dysplasia and immunodeficiency-1 (EDAID1) is caused by hemizygous mutation in the IKK-gamma gene (IKBKG, or NEMO; <a href="/entry/300248">300248</a>) on chromosome Xq28.</p><p>Hemizygous mutation in the IKBKG gene also causes X-linked recessive immunodeficiency-33 (IMD33; <a href="/entry/300636">300636</a>) in males. Heterozygous mutation in the IKBKG gene causes X-linked dominant incontinentia pigmenti (IP; <a href="/entry/308300">308300</a>) in females.</p>
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<p>Ectodermal dysplasia with immunodeficiency-1 (EDAID1) is an X-linked recessive disorder that characteristically affects only males. Affected individuals have onset of recurrent severe infections due to immunodeficiency in early infancy or in the first years of life. There is increased susceptibility to bacterial, pneumococcal, mycobacterial, and fungal infections. Laboratory studies usually show dysgammaglobulinemia with low IgG subsets and normal or increased IgA and IgM, consistent with impaired 'class-switching' of B cells, although immunologic abnormalities may be subtle compared to the clinical picture, and B- and T-cell numbers are usually normal. There is a poor antibody response to polysaccharide vaccinations, particularly pneumococcus; response to other vaccinations is variable. Patients also have features of ectodermal dysplasia, including conical incisors, hypo/anhidrosis, and thin skin or hair. Severely affected individuals may also show lymphedema, osteopetrosis, and, rarely, hematologic abnormalities. The phenotype is highly variable, likely due to different hypomorphic mutations, and may be fatal in childhood. Intravenous immunoglobulins and prophylactic antibiotics are used as treatment; some patients may benefit from bone marrow transplantation. Although only males tend to be affected with immunodeficiency, many patients inherit a mutation from a mother who has mild features of IP or conical teeth (summary by <a href="#2" class="mim-tip-reference" title="Doffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S. H., and 16 others. <strong>X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling.</strong> Nature Genet. 27: 277-285, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242109</a>] [<a href="https://doi.org/10.1038/85837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242109">Doffinger et al., 2001</a>, <a href="#11" class="mim-tip-reference" title="Orange, J. S., Jain, A., Ballas, Z. K., Schneider, L. C., Geha, R. S., Bonilla, F. A. <strong>The presentation and natural history of immunodeficiency caused by nuclear factor kappa-B essential modulator mutation.</strong> J. Allergy Clin. Immun. 113: 725-733, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15100680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15100680</a>] [<a href="https://doi.org/10.1016/j.jaci.2004.01.762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15100680">Orange et al., 2004</a>, <a href="#14" class="mim-tip-reference" title="Roberts, C. M. L., Angus, J. E., Leach, I. H., McDermott, E. M., Walker, D. A., Ravenscroft, J. C. <strong>A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency.</strong> Europ. J. Pediat. 169: 1403-1407, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20499091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20499091</a>] [<a href="https://doi.org/10.1007/s00431-010-1206-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20499091">Roberts et al., 2010</a>, <a href="#4" class="mim-tip-reference" title="Heller, S., Kolsch, U., Magg, T., Kruger, R., Scheuern, A., Schneider, H., Eichinger, A., Wahn, V., Unterwalder, N., Lorenz, M., Schwarz, K., Meisel, C., Schulz, A., Hauck, F., von Bernuth, H. <strong>T cell impairment is predictive for a severe clinical course in NEMO deficiency.</strong> J. Clin. Immun. 40: 421-434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31965418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31965418</a>] [<a href="https://doi.org/10.1007/s10875-019-00728-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31965418">Heller et al., 2020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11242109+31965418+15100680+20499091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Ectodermal Dysplasia and Immune Deficiency</em></strong></p><p>
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Also see EDAID2 (<a href="/entry/612132">612132</a>), caused by mutation in the NFKBIA gene (<a href="/entry/164008">164008</a>).</p>
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<p><a href="#17" class="mim-tip-reference" title="Zonana, J., Elder, M. E., Schneider, L. C., Orlow, S. J., Moss, C., Golabi, M., Shapira, S. K., Farndon, P. A., Wara, D. W., Emmal, S. A., Ferguson, B. M. <strong>A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).</strong> Am. J. Hum. Genet. 67: 1555-1562, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11047757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11047757</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11047757[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/10.1086/316914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11047757">Zonana et al. (2000)</a> studied males from 4 families with hypohidrotic ectodermal dysplasia and immunodeficiency segregating as an X-linked recessive trait. The patients presented in the first years of life with recurrent infections, including pneumonia, bacterial infections of the bone and soft tissue, and sepsis. Organisms included pneumococcus, Pseudomonas, pneumocystis, and atypical mycobacteria. Laboratory studies showed dysgammaglobulinemia with increased IgM and low levels of IgA and IgG, although this was somewhat variable. Other immunologic parameters were essentially normal, although there was no antibody response to pneumococcal infection or vaccination. Response to tetanus was normal in some patients. The patients also had features of ectodermal dysplasia, including conical teeth, abnormal teeth, inability to sweat or poor sweating, and sometimes sparse hair. Two brothers in family 4 had the most severe clinical course, with death occurring by 3 years of age. These boys also had osteopetrosis, thus expanding the phenotype. Despite treatment, usually with IVIg, all had significant morbidity and mortality from recurrent infections. The mothers had variable mild manifestations, ranging from normal dentition to mild hypodontia or conical teeth; 2 had some skin hyperpigmentation. One mother (family 2) had low IgA, but no immune dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11047757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Doffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S. H., and 16 others. <strong>X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling.</strong> Nature Genet. 27: 277-285, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242109</a>] [<a href="https://doi.org/10.1038/85837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242109">Doffinger et al. (2001)</a> identified 7 boys from 5 unrelated families with EDAID1. Four patients died between 9 months and 17 years of age. In all patients, ectodermal dysplasia features were somewhat milder compared to other forms of anhidrotic ectodermal dysplasia. Most children experienced failure to thrive, recurrent digestive tract infections, often with intractable diarrhea and recurrent ulcerations, recurrent respiratory tract infections, often with bronchiectasis, and recurrent skin infections, suggesting that they were generally susceptible to various gram-positive and gram-negative bacteria. The only blood immunologic abnormality detected in all patients tested was a poor antibody response to polysaccharide antigens (anti-AB isohemagglutinins and antibodies against H. influenzae and S. pneumoniae). In most patients, low levels of IgG or IgG2 were detected. Intravenous immunoglobulins and prophylactic antibiotics had occasionally been sufficient to improve clinical status when started early. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Jain, A., Ma, C. A., Liu, S., Brown, M., Cohen, J., Strober, W. <strong>Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohidrotic ectodermal dysplasia.</strong> Nature Immun. 2: 223-228, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11224521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11224521</a>] [<a href="https://doi.org/10.1038/85277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11224521">Jain et al. (2001)</a> reported 2 unrelated male patients with EDAID1 associated with increased IgM and decreased IgG. One patient presented with pneumococcal meningitis at 9 months of age, and both patients had frequent upper respiratory and sinus infections despite intravenous gamma-globulin replacement therapy. Neither patient had a history of opportunistic infections suggestive of T-cell dysfunction. One patient had conical-shaped molars and incisors, but skin biopsies for both patients confirmed the absence of eccrine sweat glands and a paucity of hair follicles, consistent with ectodermal dysplasia. Both had normal bone density and did not have Mycobacterium avium complex infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11224521" 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="Orange, J. S., Brodeur, S. R., Jain, A., Bonilla, F. A., Schneider, L. C., Kretschmer, R., Nurko, S., Rasmussen, W. L., Kohler, J. R., Gellis, S. E., Ferguson, B. M., Strominger, J. L., Zonana, J., Ramesh, N., Ballas, Z. K., Geha, R. S. <strong>Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations.</strong> J. Clin. Invest. 109: 1501-1509, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12045264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12045264</a>] [<a href="https://doi.org/10.1172/JCI14858" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12045264">Orange et al. (2002)</a> reported 3 unrelated boys with EDAID1. Patient 1 was a 2-year-old boy who presented with severe systemic infections, including Listeria sepsis, Streptococcus bovis meningitis, and recurrent CMV sepsis and colitis. Laboratory studies showed increased IgM, variably decreased IgG, and detectable diphtheria and tetanus titers. Patients 2 and 3 were teenagers with a history of recurrent infections since childhood, including sinusitis, pneumonia, oral herpetic lesions, and systemic invasive atypical Mycobacterium infections. They had normal, decreased, or increased IgG and IgA, but normal IgM, as well as decreased specific antibody levels. Both were treated with IVIg. Detailed immunologic studies showed that all patients had defective CD40 (<a href="/entry/109535">109535</a>) signaling with impaired B-cell proliferative responses and decreased activation of NFKB compared to controls. NK cell levels were normal, but there was deficient NK cell cytotoxicity that could be partially overcome in vitro and in vivo with IL2 (<a href="/entry/161560">161560</a>) treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12045264" 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="Johnston, A. M., Niemela, J., Rosenzweig, S. D., Fried, A. J., Delmonte, O. M., Fleisher, T. A., Kuehn, H. <strong>A novel mutation in IKBKG/NEMO leads to ectodermal dysplasia with severe immunodeficiency (EDA-ID). (Letter)</strong> J. Clin. Immun 36: 541-543, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27368913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27368913</a>] [<a href="https://doi.org/10.1007/s10875-016-0309-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27368913">Johnston et al. (2016)</a> reported a male infant who presented with systemic Staphylococcus aureus infection associated with multiple brain infarcts, microabscesses, and white matter abnormalities. He was noted to have features of ectodermal dysplasia, such as sparse hair and absent eyelashes and eyebrows. He also had edema of the scalp, hands, scrotum, and lower extremities. Laboratory studies showed dysgammaglobulinemia with mostly low Ig levels, whereas T, B, and NK cells were normal. The infection persisted despite treatment, and he died at 18 days of age. The patient's mother and several female relatives had features consistent with IP; X-inactivation studies on the mother showed nonrandom X-chromosome inactivation with expression of the wildtype allele. Patient peripheral blood cells showed impaired cytokine production in response to stimulation of Toll-like receptors compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27368913" 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="Heller, S., Kolsch, U., Magg, T., Kruger, R., Scheuern, A., Schneider, H., Eichinger, A., Wahn, V., Unterwalder, N., Lorenz, M., Schwarz, K., Meisel, C., Schulz, A., Hauck, F., von Bernuth, H. <strong>T cell impairment is predictive for a severe clinical course in NEMO deficiency.