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Entry
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- #131760 - EPIDERMOLYSIS BULLOSA SIMPLEX 1A, GENERALIZED SEVERE; EBS1A
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- OMIM
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<p>
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<span class="h4">#131760</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/131760"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS131760"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#history">History</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<div 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><a href="https://clinicaltrials.gov/search?cond=EPIDERMOLYSIS BULLOSA SIMPLEX 1A, GENERALIZED SEVERE" 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=11422&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.diseaseinfosearch.org/x/2577" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=131760[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=79396" 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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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0060735" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/131760" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/results?search_type=advanced&omia_id=000340,002081,002082,002281" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 254179000<br />
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<strong>ORPHA:</strong> 79396<br />
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<strong>DO:</strong> 0060735<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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131760
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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 1A, GENERALIZED SEVERE; EBS1A
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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 1A, DOWLING-MEARA TYPE<br />
|
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EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE; EBSDM<br />
|
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EPIDERMOLYSIS BULLOSA HERPETIFORMIS, DOWLING-MEARA TYPE
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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">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
|
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
|
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</th>
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<th>
|
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/17/549?start=-3&limit=10&highlight=549">
|
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17q21.2
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Epidermolysis bullosa simplex 1A, generalized severe
|
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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/131760"> 131760 </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>
|
|
<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">
|
|
KRT14
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/148066"> 148066 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/131760" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS131760" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/131760" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/131760" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal 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> GROWTH </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Other </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Growth retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/59576002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">59576002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/444896005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">444896005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151686&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151686</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001510</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001510</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Mouth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Oral blistering (perioral and intraoral) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5562889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5562889</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0200097" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0200097</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Larynx </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Laryngeal thickening, irregular (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5562888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5562888</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Blistering, generalized, recurrent, severe (occurs after mild physical trauma) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2751145&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2751145</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008066" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008066</a>]</span><br /> -
|
|
Blistering occurs in clusters ('herpetiform', 'arcuate') <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2751146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2751146</a>]</span><br /> -
|
|
Blistering of hands, elbows, feet, knees <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2751147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2751147</a>]</span><br /> -
|
|
Hemorrhagic blisters <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2751148&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2751148</a>]</span><br /> -
|
|
Hyperkeratosis of the palms and soles <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L85.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L85.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0022596&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022596</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000972" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000972</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000972" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000972</a>]</span><br /> -
|
|
Postinflammatory pigmentation (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5562883&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5562883</a>]</span><br /> -
|
|
Cleavage through epidermal basal layer seen on light microscopy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5562884&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5562884</a>]</span><br /> -
|
|
Intracytoplasmic inclusions in basal and suprabasal cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5677889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5677889</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">
|
|
|
|
- Cleavage plane through subnuclear cytoplasm of basal keratinocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5677890&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5677890</a>]</span><br /> -
|
|
Clumping of keratin tonofilaments in basal epidermal cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5562886&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5562886</a>]</span><br /> -
|
|
Subnuclear vacuolization in basal keratinocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5677891&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5677891</a>]</span><br /> -
|
|
Cytolysis of basal keratinocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5563512&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5563512</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">
|
|
|
|
- Dystrophic nails <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/87065009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">87065009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L60.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L60.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221260</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008404" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008404</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008404" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008404</a>]</span><br /> -
|
|
Nail shedding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/738291005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">738291005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/247492006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">247492006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423812&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423812</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> VOICE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hoarse cry <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2678303&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2678303</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001615" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001615</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001615" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001615</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
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<div>
|
|
<span class="mim-font">
|
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|
|
- Onset at birth or in early infancy<br /> -
|
|
Infant death may occur secondary to sepsis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/240297000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">240297000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0549159&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0549159</a>, <a href="https://bioportal.bioontology.org/search?q=C0021278&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021278</a>]</span><br /> -
|
|
Disease exacerbation during summer due to heat<br /> -
|
|
Some patients show improvement during summer or with fever<br /> -
|
|
Improvement with age<br /> -
|
|
Intrafamilial variability<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
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|
|
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</div>
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<div>
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<div>
|
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<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 keratin 14 gene (KRT14, <a href="/entry/148066#0002">148066.0002</a>)<br />
|
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|
|
</span>
|
|
</div>
|
|
|
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</div>
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</div>
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|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
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|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small">
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|
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<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/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/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/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/619594"> Epidermolysis bullosa simplex 2C, localized </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/619594"> 619594 </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">
|
|
|
|
<a href="/geneMap/12/410?start=-3&limit=10&highlight=410"> 12q13.13 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/609352"> Epidermolysis bullosa simplex 2E, with migratory circinate erythema </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/609352"> 609352 </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">
|
|
|
|
<a href="/geneMap/12/410?start=-3&limit=10&highlight=410"> 12q13.13 </a>
|
|
|
|
</span>
|
|
</td>
|
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<td>
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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/131960"> Epidermolysis bullosa simplex 2F, with mottled pigmentation </a>
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<a href="/entry/148040"> KRT5 </a>
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<a href="/entry/619555"> Epidermolysis bullosa simplex 2A, generalized severe </a>
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<a href="/entry/148040"> KRT5 </a>
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<a href="/entry/619599"> Epidermolysis bullosa simplex 2D, generalized, intermediate or severe, autosomal recessive </a>
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<a href="/entry/148040"> 148040 </a>
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<a href="/entry/131800"> Epidermolysis bullosa simplex 1C, localized </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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<a href="/entry/131760"> Epidermolysis bullosa simplex 1A, generalized severe </a>
