3396 lines
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Entry
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- #617294 - EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH OR WITHOUT CARDIOMYOPATHY; EBS6
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- OMIM
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<p>
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<span class="h4">#617294</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/617294"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
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<a href="/phenotypicSeries/PS131760"> <strong>Phenotypic Series</strong> </a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#clinicalFeatures">Clinical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#inheritance">Inheritance</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" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</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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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div><a href="https://clinicaltrials.gov/search?cond=EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH OR WITHOUT CARDIOMYOPATHY" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=26575&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1369/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=617294[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=508529" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<div>
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<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>ORPHA:</strong> 508529<br />
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">ICD+</a>
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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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617294
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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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EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH OR WITHOUT CARDIOMYOPATHY; EBS6
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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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EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING AND HAIR LOSS, WITH OR WITHOUT DILATED CARDIOMYOPATHY<br />
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EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED, WITH SCARRING AND HAIR LOSS; EBSSH
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="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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<tr class="active">
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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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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/3/900?start=-3&limit=10&highlight=900">
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3q27.1
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/617294"> 617294 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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KLHL24
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/611295"> 611295 </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 class="btn-group ">
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<a href="/clinicalSynopsis/617294" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS131760" 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')">
|
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/617294" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/617294" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<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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<p />
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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">
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<strong> INHERITANCE </strong>
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</span>
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</div>
|
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<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Mouth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Mild blistering of oral mucosa <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313170&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313170</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Heart </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Dilated left ventricle (in young adulthood) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5830146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5830146</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253541009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253541009</a>]</span><br /> -
|
|
Reduced left ventricular ejection fraction (in young adulthood) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5830147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5830147</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012664" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012664</a>]</span><br /> -
|
|
Tachycardia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86651002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86651002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/3424008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">3424008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R00.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R00.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/785.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">785.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3827868&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3827868</a>, <a href="https://bioportal.bioontology.org/search?q=C0039231&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0039231</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001649" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001649</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001649" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001649</a>]</span><br /> -
|
|
Extrasystoles <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/33413000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">33413000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/29717002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">29717002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I49.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I49.40</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I49.49" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I49.49</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/427.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427.6</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/427.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427.60</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0340464&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0340464</a>]</span><br /> -
|
|
Sudden cardiac death (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95281009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95281009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085298&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085298</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001645" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001645</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001645" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001645</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
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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">
|
|
|
|
- Areas of skin denudation at birth (limbs, abdomen) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313169&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313169</a>]</span><br /> -
|
|
Blistering at sites of mechanical stress during childhood <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313168</a>]</span><br /> -
|
|
Mild generalized itching <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313167&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313167</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/276444007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">276444007</a>]</span><br /> -
|
|
Skin defects heal with hypopigmentation and mild atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313166&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313166</a>]</span><br /> -
|
|
Hyperpigmented scarring (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4693888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4693888</a>]</span><br /> -
|
|
Whirled patterning of atrophic areas (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313164&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313164</a>]</span><br /> -
|
|
Diffuse palmoplantar keratoderma (in adulthood) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313163&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313163</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/400123002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">400123002</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007447" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007447</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin Histology </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Skin cleavage at basal keratinocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748755&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748755</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034193" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034193</a>]</span><br /> -
|
|
Decreased amounts of keratins in basal keratinocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313161&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313161</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Electron Microscopy </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Intraepidermal split above hemidesmosomes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313160&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313160</a>]</span><br /> -
|
|