</strong> J. Clin. Immun. 40: 421-434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31965418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31965418</a>] [<a href="https://doi.org/10.1007/s10875-019-00728-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31965418">Heller et al. (2020)</a> reported a boy (patient 1) with severe EDAID1. He presented in infancy with a septic Enterobacter and Pneumocystis infection associated with decreased IgG and IgM. He also had lymphedema of the lower leg. Detailed immunologic studies showed functional B- and T-cell deficiency with impaired class-switched memory B cells, impaired CD3-induced T-cell proliferation, and skewing toward naive cells, indicating a defect in adaptive immunity. There was also impaired NFKB signaling through the Toll-like receptor, IL1B, and TNFA pathways, indicating defects in innate immunity. The patient underwent hematopoietic stem cell transplantation, but developed complications, including persistent colitis. <a href="#4" class="mim-tip-reference" title="Heller, S., Kolsch, U., Magg, T., Kruger, R., Scheuern, A., Schneider, H., Eichinger, A., Wahn, V., Unterwalder, N., Lorenz, M., Schwarz, K., Meisel, C., Schulz, A., Hauck, F., von Bernuth, H. <strong>T cell impairment is predictive for a severe clinical course in NEMO deficiency.</strong> J. Clin. Immun. 40: 421-434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31965418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31965418</a>] [<a href="https://doi.org/10.1007/s10875-019-00728-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31965418">Heller et al. (2020)</a> concluded that T-cell dysfunction in EDAID1 predicts a severe clinical course. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31965418" 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>Anhidrotic Ectodermal Dysplasia with Immunodeficiency, Osteopetrosis, and Lymphedema</em></strong></p><p>
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<a href="#16" class="mim-tip-reference" title="The International Incontinentia Pigmenti Consortium. <strong>Genomic rearrangement in NEMO impairs NF-kappa-B activation and is a cause of incontinentia pigmenti.</strong> Nature 405: 466-472, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839543</a>] [<a href="https://doi.org/10.1038/35013114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839543">The International Incontinentia Pigmenti Consortium (2000)</a> reported a male infant (patient IP85) with a severe form of EDAID1. In addition to recurrent infections, the boy had osteopetrosis and lymphedema. He was born with multiple capillary hemangiomas, developed lymphedema of the lower limbs, and had failure to thrive. Despite a destructive red blood cell picture and recurrent infections due to poor immune function, he survived 2 and a half years, but eventually succumbed to a tuberculosis infection. He had had operations to remove his spleen and an intestinal stricture, and biopsies revealed abnormal capillary beds in the gut, extrahepatic erythropoiesis, and osteopetrosis. His skin developed a reticular pigmentation. Cognitive development was normal. Genetic analysis identified a hemizygous X420W mutation in the IKBKG gene (<a href="/entry/300248#0002">300248.0002</a>) that was inherited from his mother, who had IP. <a href="#8" class="mim-tip-reference" title="Mansour, S., Woffendin, H., Mitton, S., Jeffrey, I., Jakins, T., Kenwrick, S., Murday, V. A. <strong>Incontinentia pigmenti in a surviving male is accompanied by hypohidrotic ectodermal dysplasia and recurrent infection.</strong> Am. J. Med. Genet. 99: 172-177, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11241484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11241484</a>] [<a href="https://doi.org/10.1002/1096-8628(2001)9999:9999<::aid-ajmg1155>3.0.co;2-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11241484">Mansour et al. (2001)</a> presented more details of this patient (IP85), who also had hematologic disturbances, such as hemolytic anemia and thrombocytopenia. <a href="#2" class="mim-tip-reference" title="Doffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S. H., and 16 others. <strong>X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling.</strong> Nature Genet. 27: 277-285, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242109</a>] [<a href="https://doi.org/10.1038/85837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242109">Doffinger et al. (2001)</a> also studied this patient and classified him as having 'anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema' (OLEDAID), which is within the phenotypic spectrum of EDAID1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11241484+11242109+10839543" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Doffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S. H., and 16 others. <strong>X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling.</strong> Nature Genet. 27: 277-285, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242109</a>] [<a href="https://doi.org/10.1038/85837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242109">Doffinger et al. (2001)</a> reported another boy, of French descent, with a similar OLEDAID phenotype, including recurrent infections, anhidrotic ectodermal dysplasia, lymphedema, and osteopetrosis. Blood monocytes and polymorphonuclear cells were normal in number and morphology, and B- and T-cell counts and responses to vaccine protein antigens (tetanus and polio) were normal. However, serum titers of antibodies against pneumococcus were low, despite proven infection. Serum levels of immunoglobulin isotypes were normal for age, with the exception of low to normal IgG levels. This patient and the patient described by <a href="#8" class="mim-tip-reference" title="Mansour, S., Woffendin, H., Mitton, S., Jeffrey, I., Jakins, T., Kenwrick, S., Murday, V. A. <strong>Incontinentia pigmenti in a surviving male is accompanied by hypohidrotic ectodermal dysplasia and recurrent infection.</strong> Am. J. Med. Genet. 99: 172-177, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11241484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11241484</a>] [<a href="https://doi.org/10.1002/1096-8628(2001)9999:9999<::aid-ajmg1155>3.0.co;2-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11241484">Mansour et al. (2001)</a> both died in the first years of life from overwhelming infectious disease caused by a variety of microorganisms, including gram-positive cocci, gram-negative bacilli, mycobacteria, and fungi. The French boy carried a hemizygous X420W mutation in the IKBKG gene that was inherited from his mother, who had mild IP. In vitro functional expression studies showed that the X420W mutation resulted in a 50 to 60% reduction of NF-kappa-B activation. Patient cells showed impaired cellular responses to TNF-alpha (<a href="/entry/191160">191160</a>) and a lower level of IFN-gamma (<a href="/entry/147570">147570</a>) production upon costimulation with IL12 (see <a href="/entry/161560">161560</a>), IL1-beta (<a href="/entry/147720">147720</a>), or IL18 (<a href="/entry/600953">600953</a>) compared to controls. There was also evidence of impaired cellular responses to lipopolysaccharide (LPS) and dissociated cellular responses to CD154 (CD40LG; <a href="/entry/300386">300386</a>), suggesting that some but not all CD40 (<a href="/entry/109535">109535</a>)-mediated signals are NEMO-dependent in both dendritic cells and B cells. The findings indicated that the X420W mutation impairs but does not abolish NFKB activation, consistent with a hypomorphic allele and postnatal survival of the boys. <a href="#3" class="mim-tip-reference" title="Dupuis-Girod, S., Corradini, N., Hadj-Rabia, S., Fournet, J.-C., Faivre, L., Le Deist, F., Durand, P., Doffinger, R., Smahi, A., Israel, A., Courtois, G., Brousse, N., Blanche, S., Munnich, A., Fischer, A., Casanova, J.-L., Bodemer, C. <strong>Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother.</strong> Pediatrics 109: e97, 2002. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12042591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12042591</a>] [<a href="https://doi.org/10.1542/peds.109.6.e97" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12042591">Dupuis-Girod et al. (2002)</a> reported that the French patient described by <a href="#2" class="mim-tip-reference" title="Doffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S. H., and 16 others. <strong>X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling.</strong> Nature Genet. 27: 277-285, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242109</a>] [<a href="https://doi.org/10.1038/85837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242109">Doffinger et al. (2001)</a> underwent hematopoietic stem cell transplantation, but developed complications and died at 18 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11242109+11241484+12042591" 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="#14" class="mim-tip-reference" title="Roberts, C. M. L., Angus, J. E., Leach, I. H., McDermott, E. M., Walker, D. A., Ravenscroft, J. C. <strong>A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency.</strong> Europ. J. Pediat. 