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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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<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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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/148066"> KRT14 </a>
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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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<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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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<a href="/entry/131900"> 131900 </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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<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 generalized severe epidermolysis bullosa simplex-1A (EBS1A) is caused by heterozygous mutation in the KRT14 gene (<a href="/entry/148066">148066</a>) on chromosome 17q21.</p><p>Another form of generalized severe EBS, EBS2A (<a href="/entry/619555">619555</a>), is caused by mutation in the KRT5 gene (<a href="/entry/148040">148040</a>).</p>
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<strong>Description</strong>
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<p>Generalized severe epidermolysis bullosa simplex-1A (EBS1A) is an autosomal dominant skin disorder characterized by generalized intraepidermal skin blistering from minimal mechanical trauma beginning at birth. A herpetiform (arcuate) pattern of blisters, a crusting-necrotic aspect of the lesions that is often associated with inflammatory plaques, and clumping of keratin intermediate filaments seen on electron microscopy define the severe subtype of EBS. Skin fragility is very prominent at birth, and large tense blisters can occur after minimal trauma or spontaneously; the disorder may be life-threatening in the first year of life. Congenital ulcerated areas on hands and feet as well as nail involvement are common. Blistering is exacerbated by heat, humidity, and sweating. Tendency to blistering diminishes in adolescence (summary by <a href="#8" class="mim-tip-reference" title="Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others. <strong>Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.</strong> Brit. J. Derm. 183: 614-627, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32017015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32017015</a>] [<a href="https://doi.org/10.1111/bjd.18921" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32017015">Has et al., 2020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32017015" 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>Epidermolysis bullosa simplex (EBS) comprises a group of clinically and genetically heterogeneous skin disorders characterized by recurrent blistering of the skin following minor physical trauma as a result of cytolysis within basal epidermal cells. Most forms show autosomal dominant inheritance. The severe subtype of EBS was previously known as the Dowling-Meara type. The other 2 main subtypes of EBS are the generalized intermediate, previously known as Koebner, type (see <a href="/entry/131900">131900</a>) and the localized, previously known as Weber-Cockayne, type (see <a href="/entry/131800">131800</a>) (<a href="#7" class="mim-tip-reference" title="Fine, J.-D., Eady, R. A. J., Bauer, E. A., Bauer, J. W., Bruckner-Tuderman, L., Heagerty, A., Hintner, H., Hovnanian, A., Jonkman, M. F., Leigh, I., McGrath, J. A., Mellerio, J. E., Murrell, D. F., Shimizu, H., Uitto, J., Vahlquist, A., Woodley, D., Zambruno, G. <strong>The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on diagnosis and classification of EB.</strong> J. Am. Acad. Derm. 58: 931-950, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18374450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18374450</a>] [<a href="https://doi.org/10.1016/j.jaad.2008.02.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18374450">Fine et al., 2008</a>). All 3 of these main subtypes can be caused by mutation in either the KRT5 or the KRT14 gene. Rare EBS subtypes are clinically and genetically heterogeneous and include several syndromic types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18374450" 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>Other types of epidermis bullosa (EB), classified by the level of skin cleavage and other ultrastructural laboratory findings in addition to clinical features, are junctional EB (JEB; see <a href="/entry/226700">226700</a>) and dystrophic EB (DEB; see <a href="/entry/131750">131750</a>).</p><p><strong><em>Genetic Heterogeneity of Epidermolysis Bullosa Simplex</em></strong></p><p>
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Other forms of EBS that are caused by mutation in the KRT14 gene are generalized intermediate EBS1B (<a href="/entry/131900">131900</a>), previously known as the Koebner type; localized EBS1C (<a href="/entry/131800">131800</a>), previously known as the Weber-Cockayne type; and autosomal recessive generalized EBS1D (<a href="/entry/601001">601001</a>).</p><p>Forms of EBS caused by mutation in the KRT5 gene are generalized severe EBS2A (<a href="/entry/619555">619555</a>); generalized intermediate EBS2B (<a href="/entry/619588">619588</a>); localized EBS2C (<a href="/entry/619594">619594</a>); generalized autosomal recessive EBS2D (<a href="/entry/619599">619599</a>); EBS2E (<a href="/entry/609352">609352</a>), with migratory circinate erythema; and EBS2F (<a href="/entry/131960">131960</a>), with mottled pigmentation.</p><p>EBS3 (<a href="/entry/615425">615425</a>) is caused by mutation in the DST gene (<a href="/entry/113810">113810</a>). EBS4 (<a href="/entry/615028">615028</a>) is caused by mutation in the EXPH5 gene (<a href="/entry/612878">612878</a>).</p><p>Forms of EBS caused by mutation in the PLEC gene (<a href="/entry/601282">601282</a>) are EBS5A (<a href="/entry/131950">131950</a>), Ogna type; EBS5B (<a href="/entry/226670">226670</a>), with muscular dystrophy; EBS5C (<a href="/entry/612138">612138</a>), with pyloric atresia; and EBS5D (<a href="/entry/616487">616487</a>), autosomal recessive generalized intermediate.</p><p>EBS6 (<a href="/entry/617294">617294</a>), with scarring and hair loss, is caused by mutation in the KLHL24 gene (<a href="/entry/611295">611295</a>).</p><p>EBS7 (<a href="/entry/609057">609057</a>), with nephropathy and deafness, is caused by mutation in the CD151 gene (<a href="/entry/602243">602243</a>).</p><p><strong><em>Reviews</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others. <strong>Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.</strong> Brit. J. Derm. 183: 614-627, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32017015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32017015</a>] [<a href="https://doi.org/10.1111/bjd.18921" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32017015">Has et al. (2020)</a> reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32017015" 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="#7" class="mim-tip-reference" title="Fine, J.-D., Eady, R. A. J., Bauer, E. A., Bauer, J. W., Bruckner-Tuderman, L., Heagerty, A., Hintner, H., Hovnanian, A., Jonkman, M. F., Leigh, I., McGrath, J. A., Mellerio, J. E., Murrell, D. F., Shimizu, H., Uitto, J., Vahlquist, A., Woodley, D., Zambruno, G. <strong>The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on diagnosis and classification of EB.</strong> J. Am. Acad. Derm. 58: 931-950, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18374450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18374450</a>] [<a href="https://doi.org/10.1016/j.jaad.2008.02.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18374450">Fine et al. (2008)</a> reviewed phenotypic features and molecular bases of all epidermolysis bullosa subtypes, and recommended revisions in the classification system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18374450" 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="Dowling, G. B., Meara, R. H. <strong>Epidermolysis bullosa dermatitis herpetiformis.</strong> Brit. J. Derm. 66: 139-143, 1954.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13149726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13149726</a>] [<a href="https://doi.org/10.1111/j.1365-2133.1954.tb12605.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13149726">Dowling and Meara (1954)</a> first described a form of epidermolysis bullosa simplex that resembled dermatitis herpetiformis (<a href="/entry/601230">601230</a>). Onset of generalized bullae in a herpetiform (arciform) arrangement occurred during the first 3 months of life. Serous and hemorrhagic blisters could occur on any part of the body, but most frequently on the palms and soles, around the mouth, and on the trunk and neck. In general, the lesions healed without scarring, but pronounced inflammatory reactions, especially seen in hemorrhagic blisters, was accompanied by milia and occasional scar formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13149726" 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="Anton-Lamprecht, I., Schnyder, U. W. <strong>Epidermolysis bullosa herpetiformis Dowling Meara: report of a case and pathomorphogenesis.</strong> Dermatologica 164: 221-235, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7084543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7084543</a>]" pmid="7084543">Anton-Lamprecht and Schnyder (1982)</a> reported a 2-year-old girl of Turkish origin with congenital generalized blister formation in a herpetiform arrangement. Direct immunofluorescence ruled out juvenile dermatitis herpetiformis. Ultrastructural investigation of a fresh blister and clinically intact preblistering skin revealed intraepidermal blister formation via cytolysis of basal cells, preceded by clumping of tonofilaments and partial attachment to the hemidesmosomes at the dermo-epidermal junction. This type of blister formation was significantly different from all other epidermolysis bullosa types and was a characteristic feature of the Dowling-Meara type of EBS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7084543" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="McGrath, J. A., Ishida-Yamamoto, A., Tidman, M. J., Heagerty, A. H. M., Schofield, O. M. V., Eady, R. A. J. <strong>Epidermolysis bullosa simplex (Dowling-Meara): a clinicopathological review.</strong> Brit. J. Derm. 126: 421-430, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1610681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1610681</a>] [<a href="https://doi.org/10.1111/j.1365-2133.1992.tb11813.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1610681">McGrath et al. (1992)</a> reviewed the clinicopathologic features of 22 cases varying in age from 5 days to 46 years. All cases presented clinically within the first 5 days of life. Early blisters were often large (up to 5 cm in diameter), and were mostly acral and particularly periungual. Some patients presented with more widespread erosive skin changes, and 2 neonates with extensive skin involvement died as a result of overwhelming sepsis. After the neonatal period, the pattern of blistering became more proximal, with hemorrhagic, herpetiform clusters of blisters. Central healing with recurrent blistering at the margins of these areas was frequent. Other physical signs included varying degrees of intraoral blistering, nail shedding, nail dystrophy, minor scarring, palmoplantar keratoderma, a lack of seasonal variation, and improvement during later childhood. Basal cell cytolysis in association with clumping of tonofilaments was the underlying pathologic mechanism. The clumping was found even in some nonlesional skin, suggesting that it is of primary pathogenetic significance. The disease was occasionally so severe, especially during the neonatal period, as to be confused with junctional (see, e.g., <a href="/entry/226700">226700</a>) or severe recessive dystrophic EB (see, e.g., <a href="/entry/226600">226600</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1610681" 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="#11" class="mim-tip-reference" title="Kitajima, Y., Jokura, Y., Yaoita, H. <strong>Epidermolysis bullosa simplex, Dowling-Meara type: a report of two cases with different types of tonofilament clumping.</strong> Brit. J. Derm. 128: 79-85, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8427826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8427826</a>] [<a href="https://doi.org/10.1111/j.1365-2133.1993.tb00152.