Basal keratinocyte disruption and cytolysis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313159&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313159</a>]</span><br /> -
|
|
Disruption of intermediate filaments in basal keratinocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313158&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313158</a>]</span><br /> -
|
|
Reduced density of intermediate filaments in basal keratinocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313157&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313157</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Nails </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Fragile toenails <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313156&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313156</a>]</span><br /> -
|
|
Dystrophic toenails <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833225&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833225</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001810" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001810</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001810" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001810</a>]</span><br /> -
|
|
Toenails thicken with age <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313155&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313155</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Hair </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Progressive diffuse alopecia of scalp <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313154&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313154</a>]</span><br /> -
|
|
Sparse body hair (in adulthood) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313153&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313153</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002231" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002231</a>]</span><br /> -
|
|
Follicular atrophoderma (in adulthood) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313152&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313152</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/238842001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">238842001</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Elevated CK <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5830144&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5830144</a>]</span><br /> -
|
|
Elevated CKMB <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5830756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5830756</a>]</span><br /> -
|
|
Elevated pro-BNP <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5830145&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5830145</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Neonatal death can occur from extensive skin denudation and secondary infection<br /> -
|
|
Skin fragility improves with age<br /> -
|
|
Dilated cardiomyopathy may develop in young adulthood<br /> -
|
|
Sudden cardiac death may occur <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95281009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95281009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085298&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085298</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001645" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001645</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001645" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001645</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the KELCH-like-24 gene (KLHL24, <a href="/entry/611295#0001">611295.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Epidermolysis bullosa simplex
|
|
- <a href="/phenotypicSeries/PS131760">PS131760</a>
|
|
- 18 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/900?start=-3&limit=10&highlight=900"> 3q27.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617294"> Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617294"> 617294 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611295"> KLHL24 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611295"> 611295 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/6/611?start=-3&limit=10&highlight=611"> 6p12.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615425"> Epidermolysis bullosa simplex 3, localized or generalized intermediate, with bp230 deficiency </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615425"> 615425 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/113810"> DST </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/113810"> 113810 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/8/621?start=-3&limit=10&highlight=621"> 8q24.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/131950"> Epidermolysis bullosa simplex 5A, Ogna type </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/131950"> 131950 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601282"> PLEC1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601282"> 601282 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/8/621?start=-3&limit=10&highlight=621"> 8q24.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612138"> Epidermolysis bullosa simplex 5C, with pyloric atresia </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612138"> 612138 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601282"> PLEC1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601282"> 601282 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/8/621?start=-3&limit=10&highlight=621"> 8q24.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/226670"> Epidermolysis bullosa simplex 5B, with muscular dystrophy </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/226670"> 226670 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601282"> PLEC1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601282"> 601282 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/8/621?start=-3&limit=10&highlight=621"> 8q24.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616487"> ?Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616487"> 616487 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601282"> PLEC1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601282"> 601282 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/11/48?start=-3&limit=10&highlight=48"> 11p15.5 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609057"> Epidermolysis bullosa simplex 7, with nephropathy and deafness </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609057"> 609057 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/602243"> CD151 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/602243"> 602243 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/11/899?start=-3&limit=10&highlight=899"> 11q22.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615028"> Epidermolysis bullosa simplex 4, localized or generalized intermediate, autosomal recessive </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615028"> 615028 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612878"> EXPH5 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612878"> 612878 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/12/410?start=-3&limit=10&highlight=410"> 12q13.13 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619599"> Epidermolysis bullosa simplex 2D, generalized, intermediate or severe, autosomal recessive </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619599"> 619599 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/148040"> KRT5 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/148040"> 148040 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
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<a href="/geneMap/12/410?start=-3&limit=10&highlight=410"> 12q13.13 </a>
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<span class="mim-font">
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<a href="/entry/619594"> Epidermolysis bullosa simplex 2C, localized </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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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<a href="/entry/619594"> 619594 </a>
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<a href="/entry/148040"> KRT5 </a>
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<span class="mim-font">
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<a href="/entry/148040"> 148040 </a>
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<a href="/geneMap/12/410?start=-3&limit=10&highlight=410"> 12q13.13 </a>
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<span class="mim-font">
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<a href="/entry/609352"> Epidermolysis bullosa simplex 2E, with migratory circinate erythema </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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<span class="mim-font">
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<a href="/entry/609352"> 609352 </a>
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<span class="mim-font">
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<a href="/entry/148040"> KRT5 </a>
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<span class="mim-font">
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<a href="/entry/148040"> 148040 </a>
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<a href="/geneMap/12/410?start=-3&limit=10&highlight=410"> 12q13.13 </a>
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<span class="mim-font">
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<a href="/entry/619588"> Epidermolysis bullosa simplex 2B, generalized intermediate </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/619588"> 619588 </a>
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<span class="mim-font">
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<a href="/entry/148040"> KRT5 </a>
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<span class="mim-font">
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<a href="/entry/148040"> 148040 </a>
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<a href="/geneMap/12/410?start=-3&limit=10&highlight=410"> 12q13.13 </a>
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<span class="mim-font">