169: 1403-1407, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20499091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20499091</a>] [<a href="https://doi.org/10.1007/s00431-010-1206-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20499091">Roberts et al. (2010)</a> reported a 6-year-old boy with hypohidrotic ectodermal dysplasia, immunodeficiency, osteopetrosis, and lymphedema. He presented in the neonatal period with recurrent skin pustules, followed by conjunctivitis and Enterobacter septicemia associated with seizures. He later developed additional infections, including septic arthritis, gastroenteritis, and otitis media. Laboratory studies showed increased IgM, normal IgA, and fluctuating low IgG. He developed recurrent infections with group B Streptococcus, salmonella, and Molluscum contagiosum. Ectodermal dysplasia findings included conical teeth, frontal bossing, and absence of sweat glands. At around 18 months, he developed lymphedema of the hands, feet, and genitalia, as well as mild osteopetrosis on imaging. Other features included skin abnormalities, cortical ischemia, asthma, and hypothyroidism. Treatment was mostly effective and he had subsequent normal development with the ability to attend school. Genetic analysis identified a hemizygous 2-bp deletion (<a href="/entry/300248#0027">300248.0027</a>) in the IKBKG gene. His mother, who had IP, carried the mutation in heterozygous state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20499091" 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>Female Patient with Transient Immunodeficiency</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Martinez-Pomar, N., Munoz-Saa, I., Heine-Suner, D., Martin, A., Smahi, A., Matamoros, N. <strong>A new mutation in exon 7 of NEMO gene: late skewed X-chromosome inactivation in an incontinentia pigmenti female patient with immunodeficiency.</strong> Hum. Genet. 118: 458-465, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16228229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16228229</a>] [<a href="https://doi.org/10.1007/s00439-005-0068-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16228229">Martinez-Pomar et al. (2005)</a> reported a female infant who presented at birth with classic features of IP. In the first months of life, she developed recurrent infections associated with high IgM and low IgG. She was treated successfully with IVIg, and the immunodeficiency spontaneously resolved. Genetic analysis identified a heterozygous frameshift mutation in the IKBKG gene (<a href="/entry/300248#0017">300248.0017</a>). In vitro studies showed impaired IKBA degradation and defective activation of the NFKB pathway compared to controls. The X-inactivation status of peripheral blood cells from the patient was evaluated at 24, 30, 38, and 48 months of age and was found to have progressed from random at 24 and 30 months to skewed at 38 and 48 months of age, at which point her immunodeficiency had disappeared. <a href="#9" class="mim-tip-reference" title="Martinez-Pomar, N., Munoz-Saa, I., Heine-Suner, D., Martin, A., Smahi, A., Matamoros, N. <strong>A new mutation in exon 7 of NEMO gene: late skewed X-chromosome inactivation in an incontinentia pigmenti female patient with immunodeficiency.</strong> Hum. Genet. 118: 458-465, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16228229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16228229</a>] [<a href="https://doi.org/10.1007/s00439-005-0068-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16228229">Martinez-Pomar et al. (2005)</a> stated that this was the first time that selection against the mutated X chromosome in X-linked disease had been documented in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16228229" 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>Clinical management of EDAID1 depends on the severity of the disorder. Many patients respond well to IVIg and prophylactic antibiotics (summary by <a href="#11" class="mim-tip-reference" title="Orange, J. S., Jain, A., Ballas, Z. K., Schneider, L. C., Geha, R. S., Bonilla, F. A. <strong>The presentation and natural history of immunodeficiency caused by nuclear factor kappa-B essential modulator mutation.</strong> J. Allergy Clin. Immun. 113: 725-733, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15100680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15100680</a>] [<a href="https://doi.org/10.1016/j.jaci.2004.01.762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15100680">Orange et al., 2004</a>, <a href="#4" class="mim-tip-reference" title="Heller, S., Kolsch, U., Magg, T., Kruger, R., Scheuern, A., Schneider, H., Eichinger, A., Wahn, V., Unterwalder, N., Lorenz, M., Schwarz, K., Meisel, C., Schulz, A., Hauck, F., von Bernuth, H. <strong>T cell impairment is predictive for a severe clinical course in NEMO deficiency.</strong> J. Clin. Immun. 40: 421-434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31965418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31965418</a>] [<a href="https://doi.org/10.1007/s10875-019-00728-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31965418">Heller et al., 2020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=31965418+15100680" 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>Some patients with EDAID1 have had successful bone marrow transplantation, although the outcomes are variable and a few may have persistent colitis (<a href="#1" class="mim-tip-reference" title="Abbott, J. K., Quinones, R. R., de la Morena, M. T., Gelfand, E. W. <strong>Successful hematopoietic cell transplantation in patients with unique NF-kappa-B essential modulator (NEMO) mutations. (Letter)</strong> Bone Marrow Transplant. 49: 1446-1447, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25068423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25068423</a>] [<a href="https://doi.org/10.1038/bmt.2014.157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25068423">Abbott et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25068423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a boy with EDAID1 (patient 1) who had recurrent CMV infection associated with impaired NK cytotoxic function, <a href="#10" class="mim-tip-reference" title="Orange, J. S., Brodeur, S. R., Jain, A., Bonilla, F. A., Schneider, L. C., Kretschmer, R., Nurko, S., Rasmussen, W. L., Kohler, J. R., Gellis, S. E., Ferguson, B. M., Strominger, J. L., Zonana, J., Ramesh, N., Ballas, Z. K., Geha, R. S. <strong>Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations.</strong> J. Clin. Invest. 109: 1501-1509, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12045264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12045264</a>] [<a href="https://doi.org/10.1172/JCI14858" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12045264">Orange et al. (2002)</a> found that in vivo and in vitro treatment with IL2 enhanced NK cell cytotoxicity. The findings suggested that IKBKG is also important for NK cell cytotoxicity and that IL2 may benefit patients with these defects. <a href="#13" class="mim-tip-reference" title="Pai, S.-Y., Levy, O., Jabara, H. H., Glickman, J. N., Stoler-Barak, L., Sachs, J., Nurko, S., Orange, J. S., Geha, R. S. <strong>Allogeneic transplantation successfully corrects immune defects, but not susceptibility to colitis, in a patient with nuclear factor-kappa-B essential modulator deficiency.</strong> J. Allergy Clin. Immun. 122: 1113-1118, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18851875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18851875</a>] [<a href="https://doi.org/10.1016/j.jaci.2008.08.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18851875">Pai et al. (2008)</a> reported follow-up of this boy. He underwent allogeneic bone marrow transplant from an unaffected sister, which resulted in correction of several immunologic abnormalities, including restoration of cytokine production in response to TLR agonists and LPS, increased CD40-mediated B-cell proliferation, and enhanced NK cell toxicity. Unfortunately, the patient continued to have flare-ups of colitis, often associated with bacterial infections. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18851875+12045264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of EDAID1 in the families reported by <a href="#17" class="mim-tip-reference" title="Zonana, J., Elder, M. E., Schneider, L. C., Orlow, S. J., Moss, C., Golabi, M., Shapira, S. K., Farndon, P. A., Wara, D. W., Emmal, S. A., Ferguson, B. M. <strong>A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).</strong> Am. J. Hum. Genet. 67: 1555-1562, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11047757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11047757</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11047757[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/10.1086/316914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11047757">Zonana et al. (2000)</a> was consistent with X-linked recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11047757" 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 affected males from 4 unrelated families with EDAID1, <a href="#17" class="mim-tip-reference" title="Zonana, J., Elder, M. E., Schneider, L. C., Orlow, S. J., Moss, C., Golabi, M., Shapira, S. K., Farndon, P. A., Wara, D. W., Emmal, S. A., Ferguson, B. M. <strong>A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).</strong> Am. J. Hum. Genet. 67: 1555-1562, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11047757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11047757</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11047757[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/10.1086/316914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11047757">Zonana et al. (2000)</a> identified hemizygous mutations in the IKBKG gene (<a href="/entry/300248#0007">300248.0007</a>-<a href="/entry/300248#0010">300248.0010</a>). All mutations occurred in exon 10 of the gene, which encodes the C-terminal zinc finger domain, and were thus predicted to result in a loss of NFKB activation. Since mutations in this gene cause IP in females and are usually lethal in males, <a href="#17" class="mim-tip-reference" title="Zonana, J., Elder, M. E., Schneider, L. C., Orlow, S. J., Moss, C., Golabi, M., Shapira, S. K., Farndon, P. A., Wara, D. W., Emmal, S. A., Ferguson, B. M. <strong>A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).</strong> Am. J. Hum. Genet. 67: 1555-1562, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11047757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11047757</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11047757[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/10.1086/316914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11047757">Zonana et al. (2000)</a> hypothesized that the mutations identified in males with EDAID1 are hypomorphic; functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11047757" 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 2 unrelated male patients with EDAID1, <a href="#5" class="mim-tip-reference" title="Jain, A., Ma, C. A., Liu, S., Brown, M., Cohen, J., Strober, W. <strong>Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohidrotic ectodermal dysplasia.</strong> Nature Immun. 