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8427826">Kitajima et al. (1993)</a> described 2 cases of the Dowling-Meara type of EBS with severe blistering at birth that improved gradually with age. Both had vesicles and small bullae clustering in a herpetiform fashion. In 1, there was a mild pincer deformity of the nails, whereas in the other, the nail plates shed after subungual blistering but regrew without deformity. Both had histopathologic and ultrastructural evidence of cytolysis of the basal cells, but with ultrastructural differences in the form of the tonofilament clumps present in epidermal keratinocytes. One case had typical round clumping of tonofilaments, while the other had whisk-type clumping of tonofilaments. The same difference in form was observed in cultured keratinocytes. The authors suggested possible subgrouping of this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8427826" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Shemanko, C. S., Mellerio, J. E., Tidman, M. J., Lane, E. B., Eady, R. A. J. <strong>Severe palmo-plantar hyperkeratosis in Dowling-Meara epidermolysis bullosa simplex caused by a mutation in the keratin 14 gene (KRT14).</strong> J. Invest. Derm. 111: 893-895, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9804355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9804355</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1998.00388.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9804355">Shemanko et al. (1998)</a> reported a 41-year-old man with a KRT14 mutation who had widespread skin fragility and blistering from birth. From early childhood he developed severe palmoplantar hyperkeratosis that persisted despite long-term oral corticosteroid treatment and surgical excision of affected skin. The hyperkeratosis resulted in flexion contractures of the hands and considerable functional and cosmetic difficulties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9804355" 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="#16" class="mim-tip-reference" title="Sasaki, Y., Shimizu, H., Akiyama, M., Hiraoka, Y., Takizawa, Y., Yamada, S., Morishima, Y., Yamanishi, K., Aiso, S., Nishikawa, T. <strong>A recurrent keratin 14 mutation in Dowling-Meara epidermolysis bullosa simplex. (Letter)</strong> Brit. J. Derm. 141: 747-776, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583131</a>] [<a href="https://doi.org/10.1046/j.1365-2133.1999.03124.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583131">Sasaki et al. (1999)</a> reported a Japanese family with Dowling-Meara EBS of heterogeneous clinical severity and mutation in the KRT14 gene. A 5-year-old girl had the most severe phenotype, with extensive generalized blisters and erosions from birth. Her younger sister at 6 months of age had blisters restricted to the hands and feet that had presented at 3 days of age. Their father and grandfather had developed blisters in childhood mainly on the palms and soles, which improved markedly in adulthood, and had only diffuse postinflammatory pigmentation on the abdomen. Electron microscopy revealed cytolysis of the basal cells and suprabasal blister formation in the skin of all patients, while electron-dense clumped tonofilaments were observed only in the skin of the 2 daughters, not in that of the father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Shemanko, C. S., Horn, H. M., Keohane, S. G., Hepburn, N., Kerr, A. I. G., Atherton, D. J., Tidman, M. J., Lane, E. B. <strong>Laryngeal involvement in the Dowling-Meara variant of epidermolysis bullosa simplex with keratin mutations of severely disruptive potential.</strong> Brit. J. Derm. 142: 315-320, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10730767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10730767</a>] [<a href="https://doi.org/10.1046/j.1365-2133.2000.03304.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10730767">Shemanko et al. (2000)</a> described a patient (patient 1) with Dowling-Meara EBS and mutation in the KRT14 gene who had a hoarse cry, a feature not well documented in Dowling-Meara EBS but usually associated with junctional EB. The patient developed widespread blistering of the skin and buccal mucous membranes within 24 hours of birth, and was noted to have a persistently hoarse cry. Blistering remained widespread but became progressively more herpetiform, with periungual involvement and nail dystrophy. At 7 months of age, direct laryngoscopy was undertaken and irregular thickenings were seen on both vocal cords. Hoarseness persisted until age 2 years. At age 6 years, development was normal, and blisters remained widespread and herpetiform. <a href="#18" class="mim-tip-reference" title="Shemanko, C. S., Horn, H. M., Keohane, S. G., Hepburn, N., Kerr, A. I. G., Atherton, D. J., Tidman, M. J., Lane, E. B. <strong>Laryngeal involvement in the Dowling-Meara variant of epidermolysis bullosa simplex with keratin mutations of severely disruptive potential.</strong> Brit. J. Derm. 142: 315-320, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10730767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10730767</a>] [<a href="https://doi.org/10.1046/j.1365-2133.2000.03304.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10730767">Shemanko et al. (2000)</a> also studied a patient with Dowling-Meara EBS and a hoarse cry who carried a mutation in the KRT5 gene (see <a href="/entry/619555">619555</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10730767" 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="Cummins, R. E., Klingberg, S., Wesley, J., Rogers, M., Zhao, Y., Murrell, D. F. <strong>Keratin 14 point mutations at codon 119 of helix 1A resulting in different epidermolysis bullosa simplex phenotypes.</strong> J. Invest. Derm. 117: 1103-1107, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11710919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11710919</a>] [<a href="https://doi.org/10.1046/j.0022-202x.2001.01508.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11710919">Cummins et al. (2001)</a> reported a 3-year-old boy (family 1) with generalized severe EBS and mutation in the KRT14 gene. He had diffuse herpetiform blistering in the neonatal period, and also experienced erosions of the oral mucosa and had a hoarse cry. In the first year of life, severe palmoplantar hyperkeratosis, nail thickening, and marked onychogryphosis developed. The proband also had significant motor delay, crawling at 2 years of age and unable to stand or walk without assistance at age 3. Electron microscopy of nonlesional skin after friction showed suprabasal clefting. Although tonofilament clumping was not observed, a diagnosis of Dowling-Meara subtype of EBS was made based on the severity of his clinical presentation and the phenotypic hallmark of herpetiform blistering. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11710919" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Pfendner, E. G., Sadowski, S. G., Uitto, J. <strong>Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis.</strong> J. Invest. Derm. 125: 239-243, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16098032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16098032</a>] [<a href="https://doi.org/10.1111/j.0022-202X.2005.23818.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16098032">Pfendner et al. (2005)</a> studied 4 patients with Dowling-Meara EBS and mutation in the KRT14 gene. Clinical information was limited, but generalized blistering was noted to be severe in 3 of the patients; one patient had a feeding tube as well as airway involvement and tracheotomy, and another had involvement of oral and esophageal mucosa. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16098032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Titeux, M., Mazereeuw-Hautier, J., Hadj-Rabia, S., Prost, C., Tonasso, L., Fraitag, S., de Prost, Y., Hovnanian, A., Bodemer, C. <strong>Three severe cases of EBS Dowling-Meara caused by missense and frameshift mutations in the keratin 14 gene.</strong> J. Invest. Derm. 126: 773-776, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16439965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16439965</a>] [<a href="https://doi.org/10.1038/sj.jid.5700154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16439965">Titeux et al. (2006)</a> reported 3 unrelated French boys with unusually severe EBS and mutation in KRT14. From birth, all 3 had large blisters with extensive generalized skin lesions that were more pronounced on the extremities. The blisters had a herpetiform appearance and were sometimes hemorrhagic. Oral mucosa was involved, and all 3 required hospitalization in the first months of life. Patients 1 and 2 developed severe palmoplantar keratoderma and marked nail thickening in the first weeks of life, and patient 2 also had onychogryphosis. At ages 1 year (patient 1) and 2 years (patients 2 and 3), skin fragility and blistering were extensive and required constant protective measures, despite which cutaneous infections were frequent. Patients 1 and 2 had limited mobility of the hands and feet due to severe palmoplantar keratoderma with flexion contractures. Patient 3 had somewhat milder disease, although he still experienced blistering on areas of friction, with frequent episodes of palmoplantar hemorrhagic blisters and herpetiform lesions on his trunk, as well as mucosal lesions. Ultrastructural analysis of skin from patient 1 showed a deep cleavage within the cytoplasm of basal keratinocytes, with no detectable aggregates of tonofilaments. In patient 3, cleavage was beneath the nucleus or near the basal end of basal keratinocytes, and rare small tonofilament aggregates were present. Electron microscopy could not be performed on skin from patient 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16439965" 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="Diociaiuti, A., Giancristoforo, S., Pisaneschi, E., Condorelli, A. G., Boldrini, R., Zambruno, G., El Hachem, M. <strong>Hoarse cry in a newborn with epidermolysis bullosa simplex, generalized severe.</strong> Pediat. Derm. 37: 393-395, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31957133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31957133</a>] [<a href="https://doi.org/10.1111/pde.14105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31957133">Diociaiuti et al. (2020)</a> reported an Italian male infant who presented with blisters of the oral mucosa and diaper area, which rapidly extended over the body. Examination showed widespread blisters and large erosions involving the diaper area and extremities, with severe nail dystrophy, as well as extensive oral erosions. At age 1 month, hoarse cry and mild inspiratory stridor were noted. In addition, skin lesions worsened and new subungual and periungula hemorrhagic blisters and crusts appeared. Electron microscopy documented subnuclear vacuolization and tonofilament clumping in basal keratinocytes, consistent with generalized severe EB simplex. On follow-up, the patient developed blisters in the characteristic herpetiform distribution in the second month of life. There was resolution of the hoarseness and stridor by 4 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31957133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#9" class="mim-tip-reference" title="Holbrook, K. A., Wapner, R., Jackson, L., Zaeri, N. <strong>Diagnosis and prenatal diagnosis of epidermolysis bullosa herpetiformis (Dowling-Meara) in a mother, two affected children, and an affected fetus.</strong> Prenatal Diag. 12: 725-739, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1438067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1438067</a>] [<a href="https://doi.org/10.1002/pd.1970120906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1438067">Holbrook et al. (1992)</a> made a diagnosis of this disorder by in utero fetal skin biopsy. Two earlier-born sibs had been affected. The mother, who had been thought to be normal, was found to have had blistering of the skin as a child and hyperkeratotic palms and soles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1438067" 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 EBS1A in the family reported by <a href="#16" class="mim-tip-reference" title="Sasaki, Y., Shimizu, H., Akiyama, M., Hiraoka, Y., Takizawa, Y., Yamada, S., Morishima, Y., Yamanishi, K., Aiso, S., Nishikawa, T. <strong>A recurrent keratin 14 mutation in Dowling-Meara epidermolysis bullosa simplex. (Letter)</strong> Brit. J. Derm. 141: 747-776, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583131</a>] [<a href="https://doi.org/10.1046/j.1365-2133.1999.03124.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583131">Sasaki et al. (1999)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The heterozygous mutations in the KRT14 gene that were identified in patients with EBS1A by <a href="#18" class="mim-tip-reference" title="Shemanko, C. S., Horn, H. M., Keohane, S. G., Hepburn, N., Kerr, A. I. G., Atherton, D. J., Tidman, M. J., Lane, E. B. <strong>Laryngeal involvement in the Dowling-Meara variant of epidermolysis bullosa simplex with keratin mutations of severely disruptive potential.</strong> Brit. J. Derm. 142: 315-320, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10730767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10730767</a>] [<a href="https://doi.org/10.1046/j.1365-2133.2000.03304.