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<a href="/entry/131960"> Epidermolysis bullosa simplex 2F, with mottled pigmentation </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span 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 class="mim-font">
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<a href="/entry/131960"> 131960 </a>
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<span class="mim-font">
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<a href="/entry/148040"> KRT5 </a>
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<span class="mim-font">
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<a href="/entry/148040"> 148040 </a>
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<a href="/geneMap/12/410?start=-3&limit=10&highlight=410"> 12q13.13 </a>
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<span class="mim-font">
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<a href="/entry/619555"> Epidermolysis bullosa simplex 2A, generalized severe </a>
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<span class="mim-font">
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<a href="/entry/148040"> KRT5 </a>
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<a href="/entry/148040"> 148040 </a>
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<a href="/geneMap/17/549?start=-3&limit=10&highlight=549"> 17q21.2 </a>
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<span class="mim-font">
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<a href="/entry/601001"> Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<a href="/entry/601001"> 601001 </a>
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<span class="mim-font">
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<a href="/entry/148066"> KRT14 </a>
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<span class="mim-font">
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<a href="/entry/148066"> 148066 </a>
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<a href="/geneMap/17/549?start=-3&limit=10&highlight=549"> 17q21.2 </a>
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<span class="mim-font">
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<a href="/entry/131900"> Epidermolysis bullosa simplex 1B, generalized intermediate </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span 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 class="mim-font">
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<a href="/entry/131900"> 131900 </a>
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<span class="mim-font">
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<a href="/entry/148066"> KRT14 </a>
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<span class="mim-font">
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<a href="/entry/148066"> 148066 </a>
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<a href="/geneMap/17/549?start=-3&limit=10&highlight=549"> 17q21.2 </a>
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<span class="mim-font">
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<a href="/entry/131800"> Epidermolysis bullosa simplex 1C, localized </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/131800"> 131800 </a>
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<span class="mim-font">
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<a href="/entry/148066"> KRT14 </a>
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<span class="mim-font">
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<a href="/entry/148066"> 148066 </a>
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<a href="/geneMap/17/549?start=-3&limit=10&highlight=549"> 17q21.2 </a>
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<span class="mim-font">
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<a href="/entry/131760"> Epidermolysis bullosa simplex 1A, generalized severe </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/131760"> 131760 </a>
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<a href="/entry/148066"> KRT14 </a>
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<a href="/entry/148066"> 148066 </a>
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<div class="text-right small">
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that generalized intermediate epidermolysis bullosa simplex-6 with or without cardiomyopathy (EBS6) is caused by heterozygous mutation in the KLHL24 gene (<a href="/entry/611295">611295</a>) on chromosome 3q27.</p>
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<strong>Description</strong>
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<p>Generalized epidermolysis bullosa simplex-6 with scarring and hair loss, with or without dilated cardiomyopathy (EBS6) is characterized by extensive skin erosions present at birth that heal with pigmentation defects and atrophy. Skin fragility improves with age, with progressive alopecia developing by adulthood (<a href="#5" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al., 2016</a>, <a href="#4" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al., 2016</a>). In addition, patients are at risk for the development of severe dilated cardiomyopathy in young adulthood, with some requiring cardiac transplantation (<a href="#6" class="mim-tip-reference" title="Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others. <strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong> J. Invest. Derm. 139: 244-249, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30120936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30120936</a>] [<a href="https://doi.org/10.1016/j.jid.2018.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30120936">Schwieger-Briel et al., 2019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27798626+27889062+30120936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (<a href="/entry/131760">131760</a>).</p>
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<strong>Clinical Features</strong>
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<p><a href="#5" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> reported 3 unrelated patients of Han Chinese ancestry with epidermolysis bullosa simplex and mutation in the KLHL24 gene. At birth, all probands showed large areas of skin denudation on the abdomen and limbs that reepithelialized with mild atrophy. Mechanically induced blisters and erosions appeared repeatedly, most of which healed spontaneously with hypo- or hyperpigmentation and no milia. All 3 patients had mild itch, oral mucosa was mildly affected, and toenails were dystrophic. Scalp hair loss was noted in the 1 adult patient, and skin fragility improved with age: the 25-year-old woman had no spontaneous blisters, and the 2 boys, aged 6 and 7 years, were in good general health and only occasionally developed blisters at sites of mechanical stress. The woman had an affected daughter who died soon after birth due to large areas of skin denudation and secondary infection. Immunofluorescent staining for collagen XVII (COL17A1; <a href="/entry/113811">113811</a>) and desmoplakin (DSP; <a href="/entry/125647">125647</a>) in a patient skin sample revealed that the intraepidermal split was above the hemidesmosome. Transmission electron microscopy showed basal keratinocyte disruption and cytolysis, with lesions extending through the subnuclear region of the cytoplasm. Intermediate filaments in basal keratinocytes were disrupted and markedly reduced in density compared to a control sample. Immunofluorescent staining with a pan-keratin antibody showed decreased amounts of keratins in basal keratinocytes in patient skin, whereas the abundance of keratins in the suprabasal layers as well as skin differentiation markers remained unchanged. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" 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="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a> studied 14 patients from 10 unrelated families, originating from Germany (families A, C, D, G, and H), Switzerland (family B), Finland (family F), Italy (family J), and Qatar (family I), who exhibited a distinct form of EBS and had mutation in the KLHL24 gene. The clinical features changed with age, but all affected individuals had similar clinical manifestations. At birth, there were extensive skin defects (aplasia cutis congenita) present on the extremities, which healed with hypopigmentation and atrophy with a whirled pattern. Generalized blistering persisted during childhood and healed with cutaneous and follicular atrophy, linear and stellate scars, and hypopigmentation. Toenails were fragile, and became progressively thicker. Cutaneous fragility decreased in adulthood; adults exhibited dyspigmentation and atrophy of the skin, scars, follicular atrophoderma, sparse body hair, progressive diffuse alopecia of the scalp, diffuse palmoplantar keratoderma, and nail changes. The cutaneous disorder was classified as EBS based on the location of skin cleavage, which was at the level of basal keratinocytes in skin samples from all probands. The ultrastructural level of cleavage was located above the hemidesmosomes, close to the basement membrane. An 43-year-old male from the Italian family, JII.2, was reported to have dilated cardiomyopathy. <a href="#4" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a> noted that hair loss and follicular and cutaneous atrophy and scarring are not observed in classic forms of EBS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C. <strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong> Brit. J. Derm. 179: 1181-1183, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29779254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29779254</a>] [<a href="https://doi.org/10.1111/bjd.16797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29779254">Yenamandra et al. (2018)</a> reported a Dutch father and son with epidermolysis bullosa and mutation in the KLHL24 gene. Cutaneous findings were consistent with previous reports, but also included loss of dermatoglyphs, hypohidrosis, and congenital malrotation of the great toenails. The affected father also had developed rapidly progressive dilated cardiomyopathy (CMD) at age 18 years, which required cardiac transplantation within a year. Histology of explanted heart tissue showed diffuse myocyte hypertrophy and moderate to severe interstitial fibrosis, without cardiomyocyte disarray. Molecular analysis of genes associated with cardiocutaneous syndromes, hereditary cardiomyopathies, and related disorders was negative. The proband's affected 14-year-old son had a borderline enlarged left ventricle (95th centile) on 2D echocardiography. <a href="#8" class="mim-tip-reference" title="Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C. <strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong> Brit. J. Derm. 179: 1181-1183, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29779254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29779254</a>] [<a href="https://doi.org/10.1111/bjd.16797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29779254">Yenamandra et al. (2018)</a> noted that <a href="#4" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a> had reported a 43-year-old man with EBS and CMD, and suggested that the young age of most of the previously studied patients might have precluded the observation of cardiomyopathy. <a href="#7" class="mim-tip-reference" title="Vermeer, M. C. S. C., Bolling, M. C., Bliley, J. M., Arevalo Gomez, K. F., Pavez-Giani, M. G., Kramer, D., Romero-Herrera, P. H., Westenbrink, B. D., Diercks, G. F. H., van den Berg, M. P., Feinberg, A. W., Sillje, H. H. W., van der Meer, P. <strong>Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.