2: 223-228, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11224521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11224521</a>] [<a href="https://doi.org/10.1038/85277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11224521">Jain et al. (2001)</a> identified hemizygous missense mutations in the NEMO gene. Both mutations (C417R, <a href="/entry/300248#0009">300248.0009</a> and D406V, <a href="/entry/300248#0011">300248.0011</a>) occurred in the putative zinc finger domain of the protein. Detailed functional studies showed impaired CD40L-mediated degradation of IKBA (<a href="/entry/164008">164008</a>), impaired CD40L-induced class switching in patient B cells, and impaired secretion of IL12 and TNF in response to stimulation with CD40L. However, there was some cytokine response to LPS, suggesting residual innate immunity. <a href="#5" class="mim-tip-reference" title="Jain, A., Ma, C. A., Liu, S., Brown, M., Cohen, J., Strober, W. <strong>Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohidrotic ectodermal dysplasia.</strong> Nature Immun. 2: 223-228, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11224521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11224521</a>] [<a href="https://doi.org/10.1038/85277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11224521">Jain et al. (2001)</a> concluded that NEMO has a regulatory function in NFKB activation and B-cell Ig class switching. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11224521" 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 unrelated boys with EDAID1, <a href="#10" class="mim-tip-reference" title="Orange, J. S., Brodeur, S. R., Jain, A., Bonilla, F. A., Schneider, L. C., Kretschmer, R., Nurko, S., Rasmussen, W. L., Kohler, J. R., Gellis, S. E., Ferguson, B. M., Strominger, J. L., Zonana, J., Ramesh, N., Ballas, Z. K., Geha, R. S. <strong>Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations.</strong> J. Clin. Invest. 109: 1501-1509, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12045264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12045264</a>] [<a href="https://doi.org/10.1172/JCI14858" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12045264">Orange et al. (2002)</a> identified hemizygous mutations in the IKBKG gene. Two mutations occurred in the zinc finger domain (C417R, <a href="/entry/300248#0009">300248.0009</a> and Q403X, <a href="/entry/300248#0015">300248.0015</a>), and 1 occurred in the first coiled-coil domain (L153R; <a href="/entry/300248#0014">300248.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12045264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members and obligate carriers of a family with ectodermal dysplasia and immunodeficiency, originally reported by <a href="#7" class="mim-tip-reference" title="Lie, S. O., Froland, S., Brandtzaeg, P., Vandvik, B., Steen-Johnsen, J. <strong>Transient B cell immaturity with intractable diarrhoea: a possible new immunodeficiency syndrome.</strong> J. Inherit. Metab. Dis. 1: 137-143, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/117248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">117248</a>] [<a href="https://doi.org/10.1007/BF01805582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="117248">Lie et al. (1978)</a>, <a href="#12" class="mim-tip-reference" title="Orstavik, K. H., Kristiansen, M., Knudsen, G. P., Storhaug, K., Vege, A., Eiklid, K., Abrahamsen, T. G., Smahi, A., Steen-Johnsen, J. <strong>Novel splicing mutation in the NEMO (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome inactivation.</strong> Am. J. Med. Genet. 140A: 31-39, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16333836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16333836</a>] [<a href="https://doi.org/10.1002/ajmg.a.31026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16333836">Orstavik et al. (2006)</a> identified a splice site mutation in the IKBKG gene (<a href="/entry/300248#0016">300248.0016</a>). The family had 3 stillborn males, 3 affected males who were small for gestational age and died within 8 months, and 1 male who died at age 5 years. The 5-year-old had cone-shaped teeth, oligodontia, serious bacterial infections, and inflammatory bowel disease. Isolated subtle tooth anomalies were found in 3 carriers examined, of whom 2 had random X inactivation and 1 had extreme skewing. <a href="#12" class="mim-tip-reference" title="Orstavik, K. H., Kristiansen, M., Knudsen, G. P., Storhaug, K., Vege, A., Eiklid, K., Abrahamsen, T. G., Smahi, A., Steen-Johnsen, J. <strong>Novel splicing mutation in the NEMO (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome inactivation.</strong> Am. J. Med. Genet. 140A: 31-39, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16333836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16333836</a>] [<a href="https://doi.org/10.1002/ajmg.a.31026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16333836">Orstavik et al. (2006)</a> stated that this was the first report of random X inactivation in carriers of EDAID. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=117248+16333836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a boy with EDAID1, <a href="#14" class="mim-tip-reference" title="Roberts, C. M. L., Angus, J. E., Leach, I. H., McDermott, E. M., Walker, D. A., Ravenscroft, J. C. <strong>A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency.</strong> Europ. J. Pediat. 169: 1403-1407, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20499091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20499091</a>] [<a href="https://doi.org/10.1007/s00431-010-1206-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20499091">Roberts et al. (2010)</a> identified a hemizygous 2-bp deletion (c.1182_1183delTT; <a href="/entry/300248#0027">300248.0027</a>) in the IKBKG gene predicted to result in a frameshift and premature termination. His mother, who carried the mutation in heterozygous state, showed signs of IP since childhood. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20499091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a male infant with lethal EDAID1, <a href="#6" class="mim-tip-reference" title="Johnston, A. M., Niemela, J., Rosenzweig, S. D., Fried, A. J., Delmonte, O. M., Fleisher, T. A., Kuehn, H. <strong>A novel mutation in IKBKG/NEMO leads to ectodermal dysplasia with severe immunodeficiency (EDA-ID). (Letter)</strong> J. Clin. Immun 36: 541-543, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27368913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27368913</a>] [<a href="https://doi.org/10.1007/s10875-016-0309-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27368913">Johnston et al. (2016)</a> identified a hemizygous splice site mutation in the IKBKG gene (<a href="/entry/300248#0028">300248.0028</a>). Western blot analysis of patient cells showed reduced size of the IKBKG protein, consistent with a frameshift and premature termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27368913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a boy (patient 1) with EDAID1, <a href="#4" class="mim-tip-reference" title="Heller, S., Kolsch, U., Magg, T., Kruger, R., Scheuern, A., Schneider, H., Eichinger, A., Wahn, V., Unterwalder, N., Lorenz, M., Schwarz, K., Meisel, C., Schulz, A., Hauck, F., von Bernuth, H. <strong>T cell impairment is predictive for a severe clinical course in NEMO deficiency.</strong> J. Clin. Immun. 40: 421-434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31965418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31965418</a>] [<a href="https://doi.org/10.1007/s10875-019-00728-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31965418">Heller et al. (2020)</a> identified a hemizygous splice site mutation in the IKBKG gene (<a href="/entry/300248#0031">300248.0031</a>), resulting in a frameshift and premature termination, with loss of the zinc finger domain. Patient cells showed decreased IKBKG levels compared to controls; in vitro studies showed impaired degradation of IKBA and impaired IL6 production upon stimulation with IL1B and TNFA. His mother and sister, who were heterozygous for the mutation, had incontinentia pigmenti (IP; <a href="/entry/308300">308300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31965418" 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>Anhidrotic Ectodermal Dysplasia with Immunodeficiency, Osteopetrosis, and Lymphedema</em></strong></p><p>
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In 2 unrelated male patients with OLEDAID syndrome, <a href="#2" class="mim-tip-reference" title="Doffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S. H., and 16 others. <strong>X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling.</strong> Nature Genet. 27: 277-285, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242109</a>] [<a href="https://doi.org/10.1038/85837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242109">Doffinger et al. (2001)</a> identified an X420W mutation in the IKBKG gene (<a href="/entry/300248#0002">300248.0002</a>). Different alleles were present at the flanking polymorphic loci in the 2 patients, indicating 2 independent mutation events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 6-year-old boy with hypohidrotic ectodermal dysplasia, immunodeficiency, osteopetrosis, and lymphedema, <a href="#14" class="mim-tip-reference" title="Roberts, C. M. L., Angus, J. E., Leach, I. H., McDermott, E. M., Walker, D. A., Ravenscroft, J. C. <strong>A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency.</strong> Europ. J. Pediat. 169: 1403-1407, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20499091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20499091</a>] [<a href="https://doi.org/10.1007/s00431-010-1206-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20499091">Roberts et al. (2010)</a> identified a hemizygous 2-bp deletion (c.1182_1183delTT; <a href="/entry/300248#0027">300248.0027</a>) in the IKBKG gene. His mother, who had IP since childhood, carried the mutation in heterozygous state. The mutation was predicted to result in a frameshift and premature termination, but studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20499091" 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 general, patients with NKBKG mutations affecting the C-terminal zinc finger domain have a more severe clinical course with ectodermal dysplasia, whereas patients with mutations affecting the leucine zipper domain or the more N-terminal coiled-coil domains have a less severe clinical course and do not show features of ectodermal dysplasia, although isolated hypotonia and/or conical teeth may be present (<a href="#11" class="mim-tip-reference" title="Orange, J. S., Jain, A., Ballas, Z. K., Schneider, L. C., Geha, R. S., Bonilla, F. A. <strong>The presentation and natural history of immunodeficiency caused by nuclear factor kappa-B essential modulator mutation.</strong> J. Allergy Clin. Immun. 113: 725-733, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15100680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15100680</a>] [<a href="https://doi.org/10.1016/j.jaci.2004.01.762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15100680">Orange et al., 2004</a>, <a href="#4" class="mim-tip-reference" title="Heller, S., Kolsch, U., Magg, T., Kruger, R., Scheuern, A., Schneider, H., Eichinger, A., Wahn, V., Unterwalder, N., Lorenz, M., Schwarz, K., Meisel, C., Schulz, A., Hauck, F., von Bernuth, H. <strong>T cell impairment is predictive for a severe clinical course in NEMO deficiency.</strong> J. Clin. Immun. 