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10730767">Shemanko et al. (2000)</a>, <a href="#10" class="mim-tip-reference" title="Hut, P. H. L., Vlies, P. V. D., Jonkman, M. F., Verlind, E., Shimizu, H., Buys, C. H. C. M., Scheffer, H. <strong>Exempting homologous pseudogene sequences from polymerase chain reaction amplification allows genomic keratin 14 hotspot analysis.</strong> J. Invest. Derm. 114: 616-619, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10733662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10733662</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2000.00928.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10733662">Hut et al. (2000)</a>, and <a href="#14" class="mim-tip-reference" title="Pfendner, E. G., Sadowski, S. G., Uitto, J. <strong>Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis.</strong> J. Invest. Derm. 125: 239-243, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16098032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16098032</a>] [<a href="https://doi.org/10.1111/j.0022-202X.2005.23818.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16098032">Pfendner et al. (2005)</a> occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10733662+16098032+10730767" 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 2 unrelated patients with Dowling-Meara EBS, <a href="#2" class="mim-tip-reference" title="Coulombe, P. A., Hutton, M. E., Letai, A., Hebert, A., Paller, A. S., Fuchs, E. <strong>Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses.</strong> Cell 66: 1301-1311, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1717157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1717157</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90051-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1717157">Coulombe et al. (1991)</a> identified 2 different heterozygous mutations in the KRT14 gene (<a href="/entry/148066#0002">148066.0002</a>; <a href="/entry/148066#0003">148066.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1717157" 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 Japanese family with Dowling-Meara EBS, <a href="#16" class="mim-tip-reference" title="Sasaki, Y., Shimizu, H., Akiyama, M., Hiraoka, Y., Takizawa, Y., Yamada, S., Morishima, Y., Yamanishi, K., Aiso, S., Nishikawa, T. <strong>A recurrent keratin 14 mutation in Dowling-Meara epidermolysis bullosa simplex. (Letter)</strong> Brit. J. Derm. 141: 747-776, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10583131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10583131</a>] [<a href="https://doi.org/10.1046/j.1365-2133.1999.03124.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10583131">Sasaki et al. (1999)</a> detected heterozygosity for a missense mutation in the KRT14 gene (<a href="/entry/148066#0002">148066.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10583131" 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 patient with Dowling-Meara EBS and a hoarse cry, <a href="#18" class="mim-tip-reference" title="Shemanko, C. S., Horn, H. M., Keohane, S. G., Hepburn, N., Kerr, A. I. G., Atherton, D. J., Tidman, M. J., Lane, E. B. <strong>Laryngeal involvement in the Dowling-Meara variant of epidermolysis bullosa simplex with keratin mutations of severely disruptive potential.</strong> Brit. J. Derm. 142: 315-320, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10730767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10730767</a>] [<a href="https://doi.org/10.1046/j.1365-2133.2000.03304.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10730767">Shemanko et al. (2000)</a> identified a heterozygous missense mutation in the KRT14 gene (R125H; <a href="/entry/148066#0003">148066.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10730767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Hut, P. H. L., Vlies, P. V. D., Jonkman, M. F., Verlind, E., Shimizu, H., Buys, C. H. C. M., Scheffer, H. <strong>Exempting homologous pseudogene sequences from polymerase chain reaction amplification allows genomic keratin 14 hotspot analysis.</strong> J. Invest. Derm. 114: 616-619, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10733662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10733662</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2000.00928.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10733662">Hut et al. (2000)</a> identified 3 different mutations in the KRT14 gene (<a href="/entry/148066#0011">148066.0011</a>-<a href="/entry/148066#0013">148066.0013</a>) in patients with EBSDM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10733662" 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 3-year-old boy (family 1) with generalized severe EBS and a hoarse cry, <a href="#3" class="mim-tip-reference" title="Cummins, R. E., Klingberg, S., Wesley, J., Rogers, M., Zhao, Y., Murrell, D. F. <strong>Keratin 14 point mutations at codon 119 of helix 1A resulting in different epidermolysis bullosa simplex phenotypes.</strong> J. Invest. Derm. 117: 1103-1107, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11710919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11710919</a>] [<a href="https://doi.org/10.1046/j.0022-202x.2001.01508.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11710919">Cummins et al. (2001)</a> identified heterozygosity for the previously reported M119T mutation in the KRT14 gene, which was not present in his unaffected parents, indicating that the variant arose de novo in the proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11710919" 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 4 unrelated probands with Dowling-Meara EBS, <a href="#14" class="mim-tip-reference" title="Pfendner, E. G., Sadowski, S. G., Uitto, J. <strong>Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis.</strong> J. Invest. Derm. 125: 239-243, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16098032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16098032</a>] [<a href="https://doi.org/10.1111/j.0022-202X.2005.23818.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16098032">Pfendner et al. (2005)</a> identified a heterozygous mutation in the KRT14 gene (N123S; <a href="/entry/148066#0018">148066.0018</a>). All of the patients had a de novo mutation and severe generalized blistering with oral mucous membrane involvement. The mutation was predicted to severely perturb the intermediate filament network. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16098032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 18 families with various forms of EBS, <a href="#14" class="mim-tip-reference" title="Pfendner, E. G., Sadowski, S. G., Uitto, J. <strong>Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis.</strong> J. Invest. Derm. 125: 239-243, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16098032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16098032</a>] [<a href="https://doi.org/10.1111/j.0022-202X.2005.23818.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16098032">Pfendner et al. (2005)</a> identified KRT5 mutations in 7 probands and KRT14 mutations in 11 probands, indicating that mutations in either gene can result in EBS at approximately equal frequencies. A large number (15 of 18) were de novo mutations. The clinical spectrum was highly variable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16098032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 French boys with unusually severe EBS, 2 of whom developed marked palmoplantar keratoderma in infancy, <a href="#21" class="mim-tip-reference" title="Titeux, M., Mazereeuw-Hautier, J., Hadj-Rabia, S., Prost, C., Tonasso, L., Fraitag, S., de Prost, Y., Hovnanian, A., Bodemer, C. <strong>Three severe cases of EBS Dowling-Meara caused by missense and frameshift mutations in the keratin 14 gene.</strong> J. Invest. Derm. 126: 773-776, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16439965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16439965</a>] [<a href="https://doi.org/10.1038/sj.jid.5700154" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16439965">Titeux et al. (2006)</a> sequenced the KRT14 gene and identified heterozygosity for the recurrent M119T mutation in patients 1 and 2, whereas patient 3 was heterozygous for a 1-bp deletion (<a href="/entry/148066#0024">148066.0024</a>). Screening of parents revealed that the mutations arose de novo in all 3 boys. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16439965" 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>From a cohort of Iranian patients with clinical presentations and immunoepitope mapping suggestive of EBS, <a href="#22" class="mim-tip-reference" title="Vahidnezhad, H., Youssefian, L., Saeidian, A. H., Mozafari, N., Barzegar, M., Sotoudeh, S., Daneshpazhooh, M., Isaian, A., Zeinali, S., Uitto, J. <strong>KRT5 and KRT14 mutations in epidermolysis bullosa simplex with phenotypic heterogeneity, and evidence of semidominant inheritance in a multiplex family.</strong> J. Invest. Derm. 136: 1897-1901, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27283507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27283507</a>] [<a href="https://doi.org/10.1016/j.jid.2016.05.106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27283507">Vahidnezhad et al. (2016)</a> identified 4 families with heterozygous mutations in the KRT5 gene and 7 families with mutations in KRT14. Homozygous KRT14 variants were present in 3 families (see EBS1D, <a href="/entry/601001">601001</a>) and heterozygous KRT14 variants segregated in 4 families, 2 of which exhibited severe disease (see, e.g., <a href="/entry/148066#0020">148066.0020</a>). One of the probands with severe disease (family 7) was reported to have digenic inheritance, with a heterozygous variant in KRT5 as well as KRT14. The remaining 2 heterozygous families exhibited localized disease (see EBS1C, <a href="/entry/131800">131800</a>); in 1 of them (family 9), some affected individuals who were born of consanguineous unions exhibited more generalized lesions and were found to be homozygous for the segregating variant (I377T; <a href="/entry/148066#0021">148066.0021</a>). The authors designated family 9 as having a 'semidominant' mode of inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27283507" 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 an Italian male infant with generalized severe EB simplex and a hoarse cry with mild inspiratory stridor, <a href="#4" class="mim-tip-reference" title="Diociaiuti, A., Giancristoforo, S., Pisaneschi, E., Condorelli, A. G., Boldrini, R., Zambruno, G., El Hachem, M. <strong>Hoarse cry in a newborn with epidermolysis bullosa simplex, generalized severe.</strong> Pediat. Derm. 37: 393-395, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31957133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31957133</a>] [<a href="https://doi.org/10.1111/pde.14105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31957133">Diociaiuti et al. (2020)</a> identified heterozygosity for the recurrent R125C mutation in the KRT14 gene (<a href="/entry/148066#0002">148066.0002</a>). The mutation arose de novo in the proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31957133" 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="#12" class="mim-tip-reference" title="Letai, A., Coulombe, P. A., McCormick, M. B., Yu, Q.-C., Hutton, E., Fuchs, E. <strong>Disease severity correlates with position of keratin point mutations in patients with epidermolysis bullosa simplex.</strong> Proc. Nat. Acad. Sci. 90: 3197-3201, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7682695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7682695</a>] [<a href="https://doi.org/10.1073/pnas.90.8.3197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7682695">Letai et al. (1993)</a> reported that clinical severity of EBS and epidermolytic hyperkeratosis (EHK; <a href="/entry/113800">113800</a>) is related to the location of point mutations within the keratin polypeptides and the degree to which these mutations perturb keratin intermediate filament (IF) structure. Point mutations in the most severe forms have been clustered in the highly conserved ends of the K5 or K14 rod domains in EBSDM (e.g., <a href="/entry/148066#0002">148066.0002</a>) and in the corresponding regions of the K10 (e.g., <a href="/entry/148080#0003">148080.0003</a>) and K1 rod in EHK. Mutations in milder cases have been found in less-conserved regions, either within or outside the rod domain. Of 11 known Dowling-Meara EBS or EHK mutations, 6 affected a single, highly evolutionarily conserved arginine residue which, when mutated, markedly disturbs keratin filament structure and network formation. The site also appeared to be a hotspot for mutation by CpG methylation and deamination. <a href="#12" class="mim-tip-reference" title="Letai, A., Coulombe, P. A., McCormick, M. B., Yu, Q.-C., Hutton, E., Fuchs, E. <strong>Disease severity correlates with position of keratin point mutations in patients with epidermolysis bullosa simplex.