</strong> J. Clin. Invest. 131: e140615, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34292882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34292882</a>] [<a href="https://doi.org/10.1172/JCI140615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34292882">Vermeer et al. (2021)</a> provided follow-up on the Dutch father and son originally described by <a href="#8" class="mim-tip-reference" title="Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C. <strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong> Brit. J. Derm. 179: 1181-1183, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29779254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29779254</a>] [<a href="https://doi.org/10.1111/bjd.16797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29779254">Yenamandra et al. (2018)</a>. At age 18 years the son was still asymptomatic, but his echocardiogram showed definite signs of CMD, with left ventricular (LV) dilation, reduced LV ejection fraction (LVEF), and impaired global longitudinal systolic strain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27889062+29779254+34292882" 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="Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others. <strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong> J. Invest. Derm. 139: 244-249, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30120936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30120936</a>] [<a href="https://doi.org/10.1016/j.jid.2018.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30120936">Schwieger-Briel et al. (2019)</a> investigated extracutaneous features in a cohort of 18 patients from 9 families with KLHL24-associated EBS, including 10 previously described patients (<a href="#4" class="mim-tip-reference" title="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al., 2016</a>; families A, B, C, E, G, and J) as well as 8 new patients from 3 families. Mean patient age was 21.7 years, including 9 children ranging from 2 to 13 years old, and 9 adults who were 24 to 46 years old; in addition, there were 2 family members from a Chilean family (family 9) who had died of CMD at ages 39 and 54 years. Overall, 17 (85%) of the 20 patients showed evidence of cardiac involvement, with either elevated cardiac biomarkers or documented CMD. None of the patients showed a different cardiac phenotype, such as hypertrophic or restrictive cardiomyopathy or coronary artery disease. Analysis of whole-exome sequencing and multigene panel data from the cohort showed no pathogenic variants in known CMD-associated genes. The authors noted that because KLHL24-associated skin fragility and blistering improve with age, patients may not present for follow-up, and that because of reduced physical activity due to skin fragility, also may not experience early cardiac symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30120936+27889062" 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="#1" class="mim-tip-reference" title="Bolling, M. C., Jonkman, M. F. <strong>KLHL24: beyond skin fragility.</strong> J. Invest. Derm. 139: 22-24, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30579426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30579426</a>] [<a href="https://doi.org/10.1016/j.jid.2018.08.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30579426">Bolling and Jonkman (2019)</a> noted that some reports of patients with KLHL24-associated EBS included neurologic problems such as developmental delay, memory problems, learning difficulties, and seizures (<a href="#8" class="mim-tip-reference" title="Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C. <strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong> Brit. J. Derm. 179: 1181-1183, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29779254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29779254</a>] [<a href="https://doi.org/10.1111/bjd.16797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29779254">Yenamandra et al., 2018</a>; <a href="#6" class="mim-tip-reference" title="Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others. <strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong> J. Invest. Derm. 139: 244-249, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30120936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30120936</a>] [<a href="https://doi.org/10.1016/j.jid.2018.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30120936">Schwieger-Briel et al., 2019</a>). Given the high levels of expression of KLHL24 in neuronal tissue, <a href="#1" class="mim-tip-reference" title="Bolling, M. C., Jonkman, M. F. <strong>KLHL24: beyond skin fragility.</strong> J. Invest. Derm. 139: 22-24, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30579426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30579426</a>] [<a href="https://doi.org/10.1016/j.jid.2018.08.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30579426">Bolling and Jonkman (2019)</a> suggested that neurologic problems should be among the extracutaneous features sought in patients with mutations in the KLHL24 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30579426+30120936+29779254" 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="El Hachem, M., Barresi, S., Diociaiuti, A., Boldrini, R., Condorelli, A. G., Capoluongo, E., Proto, V., Scuvera, G., Has, C., Tartaglia, M., Castiglia, D. <strong>Phenotypic features of epidermolysis bullosa simplex due to KLHL24 mutations in 3 Italian cases.</strong> Acta Derm. Venereol. 99: 238-239, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30226531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30226531</a>] [<a href="https://doi.org/10.2340/00015555-3046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30226531">El Hachem et al. (2019)</a> reported 3 unrelated children with EBS and mutation in the KLHL24 gene. All 3 exhibited the typical congenital skin defects of the lower limbs, which healed rapidly but left hypopigmented atrophic patches and stellate and linear raised scars. Nail dystrophy was also present. Cardiac evaluation, including screening for cardiomyopathy markers, was normal, although the authors noted that the young ages of the patients (7 years, 5 years, and infancy) meant that possible future cardiac complications could not be excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30226531" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Grilletta, E. A. <strong>Cardiac transplant for epidermolysis bullosa simplex with KLHL24 mutation-associated cardiomyopathy.</strong> JAAD Case Rep. 5: 912-914, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31649980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31649980</a>] [<a href="https://doi.org/10.1016/j.jdcr.2019.08.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31649980">Grilletta (2019)</a> reported a 14-year-old girl with EBS and CMD and mutation in the KLHL24 gene. The proband, who was adopted, had blistering since birth with hypopigmented macular scars; symptoms were mild and the development of new blisters lessened after age 4 years. At age 14, she presented with progressive lower extremity edema, ascites, and elevated BNP (NPPB; <a href="/entry/600295">600295</a>) and cardiac troponin (see TNNI3, <a href="/entry/191044">191044</a>). Echocardiogram showed moderate dilation of all 4 chambers and a reduced LVEF of 19%, and she was diagnosed with acute congestive failure due to CMD. Within 1 month of presentation, she required implantation of a left ventricular assist device, and ultimately underwent heart transplantation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31649980" 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 EBS6 in family 1 reported by <a href="#5" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> was consistent with autosomal dominant inheritance. The heterozygous mutations in the KLHL24 gene that were identified in patients 3, 4, and 5 with EBS6 by <a href="#5" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> noted that although KLHL24 mRNA levels in EBS6 patients were comparable to controls, transfection studies in HaCaT cells showed markedly higher protein levels for mutant KLHL24 compared to wildtype. Further experiments indicated that autoubiquitination is abolished with the KLHL24 mutant, resulting in enhanced protein stability and higher abundance. After identifying KRT14 (<a href="/entry/148066">148066</a>) as a candidate ubiquitination substrate of KLHL24, the authors demonstrated dramatically lower KRT14 levels in patient skin samples compared to controls. <a href="#5" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> concluded that KLHL24 is an E3 ligase for KRT14 and that the start codon variants observed in EBS6 patients result in gain of function, inducing excessive ubiquitination and degradation of KRT14, resulting in KRT14 loss and skin fragility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" 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>Noting that desmin (DES; <a href="/entry/125660">125660</a>) belongs to the same highly conserved family of intermediate filament proteins as keratins, <a href="#7" class="mim-tip-reference" title="Vermeer, M. C. S. C., Bolling, M. C., Bliley, J. M., Arevalo Gomez, K. F., Pavez-Giani, M. G., Kramer, D., Romero-Herrera, P. H., Westenbrink, B. D., Diercks, G. F. H., van den Berg, M. P., Feinberg, A. W., Sillje, H. H. W., van der Meer, P. <strong>Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.