40: 421-434, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31965418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31965418</a>] [<a href="https://doi.org/10.1007/s10875-019-00728-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31965418">Heller et al., 2020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=31965418+15100680" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By studying responses to the TLR4 (<a href="/entry/603030">603030</a>) ligand LPS and to the bacterial chemoattractant fMLP in polymorphonuclear neutrophils (PMNs) from 1 patient with IRAK4 deficiency (<a href="/entry/607676">607676</a>) and 3 patients with NEMO deficiency causing immunodeficiency with ectodermal dysplasia, <a href="#15" class="mim-tip-reference" title="Singh, A., Zarember, K. A., Kuhns, D. B., Gallin, J. I. <strong>Impaired priming and activation of the neutrophil NADPH oxidase in patients with IRAK4 or NEMO deficiency.</strong> J. Immun. 182: 6410-6417, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19414794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19414794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19414794[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/10.4049/jimmunol.0802512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19414794">Singh et al. (2009)</a> demonstrated reduced or absent superoxide production after impaired priming and activation of the oligomeric neutrophil NADPH oxidase (NOX; see <a href="/entry/300481">300481</a>). The response was particularly weak or absent in IRAK4-deficient PMNs. NEMO-deficient PMNs had a phenotype intermediate between IRAK4-deficient PMNs and normal PMNs. Decreased LPS- and fMLP-induced phosphorylation of p38 (MAPK14; <a href="/entry/600289">600289</a>) was observed in both deficiencies. <a href="#15" class="mim-tip-reference" title="Singh, A., Zarember, K. A., Kuhns, D. B., Gallin, J. I. <strong>Impaired priming and activation of the neutrophil NADPH oxidase in patients with IRAK4 or NEMO deficiency.</strong> J. Immun. 182: 6410-6417, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19414794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19414794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19414794[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/10.4049/jimmunol.0802512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19414794">Singh et al. (2009)</a> proposed that decreased activation of NOX may contribute to increased risk of infection in patients with IRAK4 deficiency or NEMO deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19414794" 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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Abbott, J. K., Quinones, R. R., de la Morena, M. T., Gelfand, E. W.
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<strong>Successful hematopoietic cell transplantation in patients with unique NF-kappa-B essential modulator (NEMO) mutations. (Letter)</strong>
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Bone Marrow Transplant. 49: 1446-1447, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25068423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25068423</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25068423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/bmt.2014.157" target="_blank">Full Text</a>]
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Doffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S. H., and 16 others.
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<strong>X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling.</strong>
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Nature Genet. 27: 277-285, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242109</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/85837" target="_blank">Full Text</a>]
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Dupuis-Girod, S., Corradini, N., Hadj-Rabia, S., Fournet, J.-C., Faivre, L., Le Deist, F., Durand, P., Doffinger, R., Smahi, A., Israel, A., Courtois, G., Brousse, N., Blanche, S., Munnich, A., Fischer, A., Casanova, J.-L., Bodemer, C.
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<strong>Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother.</strong>
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Pediatrics 109: e97, 2002. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12042591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12042591</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12042591" 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/10.1542/peds.109.6.e97" target="_blank">Full Text</a>]
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Heller, S., Kolsch, U., Magg, T., Kruger, R., Scheuern, A., Schneider, H., Eichinger, A., Wahn, V., Unterwalder, N., Lorenz, M., Schwarz, K., Meisel, C., Schulz, A., Hauck, F., von Bernuth, H.
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<strong>T cell impairment is predictive for a severe clinical course in NEMO deficiency.</strong>
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J. Clin. Immun. 40: 421-434, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31965418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31965418</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31965418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10875-019-00728-y" target="_blank">Full Text</a>]
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Jain, A., Ma, C. A., Liu, S., Brown, M., Cohen, J., Strober, W.
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<strong>Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohidrotic ectodermal dysplasia.</strong>
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Nature Immun. 2: 223-228, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11224521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11224521</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11224521" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/85277" target="_blank">Full Text</a>]
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Johnston, A. M., Niemela, J., Rosenzweig, S. D., Fried, A. J., Delmonte, O. M., Fleisher, T. A., Kuehn, H.
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<strong>A novel mutation in IKBKG/NEMO leads to ectodermal dysplasia with severe immunodeficiency (EDA-ID). (Letter)</strong>
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J. Clin. Immun 36: 541-543, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27368913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27368913</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27368913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10875-016-0309-y" target="_blank">Full Text</a>]
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Lie, S. O., Froland, S., Brandtzaeg, P., Vandvik, B., Steen-Johnsen, J.
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<strong>Transient B cell immaturity with intractable diarrhoea: a possible new immunodeficiency syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/117248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">117248</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=117248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF01805582" target="_blank">Full Text</a>]
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Mansour, S., Woffendin, H., Mitton, S., Jeffrey, I., Jakins, T., Kenwrick, S., Murday, V. A.
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<strong>Incontinentia pigmenti in a surviving male is accompanied by hypohidrotic ectodermal dysplasia and recurrent infection.</strong>
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Am. J. Med. Genet. 99: 172-177, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11241484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11241484</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11241484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/1096-8628(2001)9999:9999<::aid-ajmg1155>3.0.co;2-y" target="_blank">Full Text</a>]
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Martinez-Pomar, N., Munoz-Saa, I., Heine-Suner, D., Martin, A., Smahi, A., Matamoros, N.
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<strong>A new mutation in exon 7 of NEMO gene: late skewed X-chromosome inactivation in an incontinentia pigmenti female patient with immunodeficiency.</strong>
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Hum. Genet. 118: 458-465, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16228229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16228229</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16228229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-005-0068-y" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Orange2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Orange, J. S., Brodeur, S. R., Jain, A., Bonilla, F. A., Schneider, L. C., Kretschmer, R., Nurko, S., Rasmussen, W. L., Kohler, J. R., Gellis, S. E., Ferguson, B. M., Strominger, J. L., Zonana, J., Ramesh, N., Ballas, Z. K., Geha, R. S.
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<strong>Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations.</strong>
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J. Clin. Invest. 109: 1501-1509, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12045264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12045264</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12045264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI14858" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Orange2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Orange, J. S., Jain, A., Ballas, Z. K., Schneider, L. C., Geha, R. S., Bonilla, F. A.
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<strong>The presentation and natural history of immunodeficiency caused by nuclear factor kappa-B essential modulator mutation.</strong>
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J. Allergy Clin. Immun. 113: 725-733, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15100680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15100680</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15100680" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jaci.2004.01.762" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
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<a id="Orstavik2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Orstavik, K. H., Kristiansen, M., Knudsen, G. P., Storhaug, K., Vege, A., Eiklid, K., Abrahamsen, T. G., Smahi, A., Steen-Johnsen, J.
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<strong>Novel splicing mutation in the NEMO (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome inactivation.</strong>
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Am. J. Med. Genet. 140A: 31-39, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16333836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16333836</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16333836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31026" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Pai2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pai, S.-Y., Levy, O., Jabara, H. H., Glickman, J. N., Stoler-Barak, L., Sachs, J., Nurko, S., Orange, J. S., Geha, R. S.