</strong> Proc. Nat. Acad. Sci. 90: 3197-3201, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7682695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7682695</a>] [<a href="https://doi.org/10.1073/pnas.90.8.3197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7682695">Letai et al. (1993)</a> suggested that arg125 of K14 and arg156 of K10 must play a special role in maintaining keratin network integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7682695" 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="Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others. <strong>Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.</strong> Brit. J. Derm. 183: 614-627, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32017015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32017015</a>] [<a href="https://doi.org/10.1111/bjd.18921" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32017015">Has et al. (2020)</a> noted that, for autosomal dominant EBS with KRT5 or KRT14 mutations, the position of the mutated residue determines the severity of the phenotype. Substitutions of highly conserved amino acids within the helix initiation or termination motifs impair heterodimerization of keratin-5 or -14 polypeptides and lead to severe EBS, whereas substitutions in other regions of the gene lead to localized EBS. Monoallelic in-frame deletion, splice site, or premature termination codon mutations usually lead to the formation of truncated proteins with dominant-negative effects. Most cases of recessively inherited EBS are caused by nonsense or frameshift mutations in KRT14. Absence of KRT5 results in a very severe phenotype with early lethality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32017015" 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 15-year review of all infants born with generalized severe EBS and notified to the National Health Service of the UK, <a href="#17" class="mim-tip-reference" title="Sathishkumar, D., Orrin, E., Terron-Kwiatkowski, A., Browne, F., Martinez, A. E., Mellerio, J. E., Ogboli, M., Hoey, S., Ozoemena, L., Liu, L., Baty, D., McGrath, J. A., Moss, C. <strong>The p.Glu477Lys mutation in keratin 5 is strongly associated with mortality in generalized severe epidermolysis bullosa simplex.</strong> J. Invest. Derm. 136: 719-721, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26743602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26743602</a>] [<a href="https://doi.org/10.1016/j.jid.2015.11.024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26743602">Sathishkumar et al. (2016)</a> identified 37 cases. Genetic analysis in 33 of those cases showed KRT5 mutations in 17, KRT14 mutations in 15, and mutations in both KRT5 and KRT14 in 1 patient. The authors noted that generalized severe EBS was associated with KRT5 and KRT14 mutations involving the highly conserved ends of the alpha-helical rod domain, the helix boundary motifs, whereas mutations outside the helix boundary motifs were associated with milder EBS phenotypes. In addition, clinical severity had been reported to be associated with the nature of the amino acid change, with changes in polarity or acidity being associated with more severe phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26743602" 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="#15" class="mim-tip-reference" title="Roth, W., Reuter, U., Wohlenberg, C., Bruckner-Tuderman, L., Magin, T. M. <strong>Cytokines as genetic modifiers in K5-/- mice and in human epidermolysis bullosa simplex.</strong> Hum. Mutat. 30: 832-841, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19267394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19267394</a>] [<a href="https://doi.org/10.1002/humu.20981" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19267394">Roth et al. (2009)</a> found that skin from Krt5-null mice showed increased levels of the inflammatory cytokines MCP1 (CCL2; <a href="/entry/158105">158105</a>), CCL19 (<a href="/entry/602227">602227</a>), and CCL20 (<a href="/entry/601960">601960</a>), all of which are regulated by NFKB (see <a href="/entry/164011">164011</a>) and involved in the recruitment, maturation, and migration of Langerhans cells in the epidermis. These changes were not observed in Krt14-null mice. The number of Langerhans cells were increased 2-fold in epidermis of neonatal Krt5-null mice. In contrast, TNFA (<a href="/entry/191160">191160</a>) was not changed, demonstrating the specificity of that process. The basal epidermis from Krt5-null mice also showed decreased p120-catenin (CTNND1; <a href="/entry/601045">601045</a>). Enhanced Langerhans cell recruitment within the epidermis was found in 5 patients with various forms of EBS due to KRT5 mutations, but not in EBS patients with KRT14 gene mutations. These data provided an explanation for distinct, keratin-type-specific genotype-phenotype correlations in EBS, and suggested that the pathophysiology of EBS involves more than mutant keratins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19267394" 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 reviewing the molecular genetics of epidermolysis bullosa, <a href="#6" class="mim-tip-reference" title="Epstein, E. H., Jr. <strong>Molecular genetics of epidermolysis bullosa.</strong> Science 256: 799-804, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1375393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1375393</a>] [<a href="https://doi.org/10.1126/science.1375393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1375393">Epstein (1992)</a> suggested that a defect in keratin intermediate filament proteins should have been suspected in EBS. <a href="#1" class="mim-tip-reference" title="Anton-Lamprecht, I., Schnyder, U. W. <strong>Epidermolysis bullosa herpetiformis Dowling Meara: report of a case and pathomorphogenesis.</strong> Dermatologica 164: 221-235, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7084543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7084543</a>]" pmid="7084543">Anton-Lamprecht and Schnyder (1982)</a> described clumping of keratin intermediate filaments as the characteristic abnormality demonstrable by electron microscopy in the more severe Dowling-Meara subtype of EBS (<a href="/entry/131760">131760</a>). They also pointed to the family reported by <a href="#20" class="mim-tip-reference" title="Sutherland, G. R., Hinton, L. <strong>Heritable fragile sites on human chromosomes. VI. Characterization of the fragile site at 12q13.</strong> Hum. Genet. 57: 217-219, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7194847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7194847</a>] [<a href="https://doi.org/10.1007/BF00282028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7194847">Sutherland and Hinton (1981)</a> in which a fragile site at 12q13 was associated with EBS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1375393+7084543+7194847" 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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Anton-Lamprecht, I., Schnyder, U. W.
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<strong>Epidermolysis bullosa herpetiformis Dowling Meara: report of a case and pathomorphogenesis.</strong>
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Dermatologica 164: 221-235, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7084543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7084543</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7084543" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Coulombe, P. A., Hutton, M. E., Letai, A., Hebert, A., Paller, A. S., Fuchs, E.
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<strong>Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses.</strong>
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Cell 66: 1301-1311, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1717157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1717157</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1717157" 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/10.1016/0092-8674(91)90051-y" target="_blank">Full Text</a>]
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Cummins, R. E., Klingberg, S., Wesley, J., Rogers, M., Zhao, Y., Murrell, D. F.
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<strong>Keratin 14 point mutations at codon 119 of helix 1A resulting in different epidermolysis bullosa simplex phenotypes.</strong>
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J. Invest. Derm. 117: 1103-1107, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11710919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11710919</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11710919" 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/10.1046/j.0022-202x.2001.01508.x" target="_blank">Full Text</a>]
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Diociaiuti, A., Giancristoforo, S., Pisaneschi, E., Condorelli, A. G., Boldrini, R., Zambruno, G., El Hachem, M.
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<strong>Hoarse cry in a newborn with epidermolysis bullosa simplex, generalized severe.</strong>
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Pediat. Derm. 37: 393-395, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31957133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31957133</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31957133" 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/pde.14105" target="_blank">Full Text</a>]
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Dowling, G. B., Meara, R. H.
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<strong>Epidermolysis bullosa dermatitis herpetiformis.</strong>
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Brit. J. Derm. 66: 139-143, 1954.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13149726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13149726</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13149726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2133.1954.tb12605.x" target="_blank">Full Text</a>]
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<strong>Molecular genetics of epidermolysis bullosa.</strong>
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Science 256: 799-804, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1375393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1375393</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1375393" 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/10.1126/science.1375393" target="_blank">Full Text</a>]
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Fine, J.-D., Eady, R. A. J., Bauer, E. A., Bauer, J. W., Bruckner-Tuderman, L., Heagerty, A., Hintner, H., Hovnanian, A., Jonkman, M. F., Leigh, I., McGrath, J. A., Mellerio, J. E., Murrell, D. F., Shimizu, H., Uitto, J., Vahlquist, A., Woodley, D., Zambruno, G.
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<strong>The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on diagnosis and classification of EB.</strong>
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J. Am. Acad. Derm. 58: 931-950, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18374450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18374450</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18374450" 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.jaad.2008.02.004" target="_blank">Full Text</a>]
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Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others.
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<strong>Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.</strong>
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Brit. J. Derm. 183: 614-627, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32017015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32017015</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32017015" 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.18921" target="_blank">Full Text</a>]
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<strong>Diagnosis and prenatal diagnosis of epidermolysis bullosa herpetiformis (Dowling-Meara) in a mother, two affected children, and an affected fetus.</strong>
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[<a href="https://doi.org/10.1002/pd.1970120906" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1523-1747.2000.00928.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1365-2133.1993.tb00152.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.90.8.3197" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1365-2133.1992.tb11813.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.0022-202X.2005.23818.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20981" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1365-2133.1999.03124.x" target="_blank">Full Text</a>]
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Sathishkumar, D., Orrin, E., Terron-Kwiatkowski, A., Browne, F., Martinez, A. E., Mellerio, J. E., Ogboli, M., Hoey, S., Ozoemena, L., Liu, L., Baty, D., McGrath, J. A., Moss, C.