</strong> J. Clin. Invest. 131: e140615, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34292882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34292882</a>] [<a href="https://doi.org/10.1172/JCI140615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34292882">Vermeer et al. (2021)</a> performed immunofluorescence analysis of explanted heart tissue from the Dutch father with EBS and CMD who was originally described by <a href="#8" class="mim-tip-reference" title="Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C. <strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong> Brit. J. Derm. 179: 1181-1183, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29779254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29779254</a>] [<a href="https://doi.org/10.1111/bjd.16797" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29779254">Yenamandra et al. (2018)</a>, and observed lower desmin intensity than that of other diseased heart explants. <a href="#7" class="mim-tip-reference" title="Vermeer, M. C. S. C., Bolling, M. C., Bliley, J. M., Arevalo Gomez, K. F., Pavez-Giani, M. G., Kramer, D., Romero-Herrera, P. H., Westenbrink, B. D., Diercks, G. F. H., van den Berg, M. P., Feinberg, A. W., Sillje, H. H. W., van der Meer, P. <strong>Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.</strong> J. Clin. Invest. 131: e140615, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34292882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34292882</a>] [<a href="https://doi.org/10.1172/JCI140615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34292882">Vermeer et al. (2021)</a> generated 3D dynamically loaded engineered heart tissues (dyn-EHTs) from human-induced pluripotent stem cell-derived cardiomyocytes from the Dutch father and his affected son, and confirmed 10-fold lower desmin levels in patient dyn-EHTs than in controls. In addition, the patient dyn-EHTs exhibited tissue dilatation, impaired mitochondrial function, decreased force values, and increased cardiomyocyte stress. HEK293 transfection studies confirmed KLHL24-mediated desmin degradation, and KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs. The authors concluded that the presence of the gain-of-function KLHL24 mutation in cardiomyocytes results in excessive degradation of desmin, affecting tissue morphology and function, which could be prevented by restoring desmin protein levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29779254+34292882" 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 3 unrelated Han Chinese patients with EBS who were negative for mutation in 18 known EB-associated genes, <a href="#5" class="mim-tip-reference" title="Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others. <strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong> Nature Genet. 48: 1508-1516, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>] [<a href="https://doi.org/10.1038/ng.3701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27798626">Lin et al. (2016)</a> performed whole-exome sequencing and identified heterozygosity for mutations in the KLHL24 gene: 2 patients had a c.1A-G transition (<a href="/entry/611295#0001">611295.0001</a>), and the remaining patient had a c.3G-T transversion (<a href="/entry/611295#0002">611295.0002</a>). Direct sequencing of KLHL24 in similarly affected EBS patients revealed 2 more individuals with heterozygous mutations: a Han Chinese boy with the c.1A-G mutation, and an Israeli Jewish boy with a c.3G-A transition (<a href="/entry/611295#0003">611295.0003</a>). The mutations were not found in the unaffected parents of the probands, in in-house databases, or in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" 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="He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C. <strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong> Am. J. Hum. Genet. 99: 1395-1404, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27889062">He et al. (2016)</a> analyzed EB-associated genes in the probands from 10 unrelated families with EBS, but found no pathogenic changes. Whole-exome sequencing in 3 families also excluded mutation in any known EB-associated genes and revealed 2 heterozygous mutations in the start codon of the KLHL24 gene: c.1A-G (<a href="/entry/611295#0001">611295.0001</a>) in a German and a Swiss family, and c.2T-C (<a href="/entry/611295#0004">611295.0004</a>) in another Swiss family. The recurrent c.1A-G mutation was subsequently identified in all affected members of the remaining 7 EBS families, including 4 from Germany, 1 from Finland, 1 from Italy, and 1 from Qatar. The mutations were not present in any of the 39 unaffected relatives who were tested, or in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889062" 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="Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others. <strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong> J. Invest. Derm. 139: 244-249, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30120936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30120936</a>] [<a href="https://doi.org/10.1016/j.jid.2018.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30120936">Schwieger-Briel et al. (2019)</a> identified 2 more EBS probands with the KLHL24 c.1A-G mutation, a 35-year-old woman from the United States (family 7) and a 28-year-old Chilean woman (family 8). Both women had normal electro- and echocardiograms; the proband from family 7 reported a syncopal episode but also had a seizure disorder of unknown origin. In addition, the authors studied a Chilean family (family 9) in which 8 members had EBS and were heterozygous for a different mutation in the translation initiation codon of KLHL24 (c.2T-G; <a href="/entry/611295#0007">611295.0007</a>); all 6 living members had elevated cardiac biomarkers, including 3 with documented CMD, and 2 family members had died a 'cardiac death' with CMD by history. Whole-exome sequencing and multigene panel data showed no pathogenic variants in known CMD-associated genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30120936" 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="El Hachem, M., Barresi, S., Diociaiuti, A., Boldrini, R., Condorelli, A. G., Capoluongo, E., Proto, V., Scuvera, G., Has, C., Tartaglia, M., Castiglia, D. <strong>Phenotypic features of epidermolysis bullosa simplex due to KLHL24 mutations in 3 Italian cases.</strong> Acta Derm. Venereol. 99: 238-239, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30226531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30226531</a>] [<a href="https://doi.org/10.2340/00015555-3046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30226531">El Hachem et al. (2019)</a> reported 3 children with EBS and heterozygosity for de novo mutations in the start codon of the KLHL24 gene: 2 boys, a 7-year-old (case 1) and an infant (case 3), were heterozygous for the previously reported c.2T-C variant (<a href="/entry/611295#0004">611295.0004</a>), and a 5-year-old girl (case 2) was heterozygous for the previously reported c.3G-A variant (<a href="/entry/611295#0003">611295.0003</a>). Cardiac evaluation, including screening for cardiomyopathy markers, was normal in all 3 of the children; however, the authors noted that due to the young ages of the patients, possible future cardiac complications could not be excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30226531" 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 14-year-old girl with EBS and severe CMD requiring heart transplantation, <a href="#3" class="mim-tip-reference" title="Grilletta, E. A. <strong>Cardiac transplant for epidermolysis bullosa simplex with KLHL24 mutation-associated cardiomyopathy.</strong> JAAD Case Rep. 5: 912-914, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31649980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31649980</a>] [<a href="https://doi.org/10.1016/j.jdcr.2019.08.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31649980">Grilletta (2019)</a> analyzed a panel of EB-associated genes and identified heterozygosity for a mutation in the initiation codon of KLHL24 (c.1A-T; <a href="/entry/611295#0008">611295.0008</a>). Because she was adopted, familial segregation could not be ascertained. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31649980" 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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Bolling, M. C., Jonkman, M. F.
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<strong>KLHL24: beyond skin fragility.</strong>
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J. Invest. Derm. 139: 22-24, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30579426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30579426</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30579426" 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.jid.2018.08.010" target="_blank">Full Text</a>]
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El Hachem, M., Barresi, S., Diociaiuti, A., Boldrini, R., Condorelli, A. G., Capoluongo, E., Proto, V., Scuvera, G., Has, C., Tartaglia, M., Castiglia, D.
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<strong>Phenotypic features of epidermolysis bullosa simplex due to KLHL24 mutations in 3 Italian cases.</strong>
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Acta Derm. Venereol. 99: 238-239, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30226531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30226531</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30226531" 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/10.2340/00015555-3046" target="_blank">Full Text</a>]
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Grilletta, E. A.