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<strong>Allogeneic transplantation successfully corrects immune defects, but not susceptibility to colitis, in a patient with nuclear factor-kappa-B essential modulator deficiency.</strong>
|
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J. Allergy Clin. Immun. 122: 1113-1118, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18851875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18851875</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18851875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.jaci.2008.08.026" target="_blank">Full Text</a>]
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<a id="14" class="mim-anchor"></a>
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<a id="Roberts2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Roberts, C. M. L., Angus, J. E., Leach, I. H., McDermott, E. M., Walker, D. A., Ravenscroft, J. C.
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<strong>A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency.</strong>
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Europ. J. Pediat. 169: 1403-1407, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20499091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20499091</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20499091" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00431-010-1206-7" target="_blank">Full Text</a>]
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Singh2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Singh, A., Zarember, K. A., Kuhns, D. B., Gallin, J. I.
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<strong>Impaired priming and activation of the neutrophil NADPH oxidase in patients with IRAK4 or NEMO deficiency.</strong>
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J. Immun. 182: 6410-6417, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19414794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19414794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19414794[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19414794" 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/10.4049/jimmunol.0802512" target="_blank">Full Text</a>]
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<a id="16" class="mim-anchor"></a>
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<a id="{The International Incontinentia Pigmenti Consortium}2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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The International Incontinentia Pigmenti Consortium.
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<strong>Genomic rearrangement in NEMO impairs NF-kappa-B activation and is a cause of incontinentia pigmenti.</strong>
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Nature 405: 466-472, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839543</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839543" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/35013114" target="_blank">Full Text</a>]
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<a id="17" class="mim-anchor"></a>
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<a id="Zonana2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zonana, J., Elder, M. E., Schneider, L. C., Orlow, S. J., Moss, C., Golabi, M., Shapira, S. K., Farndon, P. A., Wara, D. W., Emmal, S. A., Ferguson, B. M.
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<strong>A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).</strong>
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Am. J. Hum. Genet. 67: 1555-1562, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11047757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11047757</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11047757[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11047757" 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/10.1086/316914" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 06/03/2020
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Alan F. Scott - updated : 02/19/2019<br>Paul J. Converse - updated : 3/1/2011<br>Marla J. F. O'Neill - updated : 2/15/2006<br>Marla J. F. O'Neill - updated : 1/25/2006<br>Paul J. Converse - updated : 3/6/2001<br>Ada Hamosh - updated : 3/1/2001
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 12/20/2000
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 06/10/2020
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<span class="mim-text-font">
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carol : 06/09/2020<br>ckniffin : 06/03/2020<br>carol : 02/19/2019<br>carol : 11/15/2018<br>carol : 11/13/2018<br>carol : 11/09/2018<br>carol : 05/22/2012<br>mgross : 3/1/2011<br>wwang : 7/3/2008<br>wwang : 4/3/2007<br>wwang : 2/28/2007<br>terry : 2/23/2007<br>alopez : 3/20/2006<br>wwang : 2/22/2006<br>terry : 2/15/2006<br>wwang : 2/2/2006<br>terry : 1/25/2006<br>mgross : 10/4/2005<br>terry : 9/22/2005<br>carol : 9/15/2003<br>ckniffin : 9/10/2003<br>carol : 4/8/2002<br>alopez : 2/4/2002<br>terry : 11/14/2001<br>alopez : 4/24/2001<br>mgross : 3/6/2001<br>alopez : 3/2/2001<br>terry : 3/1/2001<br>carol : 12/20/2000
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<span class="mim-font">
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<strong>#</strong> 300291
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<h3>
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<span class="mim-font">
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ECTODERMAL DYSPLASIA AND IMMUNODEFICIENCY 1; EDAID1
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</h3>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH IMMUNODEFICIENCY, OSTEOPETROSIS, AND LYMPHEDEMA; OLEDAID<br />
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ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH IMMUNE DEFICIENCY<br />
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ECTODERMAL DYSPLASIA, HYPOHIDROTIC, WITH IMMUNE DEFICIENCY; HEDID<br />
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HYPER-IgM IMMUNODEFICIENCY, X-LINKED, WITH HYPOHIDROTIC ECTODERMAL DYSPLASIA; XHMED
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</span>
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</h4>
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<strong>SNOMEDCT:</strong> 703525006;
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<strong>ORPHA:</strong> 238468, 69088, 98813;
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<strong>DO:</strong> 0081078;
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</span>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</tr>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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Xq28
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</span>
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</td>
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<td>
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<span class="mim-font">
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Ectodermal dysplasia and immunodeficiency 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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300291
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</td>
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<td>
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<span class="mim-font">
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X-linked recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
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IKBKG
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</span>
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</td>
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<td>
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<span class="mim-font">
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300248
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</table>
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<p>A number sign (#) is used with this entry because of evidence that ectodermal dysplasia and immunodeficiency-1 (EDAID1) is caused by hemizygous mutation in the IKK-gamma gene (IKBKG, or NEMO; 300248) on chromosome Xq28.</p><p>Hemizygous mutation in the IKBKG gene also causes X-linked recessive immunodeficiency-33 (IMD33; 300636) in males. Heterozygous mutation in the IKBKG gene causes X-linked dominant incontinentia pigmenti (IP; 308300) in females.</p>
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<strong>Description</strong>
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<p>Ectodermal dysplasia with immunodeficiency-1 (EDAID1) is an X-linked recessive disorder that characteristically affects only males. Affected individuals have onset of recurrent severe infections due to immunodeficiency in early infancy or in the first years of life. There is increased susceptibility to bacterial, pneumococcal, mycobacterial, and fungal infections. Laboratory studies usually show dysgammaglobulinemia with low IgG subsets and normal or increased IgA and IgM, consistent with impaired 'class-switching' of B cells, although immunologic abnormalities may be subtle compared to the clinical picture, and B- and T-cell numbers are usually normal. There is a poor antibody response to polysaccharide vaccinations, particularly pneumococcus; response to other vaccinations is variable. Patients also have features of ectodermal dysplasia, including conical incisors, hypo/anhidrosis, and thin skin or hair. Severely affected individuals may also show lymphedema, osteopetrosis, and, rarely, hematologic abnormalities. The phenotype is highly variable, likely due to different hypomorphic mutations, and may be fatal in childhood. Intravenous immunoglobulins and prophylactic antibiotics are used as treatment; some patients may benefit from bone marrow transplantation. Although only males tend to be affected with immunodeficiency, many patients inherit a mutation from a mother who has mild features of IP or conical teeth (summary by Doffinger et al., 2001, Orange et al., 2004, Roberts et al., 2010, Heller et al., 2020). </p><p><strong><em>Genetic Heterogeneity of Ectodermal Dysplasia and Immune Deficiency</em></strong></p><p>
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Also see EDAID2 (612132), caused by mutation in the NFKBIA gene (164008).</p>
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<strong>Clinical Features</strong>