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<strong>The p.Glu477Lys mutation in keratin 5 is strongly associated with mortality in generalized severe epidermolysis bullosa simplex.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26743602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26743602</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26743602" 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.2015.11.024" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10730767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10730767</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10730767" 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/10.1046/j.1365-2133.2000.03304.x" target="_blank">Full Text</a>]
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<strong>Severe palmo-plantar hyperkeratosis in Dowling-Meara epidermolysis bullosa simplex caused by a mutation in the keratin 14 gene (KRT14).</strong>
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[<a href="https://doi.org/10.1046/j.1523-1747.1998.00388.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.jid.5700154" target="_blank">Full Text</a>]
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Vahidnezhad, H., Youssefian, L., Saeidian, A. H., Mozafari, N., Barzegar, M., Sotoudeh, S., Daneshpazhooh, M., Isaian, A., Zeinali, S., Uitto, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27283507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27283507</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27283507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 01/13/2022
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Marla J. F. O'Neill - updated : 11/11/2021<br>Marla J. F. O'Neill - updated : 11/09/2021<br>Cassandra L. Kniffin - reorganized : 9/14/2009<br>Cassandra L. Kniffin - updated : 8/25/2009<br>Gary A. Bellus - updated : 6/13/2000<br>Wilson H. Y. Lo - updated : 9/9/1999
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Creation Date:
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Victor A. McKusick : 6/23/1988
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 01/13/2022
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alopez : 11/11/2021<br>alopez : 11/09/2021<br>alopez : 11/01/2021<br>alopez : 10/28/2021<br>alopez : 10/26/2021<br>alopez : 10/25/2021<br>alopez : 10/20/2021<br>alopez : 07/28/2015<br>carol : 12/1/2014<br>carol : 9/14/2009<br>ckniffin : 8/25/2009<br>alopez : 6/13/2000<br>carol : 9/9/1999<br>alopez : 5/14/1998<br>mimadm : 9/24/1994<br>davew : 7/5/1994<br>carol : 12/14/1993<br>carol : 10/26/1993<br>carol : 7/6/1993<br>carol : 6/30/1993
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<strong>#</strong> 131760
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EPIDERMOLYSIS BULLOSA SIMPLEX 1A, GENERALIZED SEVERE; EBS1A
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EPIDERMOLYSIS BULLOSA SIMPLEX 1A, DOWLING-MEARA TYPE<br />
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EPIDERMOLYSIS BULLOSA SIMPLEX, DOWLING-MEARA TYPE; EBSDM<br />
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EPIDERMOLYSIS BULLOSA HERPETIFORMIS, DOWLING-MEARA TYPE
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<strong>SNOMEDCT:</strong> 254179000;
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<strong>ORPHA:</strong> 79396;
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<strong>DO:</strong> 0060735;
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<strong>Phenotype-Gene Relationships</strong>
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Phenotype
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Inheritance
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17q21.2
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Epidermolysis bullosa simplex 1A, generalized severe
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131760
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Autosomal dominant
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KRT14
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148066
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<p>A number sign (#) is used with this entry because generalized severe epidermolysis bullosa simplex-1A (EBS1A) is caused by heterozygous mutation in the KRT14 gene (148066) on chromosome 17q21.</p><p>Another form of generalized severe EBS, EBS2A (619555), is caused by mutation in the KRT5 gene (148040).</p>
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<p>Generalized severe epidermolysis bullosa simplex-1A (EBS1A) is an autosomal dominant skin disorder characterized by generalized intraepidermal skin blistering from minimal mechanical trauma beginning at birth. A herpetiform (arcuate) pattern of blisters, a crusting-necrotic aspect of the lesions that is often associated with inflammatory plaques, and clumping of keratin intermediate filaments seen on electron microscopy define the severe subtype of EBS. Skin fragility is very prominent at birth, and large tense blisters can occur after minimal trauma or spontaneously; the disorder may be life-threatening in the first year of life. Congenital ulcerated areas on hands and feet as well as nail involvement are common. Blistering is exacerbated by heat, humidity, and sweating. Tendency to blistering diminishes in adolescence (summary by Has et al., 2020). </p><p>Epidermolysis bullosa simplex (EBS) comprises a group of clinically and genetically heterogeneous skin disorders characterized by recurrent blistering of the skin following minor physical trauma as a result of cytolysis within basal epidermal cells. Most forms show autosomal dominant inheritance. The severe subtype of EBS was previously known as the Dowling-Meara type. The other 2 main subtypes of EBS are the generalized intermediate, previously known as Koebner, type (see 131900) and the localized, previously known as Weber-Cockayne, type (see 131800) (Fine et al., 2008). All 3 of these main subtypes can be caused by mutation in either the KRT5 or the KRT14 gene. Rare EBS subtypes are clinically and genetically heterogeneous and include several syndromic types. </p><p>Other types of epidermis bullosa (EB), classified by the level of skin cleavage and other ultrastructural laboratory findings in addition to clinical features, are junctional EB (JEB; see 226700) and dystrophic EB (DEB; see 131750).</p><p><strong><em>Genetic Heterogeneity of Epidermolysis Bullosa Simplex</em></strong></p><p>
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Other forms of EBS that are caused by mutation in the KRT14 gene are generalized intermediate EBS1B (131900), previously known as the Koebner type; localized EBS1C (131800), previously known as the Weber-Cockayne type; and autosomal recessive generalized EBS1D (601001).</p><p>Forms of EBS caused by mutation in the KRT5 gene are generalized severe EBS2A (619555); generalized intermediate EBS2B (619588); localized EBS2C (619594); generalized autosomal recessive EBS2D (619599); EBS2E (609352), with migratory circinate erythema; and EBS2F (131960), with mottled pigmentation.</p><p>EBS3 (615425) is caused by mutation in the DST gene (113810). EBS4 (615028) is caused by mutation in the EXPH5 gene (612878).</p><p>Forms of EBS caused by mutation in the PLEC gene (601282) are EBS5A (131950), Ogna type; EBS5B (226670), with muscular dystrophy; EBS5C (612138), with pyloric atresia; and EBS5D (616487), autosomal recessive generalized intermediate.</p><p>EBS6 (617294), with scarring and hair loss, is caused by mutation in the KLHL24 gene (611295).</p><p>EBS7 (609057), with nephropathy and deafness, is caused by mutation in the CD151 gene (602243).</p><p><strong><em>Reviews</em></strong></p><p>
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Has et al. (2020) reviewed characteristic features and molecular bases of the subtypes of epidermolysis bullosa, and provided a consensus reclassification of disorders with skin fragility. </p><p>Fine et al. (2008) reviewed phenotypic features and molecular bases of all epidermolysis bullosa subtypes, and recommended revisions in the classification system. </p>
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<p>Dowling and Meara (1954) first described a form of epidermolysis bullosa simplex that resembled dermatitis herpetiformis (601230). Onset of generalized bullae in a herpetiform (arciform) arrangement occurred during the first 3 months of life. Serous and hemorrhagic blisters could occur on any part of the body, but most frequently on the palms and soles, around the mouth, and on the trunk and neck. In general, the lesions healed without scarring, but pronounced inflammatory reactions, especially seen in hemorrhagic blisters, was accompanied by milia and occasional scar formation. </p><p>Anton-Lamprecht and Schnyder (1982) reported a 2-year-old girl of Turkish origin with congenital generalized blister formation in a herpetiform arrangement. Direct immunofluorescence ruled out juvenile dermatitis herpetiformis. Ultrastructural investigation of a fresh blister and clinically intact preblistering skin revealed intraepidermal blister formation via cytolysis of basal cells, preceded by clumping of tonofilaments and partial attachment to the hemidesmosomes at the dermo-epidermal junction. This type of blister formation was significantly different from all other epidermolysis bullosa types and was a characteristic feature of the Dowling-Meara type of EBS. </p><p>McGrath et al. (1992) reviewed the clinicopathologic features of 22 cases varying in age from 5 days to 46 years. All cases presented clinically within the first 5 days of life. Early blisters were often large (up to 5 cm in diameter), and were mostly acral and particularly periungual. Some patients presented with more widespread erosive skin changes, and 2 neonates with extensive skin involvement died as a result of overwhelming sepsis. After the neonatal period, the pattern of blistering became more proximal, with hemorrhagic, herpetiform clusters of blisters. Central healing with recurrent blistering at the margins of these areas was frequent. Other physical signs included varying degrees of intraoral blistering, nail shedding, nail dystrophy, minor scarring, palmoplantar keratoderma, a lack of seasonal variation, and improvement during later childhood. Basal cell cytolysis in association with clumping of tonofilaments was the underlying pathologic mechanism. The clumping was found even in some nonlesional skin, suggesting that it is of primary pathogenetic significance. The disease was occasionally so severe, especially during the neonatal period, as to be confused with junctional (see, e.g., 226700) or severe recessive dystrophic EB (see, e.g., 226600). </p><p>Kitajima et al. (1993) described 2 cases of the Dowling-Meara type of EBS with severe blistering at birth that improved gradually with age. Both had vesicles and small bullae clustering in a herpetiform fashion. In 1, there was a mild pincer deformity of the nails, whereas in the other, the nail plates shed after subungual blistering but regrew without deformity. Both had histopathologic and ultrastructural evidence of cytolysis of the basal cells, but with ultrastructural differences in the form of the tonofilament clumps present in epidermal keratinocytes. One case had typical round clumping of tonofilaments, while the other had whisk-type clumping of tonofilaments. The same difference in form was observed in cultured keratinocytes. The authors suggested possible subgrouping of this disorder. </p><p>Shemanko et al. (1998) reported a 41-year-old man with a KRT14 mutation who had widespread skin fragility and blistering from birth. From early childhood he developed severe palmoplantar hyperkeratosis that persisted despite long-term oral corticosteroid treatment and surgical excision of affected skin. The hyperkeratosis resulted in flexion contractures of the hands and considerable functional and cosmetic difficulties. </p><p>Sasaki et al. (1999) reported a Japanese family with Dowling-Meara EBS of heterogeneous clinical severity and mutation in the KRT14 gene. A 5-year-old girl had the most severe phenotype, with extensive generalized blisters and erosions from birth. Her younger sister at 6 months of age had blisters restricted to the hands and feet that had presented at 3 days of age. Their father and grandfather had developed blisters in childhood mainly on the palms and soles, which improved markedly in adulthood, and had only diffuse postinflammatory pigmentation on the abdomen. Electron microscopy revealed cytolysis of the basal cells and suprabasal blister formation in the skin of all patients, while electron-dense clumped tonofilaments were observed only in the skin of the 2 daughters, not in that of the father. </p><p>Shemanko et al. (2000) described a patient (patient 1) with Dowling-Meara EBS and mutation in the KRT14 gene who had a hoarse cry, a feature