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<strong>Cardiac transplant for epidermolysis bullosa simplex with KLHL24 mutation-associated cardiomyopathy.</strong>
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JAAD Case Rep. 5: 912-914, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31649980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31649980</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31649980" 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.jdcr.2019.08.009" target="_blank">Full Text</a>]
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He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C.
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<strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong>
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Am. J. Hum. Genet. 99: 1395-1404, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27889062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27889062</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27889062" 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.ajhg.2016.11.005" target="_blank">Full Text</a>]
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Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others.
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<strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong>
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Nature Genet. 48: 1508-1516, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27798626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27798626</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27798626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.3701" target="_blank">Full Text</a>]
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Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others.
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<strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong>
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J. Invest. Derm. 139: 244-249, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30120936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30120936</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30120936" 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.jid.2018.07.022" target="_blank">Full Text</a>]
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Vermeer, M. C. S. C., Bolling, M. C., Bliley, J. M., Arevalo Gomez, K. F., Pavez-Giani, M. G., Kramer, D., Romero-Herrera, P. H., Westenbrink, B. D., Diercks, G. F. H., van den Berg, M. P., Feinberg, A. W., Sillje, H. H. W., van der Meer, P.
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<strong>Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.</strong>
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J. Clin. Invest. 131: e140615, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34292882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34292882</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34292882" 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/JCI140615" target="_blank">Full Text</a>]
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<a id="Yenamandra2018" class="mim-anchor"></a>
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Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C.
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<strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong>
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Brit. J. Derm. 179: 1181-1183, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29779254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29779254</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29779254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/bjd.16797" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 02/08/2023
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Marla J. F. O'Neill : 01/06/2017
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alopez : 02/08/2023
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alopez : 11/01/2021<br>alopez : 10/29/2021<br>alopez : 10/29/2021<br>carol : 01/14/2017<br>alopez : 01/11/2017
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EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH OR WITHOUT CARDIOMYOPATHY; EBS6
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EPIDERMOLYSIS BULLOSA SIMPLEX 6, GENERALIZED INTERMEDIATE, WITH SCARRING AND HAIR LOSS, WITH OR WITHOUT DILATED CARDIOMYOPATHY<br />
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EPIDERMOLYSIS BULLOSA SIMPLEX, GENERALIZED, WITH SCARRING AND HAIR LOSS; EBSSH
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<strong>ORPHA:</strong> 508529;
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3q27.1
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Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy
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617294
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Autosomal dominant
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3
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KLHL24
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611295
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<p>A number sign (#) is used with this entry because of evidence that generalized intermediate epidermolysis bullosa simplex-6 with or without cardiomyopathy (EBS6) is caused by heterozygous mutation in the KLHL24 gene (611295) on chromosome 3q27.</p>
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<p>Generalized epidermolysis bullosa simplex-6 with scarring and hair loss, with or without dilated cardiomyopathy (EBS6) is characterized by extensive skin erosions present at birth that heal with pigmentation defects and atrophy. Skin fragility improves with age, with progressive alopecia developing by adulthood (Lin et al., 2016, He et al., 2016). In addition, patients are at risk for the development of severe dilated cardiomyopathy in young adulthood, with some requiring cardiac transplantation (Schwieger-Briel et al., 2019). </p><p>For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (131760).</p>
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<p>Lin et al. (2016) reported 3 unrelated patients of Han Chinese ancestry with epidermolysis bullosa simplex and mutation in the KLHL24 gene. At birth, all probands showed large areas of skin denudation on the abdomen and limbs that reepithelialized with mild atrophy. Mechanically induced blisters and erosions appeared repeatedly, most of which healed spontaneously with hypo- or hyperpigmentation and no milia. All 3 patients had mild itch, oral mucosa was mildly affected, and toenails were dystrophic. Scalp hair loss was noted in the 1 adult patient, and skin fragility improved with age: the 25-year-old woman had no spontaneous blisters, and the 2 boys, aged 6 and 7 years, were in good general health and only occasionally developed blisters at sites of mechanical stress. The woman had an affected daughter who died soon after birth due to large areas of skin denudation and secondary infection. Immunofluorescent staining for collagen XVII (COL17A1; 113811) and desmoplakin (DSP; 125647) in a patient skin sample revealed that the intraepidermal split was above the hemidesmosome. Transmission electron microscopy showed basal keratinocyte disruption and cytolysis, with lesions extending through the subnuclear region of the cytoplasm. Intermediate filaments in basal keratinocytes were disrupted and markedly reduced in density compared to a control sample. Immunofluorescent staining with a pan-keratin antibody showed decreased amounts of keratins in basal keratinocytes in patient skin, whereas the abundance of keratins in the suprabasal layers as well as skin differentiation markers remained unchanged. </p><p>He et al. (2016) studied 14 patients from 10 unrelated families, originating from Germany (families A, C, D, G, and H), Switzerland (family B), Finland (family F), Italy (family J), and Qatar (family I), who exhibited a distinct form of EBS and had mutation in the KLHL24 gene. The clinical features changed with age, but all affected individuals had similar clinical