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<p>Zonana et al. (2000) studied males from 4 families with hypohidrotic ectodermal dysplasia and immunodeficiency segregating as an X-linked recessive trait. The patients presented in the first years of life with recurrent infections, including pneumonia, bacterial infections of the bone and soft tissue, and sepsis. Organisms included pneumococcus, Pseudomonas, pneumocystis, and atypical mycobacteria. Laboratory studies showed dysgammaglobulinemia with increased IgM and low levels of IgA and IgG, although this was somewhat variable. Other immunologic parameters were essentially normal, although there was no antibody response to pneumococcal infection or vaccination. Response to tetanus was normal in some patients. The patients also had features of ectodermal dysplasia, including conical teeth, abnormal teeth, inability to sweat or poor sweating, and sometimes sparse hair. Two brothers in family 4 had the most severe clinical course, with death occurring by 3 years of age. These boys also had osteopetrosis, thus expanding the phenotype. Despite treatment, usually with IVIg, all had significant morbidity and mortality from recurrent infections. The mothers had variable mild manifestations, ranging from normal dentition to mild hypodontia or conical teeth; 2 had some skin hyperpigmentation. One mother (family 2) had low IgA, but no immune dysfunction. </p><p>Doffinger et al. (2001) identified 7 boys from 5 unrelated families with EDAID1. Four patients died between 9 months and 17 years of age. In all patients, ectodermal dysplasia features were somewhat milder compared to other forms of anhidrotic ectodermal dysplasia. Most children experienced failure to thrive, recurrent digestive tract infections, often with intractable diarrhea and recurrent ulcerations, recurrent respiratory tract infections, often with bronchiectasis, and recurrent skin infections, suggesting that they were generally susceptible to various gram-positive and gram-negative bacteria. The only blood immunologic abnormality detected in all patients tested was a poor antibody response to polysaccharide antigens (anti-AB isohemagglutinins and antibodies against H. influenzae and S. pneumoniae). In most patients, low levels of IgG or IgG2 were detected. Intravenous immunoglobulins and prophylactic antibiotics had occasionally been sufficient to improve clinical status when started early. </p><p>Jain et al. (2001) reported 2 unrelated male patients with EDAID1 associated with increased IgM and decreased IgG. One patient presented with pneumococcal meningitis at 9 months of age, and both patients had frequent upper respiratory and sinus infections despite intravenous gamma-globulin replacement therapy. Neither patient had a history of opportunistic infections suggestive of T-cell dysfunction. One patient had conical-shaped molars and incisors, but skin biopsies for both patients confirmed the absence of eccrine sweat glands and a paucity of hair follicles, consistent with ectodermal dysplasia. Both had normal bone density and did not have Mycobacterium avium complex infection. </p><p>Orange et al. (2002) reported 3 unrelated boys with EDAID1. Patient 1 was a 2-year-old boy who presented with severe systemic infections, including Listeria sepsis, Streptococcus bovis meningitis, and recurrent CMV sepsis and colitis. Laboratory studies showed increased IgM, variably decreased IgG, and detectable diphtheria and tetanus titers. Patients 2 and 3 were teenagers with a history of recurrent infections since childhood, including sinusitis, pneumonia, oral herpetic lesions, and systemic invasive atypical Mycobacterium infections. They had normal, decreased, or increased IgG and IgA, but normal IgM, as well as decreased specific antibody levels. Both were treated with IVIg. Detailed immunologic studies showed that all patients had defective CD40 (109535) signaling with impaired B-cell proliferative responses and decreased activation of NFKB compared to controls. NK cell levels were normal, but there was deficient NK cell cytotoxicity that could be partially overcome in vitro and in vivo with IL2 (161560) treatment. </p><p>Johnston et al. (2016) reported a male infant who presented with systemic Staphylococcus aureus infection associated with multiple brain infarcts, microabscesses, and white matter abnormalities. He was noted to have features of ectodermal dysplasia, such as sparse hair and absent eyelashes and eyebrows. He also had edema of the scalp, hands, scrotum, and lower extremities. Laboratory studies showed dysgammaglobulinemia with mostly low Ig levels, whereas T, B, and NK cells were normal. The infection persisted despite treatment, and he died at 18 days of age. The patient's mother and several female relatives had features consistent with IP; X-inactivation studies on the mother showed nonrandom X-chromosome inactivation with expression of the wildtype allele. Patient peripheral blood cells showed impaired cytokine production in response to stimulation of Toll-like receptors compared to controls. </p><p>Heller et al. (2020) reported a boy (patient 1) with severe EDAID1. He presented in infancy with a septic Enterobacter and Pneumocystis infection associated with decreased IgG and IgM. He also had lymphedema of the lower leg. Detailed immunologic studies showed functional B- and T-cell deficiency with impaired class-switched memory B cells, impaired CD3-induced T-cell proliferation, and skewing toward naive cells, indicating a defect in adaptive immunity. There was also impaired NFKB signaling through the Toll-like receptor, IL1B, and TNFA pathways, indicating defects in innate immunity. The patient underwent hematopoietic stem cell transplantation, but developed complications, including persistent colitis. Heller et al. (2020) concluded that T-cell dysfunction in EDAID1 predicts a severe clinical course. </p><p><strong><em>Anhidrotic Ectodermal Dysplasia with Immunodeficiency, Osteopetrosis, and Lymphedema</em></strong></p><p>
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The International Incontinentia Pigmenti Consortium (2000) reported a male infant (patient IP85) with a severe form of EDAID1. In addition to recurrent infections, the boy had osteopetrosis and lymphedema. He was born with multiple capillary hemangiomas, developed lymphedema of the lower limbs, and had failure to thrive. Despite a destructive red blood cell picture and recurrent infections due to poor immune function, he survived 2 and a half years, but eventually succumbed to a tuberculosis infection. He had had operations to remove his spleen and an intestinal stricture, and biopsies revealed abnormal capillary beds in the gut, extrahepatic erythropoiesis, and osteopetrosis. His skin developed a reticular pigmentation. Cognitive development was normal. Genetic analysis identified a hemizygous X420W mutation in the IKBKG gene (300248.0002) that was inherited from his mother, who had IP. Mansour et al. (2001) presented more details of this patient (IP85), who also had hematologic disturbances, such as hemolytic anemia and thrombocytopenia. Doffinger et al. (2001) also studied this patient and classified him as having 'anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema' (OLEDAID), which is within the phenotypic spectrum of EDAID1. </p><p>Doffinger et al. (2001) reported another boy, of French descent, with a similar OLEDAID phenotype, including recurrent infections, anhidrotic ectodermal dysplasia, lymphedema, and osteopetrosis. Blood monocytes and polymorphonuclear cells were normal in number and morphology, and B- and T-cell counts and responses to vaccine protein antigens (tetanus and polio) were normal. However, serum titers of antibodies against pneumococcus were low, despite proven infection. Serum levels of immunoglobulin isotypes were normal for age, with the exception of low to normal IgG levels. This patient and the patient described by Mansour et al. (2001) both died in the first years of life from overwhelming infectious disease caused by a variety of microorganisms, including gram-positive cocci, gram-negative bacilli, mycobacteria, and fungi. The French boy carried a hemizygous X420W mutation in the IKBKG gene that was inherited from his mother, who had mild IP. In vitro functional expression studies showed that the X420W mutation resulted in a 50 to 60% reduction of NF-kappa-B activation. Patient cells showed impaired cellular responses to TNF-alpha (191160) and a lower level of IFN-gamma (147570) production upon costimulation with IL12 (see 161560), IL1-beta (147720), or IL18 (600953) compared to controls. There was also evidence of impaired cellular responses to lipopolysaccharide (LPS) and dissociated cellular responses to CD154 (CD40LG; 300386), suggesting that some but not all CD40 (109535)-mediated signals are NEMO-dependent in both dendritic cells and B cells. The findings indicated that the X420W mutation impairs but does not abolish NFKB activation, consistent with a hypomorphic allele and postnatal survival of the boys. Dupuis-Girod et al. (2002) reported that the French patient described by Doffinger et al. (2001) underwent hematopoietic stem cell transplantation, but developed complications and died at 18 months of age. </p><p>Roberts et al. (2010) reported a 6-year-old boy with hypohidrotic ectodermal dysplasia, immunodeficiency, osteopetrosis, and lymphedema. He presented in the neonatal period with recurrent skin pustules, followed by conjunctivitis and Enterobacter septicemia associated with seizures. He later developed additional infections, including septic arthritis, gastroenteritis, and otitis media. Laboratory studies showed increased IgM, normal IgA, and fluctuating low IgG. He developed recurrent infections with group B Streptococcus, salmonella, and Molluscum contagiosum. Ectodermal dysplasia findings included conical teeth, frontal bossing, and absence of sweat glands. At around 18 months, he developed lymphedema of the hands, feet, and genitalia, as well as mild osteopetrosis on imaging. Other features included skin abnormalities, cortical ischemia, asthma, and hypothyroidism. Treatment was mostly effective and he had subsequent normal development with the ability to attend school. Genetic analysis identified a hemizygous 2-bp deletion (300248.0027) in the IKBKG gene. His mother, who had IP, carried the mutation in heterozygous state. </p><p><strong><em>Female Patient with Transient Immunodeficiency</em></strong></p><p>
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Martinez-Pomar et al. (2005) reported a female infant who presented at birth with classic features of IP. In the first months of life, she developed recurrent infections associated with high IgM and low IgG. She was treated successfully with IVIg, and the immunodeficiency spontaneously resolved. Genetic analysis identified a heterozygous frameshift mutation in the IKBKG gene (300248.0017). In vitro studies showed impaired IKBA degradation and defective activation of the NFKB pathway compared to controls. The X-inactivation status of peripheral blood cells from the patient was evaluated at 24, 30, 38, and 48 months of age and was found to have progressed from random at 24 and 30 months to skewed at 38 and 48 months of age, at which point her immunodeficiency had disappeared. Martinez-Pomar et al. (2005) stated that this was the first time that selection against the mutated X chromosome in X-linked disease had been documented in vivo. </p>
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<strong>Clinical Management</strong>