not well documented in Dowling-Meara EBS but usually associated with junctional EB. The patient developed widespread blistering of the skin and buccal mucous membranes within 24 hours of birth, and was noted to have a persistently hoarse cry. Blistering remained widespread but became progressively more herpetiform, with periungual involvement and nail dystrophy. At 7 months of age, direct laryngoscopy was undertaken and irregular thickenings were seen on both vocal cords. Hoarseness persisted until age 2 years. At age 6 years, development was normal, and blisters remained widespread and herpetiform. Shemanko et al. (2000) also studied a patient with Dowling-Meara EBS and a hoarse cry who carried a mutation in the KRT5 gene (see 619555). </p><p>Cummins et al. (2001) reported a 3-year-old boy (family 1) with generalized severe EBS and mutation in the KRT14 gene. He had diffuse herpetiform blistering in the neonatal period, and also experienced erosions of the oral mucosa and had a hoarse cry. In the first year of life, severe palmoplantar hyperkeratosis, nail thickening, and marked onychogryphosis developed. The proband also had significant motor delay, crawling at 2 years of age and unable to stand or walk without assistance at age 3. Electron microscopy of nonlesional skin after friction showed suprabasal clefting. Although tonofilament clumping was not observed, a diagnosis of Dowling-Meara subtype of EBS was made based on the severity of his clinical presentation and the phenotypic hallmark of herpetiform blistering. </p><p>Pfendner et al. (2005) studied 4 patients with Dowling-Meara EBS and mutation in the KRT14 gene. Clinical information was limited, but generalized blistering was noted to be severe in 3 of the patients; one patient had a feeding tube as well as airway involvement and tracheotomy, and another had involvement of oral and esophageal mucosa. </p><p>Titeux et al. (2006) reported 3 unrelated French boys with unusually severe EBS and mutation in KRT14. From birth, all 3 had large blisters with extensive generalized skin lesions that were more pronounced on the extremities. The blisters had a herpetiform appearance and were sometimes hemorrhagic. Oral mucosa was involved, and all 3 required hospitalization in the first months of life. Patients 1 and 2 developed severe palmoplantar keratoderma and marked nail thickening in the first weeks of life, and patient 2 also had onychogryphosis. At ages 1 year (patient 1) and 2 years (patients 2 and 3), skin fragility and blistering were extensive and required constant protective measures, despite which cutaneous infections were frequent. Patients 1 and 2 had limited mobility of the hands and feet due to severe palmoplantar keratoderma with flexion contractures. Patient 3 had somewhat milder disease, although he still experienced blistering on areas of friction, with frequent episodes of palmoplantar hemorrhagic blisters and herpetiform lesions on his trunk, as well as mucosal lesions. Ultrastructural analysis of skin from patient 1 showed a deep cleavage within the cytoplasm of basal keratinocytes, with no detectable aggregates of tonofilaments. In patient 3, cleavage was beneath the nucleus or near the basal end of basal keratinocytes, and rare small tonofilament aggregates were present. Electron microscopy could not be performed on skin from patient 2. </p><p>Diociaiuti et al. (2020) reported an Italian male infant who presented with blisters of the oral mucosa and diaper area, which rapidly extended over the body. Examination showed widespread blisters and large erosions involving the diaper area and extremities, with severe nail dystrophy, as well as extensive oral erosions. At age 1 month, hoarse cry and mild inspiratory stridor were noted. In addition, skin lesions worsened and new subungual and periungula hemorrhagic blisters and crusts appeared. Electron microscopy documented subnuclear vacuolization and tonofilament clumping in basal keratinocytes, consistent with generalized severe EB simplex. On follow-up, the patient developed blisters in the characteristic herpetiform distribution in the second month of life. There was resolution of the hoarseness and stridor by 4 months of age. </p>
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<p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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Holbrook et al. (1992) made a diagnosis of this disorder by in utero fetal skin biopsy. Two earlier-born sibs had been affected. The mother, who had been thought to be normal, was found to have had blistering of the skin as a child and hyperkeratotic palms and soles. </p>
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<p>The transmission pattern of EBS1A in the family reported by Sasaki et al. (1999) was consistent with autosomal dominant inheritance. </p><p>The heterozygous mutations in the KRT14 gene that were identified in patients with EBS1A by Shemanko et al. (2000), Hut et al. (2000), and Pfendner et al. (2005) occurred de novo. </p>
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<p>In 2 unrelated patients with Dowling-Meara EBS, Coulombe et al. (1991) identified 2 different heterozygous mutations in the KRT14 gene (148066.0002; 148066.0003). </p><p>In a Japanese family with Dowling-Meara EBS, Sasaki et al. (1999) detected heterozygosity for a missense mutation in the KRT14 gene (148066.0002). </p><p>In a patient with Dowling-Meara EBS and a hoarse cry, Shemanko et al. (2000) identified a heterozygous missense mutation in the KRT14 gene (R125H; 148066.0003). </p><p>Hut et al. (2000) identified 3 different mutations in the KRT14 gene (148066.0011-148066.0013) in patients with EBSDM. </p><p>In a 3-year-old boy (family 1) with generalized severe EBS and a hoarse cry, Cummins et al. (2001) identified heterozygosity for the previously reported M119T mutation in the KRT14 gene, which was not present in his unaffected parents, indicating that the variant arose de novo in the proband. </p><p>In 4 unrelated probands with Dowling-Meara EBS, Pfendner et al. (2005) identified a heterozygous mutation in the KRT14 gene (N123S; 148066.0018). All of the patients had a de novo mutation and severe generalized blistering with oral mucous membrane involvement. The mutation was predicted to severely perturb the intermediate filament network. </p><p>Among 18 families with various forms of EBS, Pfendner et al. (2005) identified KRT5 mutations in 7 probands and KRT14 mutations in 11 probands, indicating that mutations in either gene can result in EBS at approximately equal frequencies. A large number (15 of 18) were de novo mutations. The clinical spectrum was highly variable. </p><p>In 3 French boys with unusually severe EBS, 2 of whom developed marked palmoplantar keratoderma in infancy, Titeux et al. (2006) sequenced the KRT14 gene and identified heterozygosity for the recurrent M119T mutation in patients 1 and 2, whereas patient 3 was heterozygous for a 1-bp deletion (148066.0024). Screening of parents revealed that the mutations arose de novo in all 3 boys. </p><p>From a cohort of Iranian patients with clinical presentations and immunoepitope mapping suggestive of EBS, Vahidnezhad et al. (2016) identified 4 families with heterozygous mutations in the KRT5 gene and 7 families with mutations in KRT14. Homozygous KRT14 variants were present in 3 families (see EBS1D, 601001) and heterozygous KRT14 variants segregated in 4 families, 2 of which exhibited severe disease (see, e.g., 148066.0020). One of the probands with severe disease (family 7) was reported to have digenic inheritance, with a heterozygous variant in KRT5 as well as KRT14. The remaining 2 heterozygous families exhibited localized disease (see EBS1C, 131800); in 1 of them (family 9), some affected individuals who were born of consanguineous unions exhibited more generalized lesions and were found to be homozygous for the segregating variant (I377T; 148066.0021). The authors designated family 9 as having a 'semidominant' mode of inheritance. </p><p>In an Italian male infant with generalized severe EB simplex and a hoarse cry with mild inspiratory stridor, Diociaiuti et al. (2020) identified heterozygosity for the recurrent R125C mutation in the KRT14 gene (148066.0002). The mutation arose de novo in the proband. </p>
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<p>Letai et al. (1993) reported that clinical severity of EBS and epidermolytic hyperkeratosis (EHK; 113800) is related to the location of point mutations within the keratin polypeptides and the degree to which these mutations perturb keratin intermediate filament (IF) structure. Point mutations in the most severe forms have been clustered in the highly conserved ends of the K5 or K14 rod domains in EBSDM (e.g., 148066.0002) and in the corresponding regions of the K10 (e.g., 148080.0003) and K1 rod in EHK. Mutations in milder cases have been found in less-conserved regions, either within or outside the rod domain. Of 11 known Dowling-Meara EBS or EHK mutations, 6 affected a single, highly evolutionarily conserved arginine residue which, when mutated, markedly disturbs keratin filament structure and network formation. The site also appeared to be a hotspot for mutation by CpG methylation and deamination. Letai et al. (1993) suggested that arg125 of K14 and arg156 of K10 must play a special role in maintaining keratin network integrity. </p><p>Has et al. (2020) noted that, for autosomal dominant EBS with KRT5 or KRT14 mutations, the position of the mutated residue determines the severity of the phenotype. Substitutions of highly conserved amino acids within the helix initiation or termination motifs impair heterodimerization of keratin-5 or -14 polypeptides and lead to severe EBS, whereas substitutions in other regions of the gene lead to localized EBS. Monoallelic in-frame deletion, splice site, or premature termination codon mutations usually lead to the formation of truncated proteins with dominant-negative effects. Most cases of recessively inherited EBS are caused by nonsense or frameshift mutations in KRT14. Absence of KRT5 results in a very severe phenotype with early lethality. </p><p>In a 15-year review of all infants born with generalized severe EBS and notified to the National Health Service of the UK, Sathishkumar et al. (2016) identified 37 cases. Genetic analysis in 33 of those cases showed KRT5 mutations in 17, KRT14 mutations in 15, and mutations in both KRT5 and KRT14 in 1 patient. The authors noted that generalized severe EBS was associated with KRT5 and KRT14 mutations involving the highly conserved ends of the alpha-helical rod domain, the helix boundary motifs, whereas mutations outside the helix boundary motifs were associated with milder EBS phenotypes. In addition, clinical severity had been reported to be associated with the nature of the amino acid change, with changes in polarity or acidity being associated with more severe phenotypes. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<p>Roth et al. (2009) found that skin from Krt5-null mice showed increased levels of the inflammatory cytokines MCP1 (CCL2; 158105), CCL19 (602227), and CCL20 (601960), all of which are regulated by NFKB (see 164011) and involved in the recruitment, maturation, and migration of Langerhans cells in the epidermis. These changes were not observed in Krt14-null mice. The number of Langerhans cells were increased 2-fold in epidermis of neonatal Krt5-null mice. In contrast, TNFA (191160) was not changed, demonstrating the specificity of that process. The basal epidermis from Krt5-null mice also showed decreased p120-catenin (CTNND1; 601045). Enhanced Langerhans cell recruitment within the epidermis was found in 5 patients with various forms of EBS due to KRT5 mutations, but not in EBS patients with KRT14 gene mutations. These data provided an explanation for distinct, keratin-type-specific genotype-phenotype correlations in EBS, and suggested that the pathophysiology of EBS involves more than mutant keratins. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In reviewing the molecular genetics of epidermolysis bullosa, Epstein (1992) suggested that a defect in keratin intermediate filament proteins should have been suspected in EBS. Anton-Lamprecht and Schnyder (1982) described clumping of keratin intermediate filaments as the characteristic abnormality demonstrable by electron microscopy in the more severe Dowling-Meara subtype of EBS (131760). They also pointed to the family reported by Sutherland and Hinton (1981) in which a fragile site at 12q13 was associated with EBS. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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<div>
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<ol>
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Coulombe, P. A., Hutton, M. E., Letai, A., Hebert, A., Paller, A. S., Fuchs, E.