manifestations. At birth, there were extensive skin defects (aplasia cutis congenita) present on the extremities, which healed with hypopigmentation and atrophy with a whirled pattern. Generalized blistering persisted during childhood and healed with cutaneous and follicular atrophy, linear and stellate scars, and hypopigmentation. Toenails were fragile, and became progressively thicker. Cutaneous fragility decreased in adulthood; adults exhibited dyspigmentation and atrophy of the skin, scars, follicular atrophoderma, sparse body hair, progressive diffuse alopecia of the scalp, diffuse palmoplantar keratoderma, and nail changes. The cutaneous disorder was classified as EBS based on the location of skin cleavage, which was at the level of basal keratinocytes in skin samples from all probands. The ultrastructural level of cleavage was located above the hemidesmosomes, close to the basement membrane. An 43-year-old male from the Italian family, JII.2, was reported to have dilated cardiomyopathy. He et al. (2016) noted that hair loss and follicular and cutaneous atrophy and scarring are not observed in classic forms of EBS. </p><p>Yenamandra et al. (2018) reported a Dutch father and son with epidermolysis bullosa and mutation in the KLHL24 gene. Cutaneous findings were consistent with previous reports, but also included loss of dermatoglyphs, hypohidrosis, and congenital malrotation of the great toenails. The affected father also had developed rapidly progressive dilated cardiomyopathy (CMD) at age 18 years, which required cardiac transplantation within a year. Histology of explanted heart tissue showed diffuse myocyte hypertrophy and moderate to severe interstitial fibrosis, without cardiomyocyte disarray. Molecular analysis of genes associated with cardiocutaneous syndromes, hereditary cardiomyopathies, and related disorders was negative. The proband's affected 14-year-old son had a borderline enlarged left ventricle (95th centile) on 2D echocardiography. Yenamandra et al. (2018) noted that He et al. (2016) had reported a 43-year-old man with EBS and CMD, and suggested that the young age of most of the previously studied patients might have precluded the observation of cardiomyopathy. Vermeer et al. (2021) provided follow-up on the Dutch father and son originally described by Yenamandra et al. (2018). At age 18 years the son was still asymptomatic, but his echocardiogram showed definite signs of CMD, with left ventricular (LV) dilation, reduced LV ejection fraction (LVEF), and impaired global longitudinal systolic strain. </p><p>Schwieger-Briel et al. (2019) investigated extracutaneous features in a cohort of 18 patients from 9 families with KLHL24-associated EBS, including 10 previously described patients (He et al., 2016; families A, B, C, E, G, and J) as well as 8 new patients from 3 families. Mean patient age was 21.7 years, including 9 children ranging from 2 to 13 years old, and 9 adults who were 24 to 46 years old; in addition, there were 2 family members from a Chilean family (family 9) who had died of CMD at ages 39 and 54 years. Overall, 17 (85%) of the 20 patients showed evidence of cardiac involvement, with either elevated cardiac biomarkers or documented CMD. None of the patients showed a different cardiac phenotype, such as hypertrophic or restrictive cardiomyopathy or coronary artery disease. Analysis of whole-exome sequencing and multigene panel data from the cohort showed no pathogenic variants in known CMD-associated genes. The authors noted that because KLHL24-associated skin fragility and blistering improve with age, patients may not present for follow-up, and that because of reduced physical activity due to skin fragility, also may not experience early cardiac symptoms. </p><p>Bolling and Jonkman (2019) noted that some reports of patients with KLHL24-associated EBS included neurologic problems such as developmental delay, memory problems, learning difficulties, and seizures (Yenamandra et al., 2018; Schwieger-Briel et al., 2019). Given the high levels of expression of KLHL24 in neuronal tissue, Bolling and Jonkman (2019) suggested that neurologic problems should be among the extracutaneous features sought in patients with mutations in the KLHL24 gene. </p><p>El Hachem et al. (2019) reported 3 unrelated children with EBS and mutation in the KLHL24 gene. All 3 exhibited the typical congenital skin defects of the lower limbs, which healed rapidly but left hypopigmented atrophic patches and stellate and linear raised scars. Nail dystrophy was also present. Cardiac evaluation, including screening for cardiomyopathy markers, was normal, although the authors noted that the young ages of the patients (7 years, 5 years, and infancy) meant that possible future cardiac complications could not be excluded. </p><p>Grilletta (2019) reported a 14-year-old girl with EBS and CMD and mutation in the KLHL24 gene. The proband, who was adopted, had blistering since birth with hypopigmented macular scars; symptoms were mild and the development of new blisters lessened after age 4 years. At age 14, she presented with progressive lower extremity edema, ascites, and elevated BNP (NPPB; 600295) and cardiac troponin (see TNNI3, 191044). Echocardiogram showed moderate dilation of all 4 chambers and a reduced LVEF of 19%, and she was diagnosed with acute congestive failure due to CMD. Within 1 month of presentation, she required implantation of a left ventricular assist device, and ultimately underwent heart transplantation. </p>
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<p>The transmission pattern of EBS6 in family 1 reported by Lin et al. (2016) was consistent with autosomal dominant inheritance. The heterozygous mutations in the KLHL24 gene that were identified in patients 3, 4, and 5 with EBS6 by Lin et al. (2016) occurred de novo. </p>
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<p>Lin et al. (2016) noted that although KLHL24 mRNA levels in EBS6 patients were comparable to controls, transfection studies in HaCaT cells showed markedly higher protein levels for mutant KLHL24 compared to wildtype. Further experiments indicated that autoubiquitination is abolished with the KLHL24 mutant, resulting in enhanced protein stability and higher abundance. After identifying KRT14 (148066) as a candidate ubiquitination substrate of KLHL24, the authors demonstrated dramatically lower KRT14 levels in patient skin samples compared to controls. Lin et al. (2016) concluded that KLHL24 is an E3 ligase for KRT14 and that the start codon variants observed in EBS6 patients result in gain of function, inducing excessive ubiquitination and degradation of KRT14, resulting in KRT14 loss and skin fragility. </p><p>Noting that desmin (DES; 125660) belongs to the same highly conserved family of intermediate filament proteins as keratins, Vermeer et al. (2021) performed immunofluorescence analysis of explanted heart tissue from the Dutch father with EBS and CMD who was originally described by Yenamandra et al. (2018), and observed lower desmin intensity than that of other diseased heart explants. Vermeer et al. (2021) generated 3D dynamically loaded engineered heart tissues (dyn-EHTs) from human-induced pluripotent stem cell-derived cardiomyocytes from the Dutch father and his affected son, and confirmed 10-fold lower desmin levels in patient dyn-EHTs than in controls. In addition, the patient dyn-EHTs exhibited tissue dilatation, impaired mitochondrial function, decreased force values, and increased cardiomyocyte stress. HEK293 transfection studies confirmed KLHL24-mediated desmin degradation, and KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs. The authors concluded that the presence of the gain-of-function KLHL24 mutation in cardiomyocytes results in excessive degradation of desmin, affecting tissue morphology and function, which could be prevented by restoring desmin protein levels. </p>
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<strong>Molecular Genetics</strong>