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<p>Clinical management of EDAID1 depends on the severity of the disorder. Many patients respond well to IVIg and prophylactic antibiotics (summary by Orange et al., 2004, Heller et al., 2020). </p><p>Some patients with EDAID1 have had successful bone marrow transplantation, although the outcomes are variable and a few may have persistent colitis (Abbott et al., 2014). </p><p>In a boy with EDAID1 (patient 1) who had recurrent CMV infection associated with impaired NK cytotoxic function, Orange et al. (2002) found that in vivo and in vitro treatment with IL2 enhanced NK cell cytotoxicity. The findings suggested that IKBKG is also important for NK cell cytotoxicity and that IL2 may benefit patients with these defects. Pai et al. (2008) reported follow-up of this boy. He underwent allogeneic bone marrow transplant from an unaffected sister, which resulted in correction of several immunologic abnormalities, including restoration of cytokine production in response to TLR agonists and LPS, increased CD40-mediated B-cell proliferation, and enhanced NK cell toxicity. Unfortunately, the patient continued to have flare-ups of colitis, often associated with bacterial infections. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of EDAID1 in the families reported by Zonana et al. (2000) was consistent with X-linked recessive inheritance. </p>
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<strong>Molecular Genetics</strong>
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<p>In affected males from 4 unrelated families with EDAID1, Zonana et al. (2000) identified hemizygous mutations in the IKBKG gene (300248.0007-300248.0010). All mutations occurred in exon 10 of the gene, which encodes the C-terminal zinc finger domain, and were thus predicted to result in a loss of NFKB activation. Since mutations in this gene cause IP in females and are usually lethal in males, Zonana et al. (2000) hypothesized that the mutations identified in males with EDAID1 are hypomorphic; functional studies of the variants were not performed. </p><p>In 2 unrelated male patients with EDAID1, Jain et al. (2001) identified hemizygous missense mutations in the NEMO gene. Both mutations (C417R, 300248.0009 and D406V, 300248.0011) occurred in the putative zinc finger domain of the protein. Detailed functional studies showed impaired CD40L-mediated degradation of IKBA (164008), impaired CD40L-induced class switching in patient B cells, and impaired secretion of IL12 and TNF in response to stimulation with CD40L. However, there was some cytokine response to LPS, suggesting residual innate immunity. Jain et al. (2001) concluded that NEMO has a regulatory function in NFKB activation and B-cell Ig class switching. </p><p>In 3 unrelated boys with EDAID1, Orange et al. (2002) identified hemizygous mutations in the IKBKG gene. Two mutations occurred in the zinc finger domain (C417R, 300248.0009 and Q403X, 300248.0015), and 1 occurred in the first coiled-coil domain (L153R; 300248.0014). </p><p>In affected members and obligate carriers of a family with ectodermal dysplasia and immunodeficiency, originally reported by Lie et al. (1978), Orstavik et al. (2006) identified a splice site mutation in the IKBKG gene (300248.0016). The family had 3 stillborn males, 3 affected males who were small for gestational age and died within 8 months, and 1 male who died at age 5 years. The 5-year-old had cone-shaped teeth, oligodontia, serious bacterial infections, and inflammatory bowel disease. Isolated subtle tooth anomalies were found in 3 carriers examined, of whom 2 had random X inactivation and 1 had extreme skewing. Orstavik et al. (2006) stated that this was the first report of random X inactivation in carriers of EDAID. </p><p>In a boy with EDAID1, Roberts et al. (2010) identified a hemizygous 2-bp deletion (c.1182_1183delTT; 300248.0027) in the IKBKG gene predicted to result in a frameshift and premature termination. His mother, who carried the mutation in heterozygous state, showed signs of IP since childhood. Functional studies of the variant were not performed. </p><p>In a male infant with lethal EDAID1, Johnston et al. (2016) identified a hemizygous splice site mutation in the IKBKG gene (300248.0028). Western blot analysis of patient cells showed reduced size of the IKBKG protein, consistent with a frameshift and premature termination. </p><p>In a boy (patient 1) with EDAID1, Heller et al. (2020) identified a hemizygous splice site mutation in the IKBKG gene (300248.0031), resulting in a frameshift and premature termination, with loss of the zinc finger domain. Patient cells showed decreased IKBKG levels compared to controls; in vitro studies showed impaired degradation of IKBA and impaired IL6 production upon stimulation with IL1B and TNFA. His mother and sister, who were heterozygous for the mutation, had incontinentia pigmenti (IP; 308300). </p><p><strong><em>Anhidrotic Ectodermal Dysplasia with Immunodeficiency, Osteopetrosis, and Lymphedema</em></strong></p><p>
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In 2 unrelated male patients with OLEDAID syndrome, Doffinger et al. (2001) identified an X420W mutation in the IKBKG gene (300248.0002). Different alleles were present at the flanking polymorphic loci in the 2 patients, indicating 2 independent mutation events. </p><p>In a 6-year-old boy with hypohidrotic ectodermal dysplasia, immunodeficiency, osteopetrosis, and lymphedema, Roberts et al. (2010) identified a hemizygous 2-bp deletion (c.1182_1183delTT; 300248.0027) in the IKBKG gene. His mother, who had IP since childhood, carried the mutation in heterozygous state. The mutation was predicted to result in a frameshift and premature termination, but studies of patient cells were not performed. </p>
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<p>In general, patients with NKBKG mutations affecting the C-terminal zinc finger domain have a more severe clinical course with ectodermal dysplasia, whereas patients with mutations affecting the leucine zipper domain or the more N-terminal coiled-coil domains have a less severe clinical course and do not show features of ectodermal dysplasia, although isolated hypotonia and/or conical teeth may be present (Orange et al., 2004, Heller et al., 2020). </p>
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<p>By studying responses to the TLR4 (603030) ligand LPS and to the bacterial chemoattractant fMLP in polymorphonuclear neutrophils (PMNs) from 1 patient with IRAK4 deficiency (607676) and 3 patients with NEMO deficiency causing immunodeficiency with ectodermal dysplasia, Singh et al. (2009) demonstrated reduced or absent superoxide production after impaired priming and activation of the oligomeric neutrophil NADPH oxidase (NOX; see 300481). The response was particularly weak or absent in IRAK4-deficient PMNs. NEMO-deficient PMNs had a phenotype intermediate between IRAK4-deficient PMNs and normal PMNs. Decreased LPS- and fMLP-induced phosphorylation of p38 (MAPK14; 600289) was observed in both deficiencies. Singh et al. (2009) proposed that decreased activation of NOX may contribute to increased risk of infection in patients with IRAK4 deficiency or NEMO deficiency. </p>
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<strong>REFERENCES</strong>
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Abbott, J. K., Quinones, R. R., de la Morena, M. T., Gelfand, E. W.
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<strong>Successful hematopoietic cell transplantation in patients with unique NF-kappa-B essential modulator (NEMO) mutations. (Letter)</strong>
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Bone Marrow Transplant. 49: 1446-1447, 2014.
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[PubMed: 25068423]
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[Full Text: https://doi.org/10.1038/bmt.2014.157]
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Doffinger, R., Smahi, A., Bessia, C., Geissmann, F., Feinberg, J., Durandy, A., Bodemer, C., Kenwrick, S., Dupuis-Girod, S., Blanche, S., Wood, P., Rabia, S. H., and 16 others.
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<strong>X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling.</strong>
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Nature Genet. 27: 277-285, 2001.
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[PubMed: 11242109]
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[Full Text: https://doi.org/10.1038/85837]
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Dupuis-Girod, S., Corradini, N., Hadj-Rabia, S., Fournet, J.-C., Faivre, L., Le Deist, F., Durand, P., Doffinger, R., Smahi, A., Israel, A., Courtois, G., Brousse, N., Blanche, S., Munnich, A., Fischer, A., Casanova, J.-L., Bodemer, C.
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<strong>Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother.</strong>
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Pediatrics 109: e97, 2002. Note: Electronic Article.
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[PubMed: 12042591]
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[Full Text: https://doi.org/10.1542/peds.109.6.e97]
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Heller, S., Kolsch, U., Magg, T., Kruger, R., Scheuern, A., Schneider, H., Eichinger, A., Wahn, V., Unterwalder, N., Lorenz, M., Schwarz, K., Meisel, C., Schulz, A., Hauck, F., von Bernuth, H.
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<strong>T cell impairment is predictive for a severe clinical course in NEMO deficiency.</strong>
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J. Clin. Immun. 40: 421-434, 2020.
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[PubMed: 31965418]
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[Full Text: https://doi.org/10.1007/s10875-019-00728-y]
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Jain, A., Ma, C. A., Liu, S., Brown, M., Cohen, J., Strober, W.
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<strong>Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohidrotic ectodermal dysplasia.</strong>
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Nature Immun. 2: 223-228, 2001.
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[PubMed: 11224521]
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[Full Text: https://doi.org/10.1038/85277]
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Johnston, A. M., Niemela, J., Rosenzweig, S. D., Fried, A. J., Delmonte, O. M., Fleisher, T. A., Kuehn, H.
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<strong>A novel mutation in IKBKG/NEMO leads to ectodermal dysplasia with severe immunodeficiency (EDA-ID). (Letter)</strong>
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J. Clin. Immun 36: 541-543, 2016.
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[PubMed: 27368913]
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[Full Text: https://doi.org/10.1007/s10875-016-0309-y]
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Lie, S. O., Froland, S., Brandtzaeg, P., Vandvik, B., Steen-Johnsen, J.
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<strong>Transient B cell immaturity with intractable diarrhoea: a possible new immunodeficiency syndrome.</strong>
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Zonana, J., Elder, M. E., Schneider, L. C., Orlow, S. J., Moss, C., Golabi, M., Shapira, S. K., Farndon, P. A., Wara, D. W., Emmal, S. A., Ferguson, B. M.
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