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Cummins, R. E., Klingberg, S., Wesley, J., Rogers, M., Zhao, Y., Murrell, D. F.
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Dowling, G. B., Meara, R. H.
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Fine, J.-D., Eady, R. A. J., Bauer, E. A., Bauer, J. W., Bruckner-Tuderman, L., Heagerty, A., Hintner, H., Hovnanian, A., Jonkman, M. F., Leigh, I., McGrath, J. A., Mellerio, J. E., Murrell, D. F., Shimizu, H., Uitto, J., Vahlquist, A., Woodley, D., Zambruno, G.
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<strong>The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on diagnosis and classification of EB.</strong>
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J. Am. Acad. Derm. 58: 931-950, 2008.
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[Full Text: https://doi.org/10.1016/j.jaad.2008.02.004]
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Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others.
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<strong>Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.</strong>
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Brit. J. Derm. 183: 614-627, 2020.
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Holbrook, K. A., Wapner, R., Jackson, L., Zaeri, N.
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Prenatal Diag. 12: 725-739, 1992.
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[Full Text: https://doi.org/10.1002/pd.1970120906]
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Hut, P. H. L., Vlies, P. V. D., Jonkman, M. F., Verlind, E., Shimizu, H., Buys, C. H. C. M., Scheffer, H.
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<strong>Exempting homologous pseudogene sequences from polymerase chain reaction amplification allows genomic keratin 14 hotspot analysis.</strong>
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Kitajima, Y., Jokura, Y., Yaoita, H.
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<strong>Epidermolysis bullosa simplex, Dowling-Meara type: a report of two cases with different types of tonofilament clumping.</strong>
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Brit. J. Derm. 128: 79-85, 1993.
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[Full Text: https://doi.org/10.1111/j.1365-2133.1993.tb00152.x]
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<p class="mim-text-font">
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Letai, A., Coulombe, P. A., McCormick, M. B., Yu, Q.-C., Hutton, E., Fuchs, E.
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<strong>Disease severity correlates with position of keratin point mutations in patients with epidermolysis bullosa simplex.</strong>
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Proc. Nat. Acad. Sci. 90: 3197-3201, 1993.
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[PubMed: 7682695]
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[Full Text: https://doi.org/10.1073/pnas.90.8.3197]
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McGrath, J. A., Ishida-Yamamoto, A., Tidman, M. J., Heagerty, A. H. M., Schofield, O. M. V., Eady, R. A. J.
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<strong>Epidermolysis bullosa simplex (Dowling-Meara): a clinicopathological review.</strong>
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Brit. J. Derm. 126: 421-430, 1992.
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[PubMed: 1610681]
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[Full Text: https://doi.org/10.1111/j.1365-2133.1992.tb11813.x]
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Pfendner, E. G., Sadowski, S. G., Uitto, J.
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<strong>Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis.</strong>
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Roth, W., Reuter, U., Wohlenberg, C., Bruckner-Tuderman, L., Magin, T. M.
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<strong>Cytokines as genetic modifiers in K5-/- mice and in human epidermolysis bullosa simplex.</strong>
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Hum. Mutat. 30: 832-841, 2009.
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<p class="mim-text-font">
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Sasaki, Y., Shimizu, H., Akiyama, M., Hiraoka, Y., Takizawa, Y., Yamada, S., Morishima, Y., Yamanishi, K., Aiso, S., Nishikawa, T.
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<strong>A recurrent keratin 14 mutation in Dowling-Meara epidermolysis bullosa simplex. (Letter)</strong>
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Brit. J. Derm. 141: 747-776, 1999.
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<p class="mim-text-font">
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Sathishkumar, D., Orrin, E., Terron-Kwiatkowski, A., Browne, F., Martinez, A. E., Mellerio, J. E., Ogboli, M., Hoey, S., Ozoemena, L., Liu, L., Baty, D., McGrath, J. A., Moss, C.
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<strong>The p.Glu477Lys mutation in keratin 5 is strongly associated with mortality in generalized severe epidermolysis bullosa simplex.</strong>
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<p class="mim-text-font">
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Shemanko, C. S., Horn, H. M., Keohane, S. G., Hepburn, N., Kerr, A. I. G., Atherton, D. J., Tidman, M. J., Lane, E. B.
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<strong>Laryngeal involvement in the Dowling-Meara variant of epidermolysis bullosa simplex with keratin mutations of severely disruptive potential.</strong>
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<p class="mim-text-font">
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Shemanko, C. S., Mellerio, J. E., Tidman, M. J., Lane, E. B., Eady, R. A. J.
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<strong>Severe palmo-plantar hyperkeratosis in Dowling-Meara epidermolysis bullosa simplex caused by a mutation in the keratin 14 gene (KRT14).</strong>
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[PubMed: 9804355]
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[Full Text: https://doi.org/10.1046/j.1523-1747.1998.00388.x]
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</p>
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<p class="mim-text-font">
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Sutherland, G. R., Hinton, L.
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<strong>Heritable fragile sites on human chromosomes. VI. Characterization of the fragile site at 12q13.</strong>
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Hum. Genet. 57: 217-219, 1981.
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[PubMed: 7194847]
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[Full Text: https://doi.org/10.1007/BF00282028]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Titeux, M., Mazereeuw-Hautier, J., Hadj-Rabia, S., Prost, C., Tonasso, L., Fraitag, S., de Prost, Y., Hovnanian, A., Bodemer, C.
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<strong>Three severe cases of EBS Dowling-Meara caused by missense and frameshift mutations in the keratin 14 gene.</strong>
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J. Invest. Derm. 126: 773-776, 2006.
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[PubMed: 16439965]
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[Full Text: https://doi.org/10.1038/sj.jid.5700154]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Vahidnezhad, H., Youssefian, L., Saeidian, A. H., Mozafari, N., Barzegar, M., Sotoudeh, S., Daneshpazhooh, M., Isaian, A., Zeinali, S., Uitto, J.
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<strong>KRT5 and KRT14 mutations in epidermolysis bullosa simplex with phenotypic heterogeneity, and evidence of semidominant inheritance in a multiplex family.</strong>
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J. Invest. Derm. 136: 1897-1901, 2016.
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[PubMed: 27283507]
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[Full Text: https://doi.org/10.1016/j.jid.2016.05.106]
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</p>
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</li>
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</ol>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 01/13/2022<br>Marla J. F. O'Neill - updated : 11/11/2021<br>Marla J. F. O'Neill - updated : 11/09/2021<br>Cassandra L. Kniffin - reorganized : 9/14/2009<br>Cassandra L. Kniffin - updated : 8/25/2009<br>Gary A. Bellus - updated : 6/13/2000<br>Wilson H. Y. Lo - updated : 9/9/1999
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</span>
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/23/1988
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Edit History:
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