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<p>In 3 unrelated Han Chinese patients with EBS who were negative for mutation in 18 known EB-associated genes, Lin et al. (2016) performed whole-exome sequencing and identified heterozygosity for mutations in the KLHL24 gene: 2 patients had a c.1A-G transition (611295.0001), and the remaining patient had a c.3G-T transversion (611295.0002). Direct sequencing of KLHL24 in similarly affected EBS patients revealed 2 more individuals with heterozygous mutations: a Han Chinese boy with the c.1A-G mutation, and an Israeli Jewish boy with a c.3G-A transition (611295.0003). The mutations were not found in the unaffected parents of the probands, in in-house databases, or in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. </p><p>He et al. (2016) analyzed EB-associated genes in the probands from 10 unrelated families with EBS, but found no pathogenic changes. Whole-exome sequencing in 3 families also excluded mutation in any known EB-associated genes and revealed 2 heterozygous mutations in the start codon of the KLHL24 gene: c.1A-G (611295.0001) in a German and a Swiss family, and c.2T-C (611295.0004) in another Swiss family. The recurrent c.1A-G mutation was subsequently identified in all affected members of the remaining 7 EBS families, including 4 from Germany, 1 from Finland, 1 from Italy, and 1 from Qatar. The mutations were not present in any of the 39 unaffected relatives who were tested, or in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. </p><p>Schwieger-Briel et al. (2019) identified 2 more EBS probands with the KLHL24 c.1A-G mutation, a 35-year-old woman from the United States (family 7) and a 28-year-old Chilean woman (family 8). Both women had normal electro- and echocardiograms; the proband from family 7 reported a syncopal episode but also had a seizure disorder of unknown origin. In addition, the authors studied a Chilean family (family 9) in which 8 members had EBS and were heterozygous for a different mutation in the translation initiation codon of KLHL24 (c.2T-G; 611295.0007); all 6 living members had elevated cardiac biomarkers, including 3 with documented CMD, and 2 family members had died a 'cardiac death' with CMD by history. Whole-exome sequencing and multigene panel data showed no pathogenic variants in known CMD-associated genes. </p><p>El Hachem et al. (2019) reported 3 children with EBS and heterozygosity for de novo mutations in the start codon of the KLHL24 gene: 2 boys, a 7-year-old (case 1) and an infant (case 3), were heterozygous for the previously reported c.2T-C variant (611295.0004), and a 5-year-old girl (case 2) was heterozygous for the previously reported c.3G-A variant (611295.0003). Cardiac evaluation, including screening for cardiomyopathy markers, was normal in all 3 of the children; however, the authors noted that due to the young ages of the patients, possible future cardiac complications could not be excluded. </p><p>In a 14-year-old girl with EBS and severe CMD requiring heart transplantation, Grilletta (2019) analyzed a panel of EB-associated genes and identified heterozygosity for a mutation in the initiation codon of KLHL24 (c.1A-T; 611295.0008). Because she was adopted, familial segregation could not be ascertained. </p>
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<strong>REFERENCES</strong>
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Bolling, M. C., Jonkman, M. F.
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<strong>KLHL24: beyond skin fragility.</strong>
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J. Invest. Derm. 139: 22-24, 2019.
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[PubMed: 30579426]
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[Full Text: https://doi.org/10.1016/j.jid.2018.08.010]
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El Hachem, M., Barresi, S., Diociaiuti, A., Boldrini, R., Condorelli, A. G., Capoluongo, E., Proto, V., Scuvera, G., Has, C., Tartaglia, M., Castiglia, D.
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<strong>Phenotypic features of epidermolysis bullosa simplex due to KLHL24 mutations in 3 Italian cases.</strong>
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Acta Derm. Venereol. 99: 238-239, 2019.
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[PubMed: 30226531]
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[Full Text: https://doi.org/10.2340/00015555-3046]
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Grilletta, E. A.
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<strong>Cardiac transplant for epidermolysis bullosa simplex with KLHL24 mutation-associated cardiomyopathy.</strong>
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JAAD Case Rep. 5: 912-914, 2019.
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[PubMed: 31649980]
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[Full Text: https://doi.org/10.1016/j.jdcr.2019.08.009]
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He, Y., Maier, K., Leppert, J., Hausser, I., Schwieger-Briel, A., Weibel, L., Theiler, M., Kiritsi, D., Busch, H., Boerries, M., Hannula-Jouppi, K., Heikkila, H., Tasanen, K., Castiglia, D., Zambruno, G., Has, C.
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<strong>Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.</strong>
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Am. J. Hum. Genet. 99: 1395-1404, 2016.
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[PubMed: 27889062]
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[Full Text: https://doi.org/10.1016/j.ajhg.2016.11.005]
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Lin, Z., Li, S., Feng, C., Yang, S., Wang, H., Ma, D., Zhang, J., Gou, M., Bu, D., Zhang, T., Kong, X., Wang, X., and 15 others.
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<strong>Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.</strong>
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Nature Genet. 48: 1508-1516, 2016.
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[PubMed: 27798626]
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[Full Text: https://doi.org/10.1038/ng.3701]
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Schwieger-Briel, A., Fuentes, I., Castiglia, D., Barbato, A., Greutmann, M., Leppert, J., Duchatelet, S., Hovnanian, A., Burattini, S., Yubero, M. J., Ibanez-Arenas, R., Rebolledo-Jaramillo, B., and 9 others.
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<strong>Epidermolysis bullosa simplex with KLHL24 mutations is associated with dilated cardiomyopathy.</strong>
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J. Invest. Derm. 139: 244-249, 2019.
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[PubMed: 30120936]
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[Full Text: https://doi.org/10.1016/j.jid.2018.07.022]
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Vermeer, M. C. S. C., Bolling, M. C., Bliley, J. M., Arevalo Gomez, K. F., Pavez-Giani, M. G., Kramer, D., Romero-Herrera, P. H., Westenbrink, B. D., Diercks, G. F. H., van den Berg, M. P., Feinberg, A. W., Sillje, H. H. W., van der Meer, P.
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<strong>Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.</strong>
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J. Clin. Invest. 131: e140615, 2021.
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[PubMed: 34292882]
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[Full Text: https://doi.org/10.1172/JCI140615]
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Yenamandra, V. K., van den Akker, P. C., Lemmink, H. H., Jan, S. Z., Diercks, G. F. H., Vermeer, M., van den Berg, M. P., van der Meer, P., Pasmooij, A. M. G., Sinke, R. J., Jonkman, M. F., Bolling, M. C.
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<strong>Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.</strong>
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Brit. J. Derm. 179: 1181-1183, 2018.
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[PubMed: 29779254]
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[Full Text: https://doi.org/10.1111/bjd.16797]
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Marla J. F. O'Neill - updated : 02/08/2023
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