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<title>
Entry
- #615522 - COLE DISEASE; COLED
- OMIM
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<span class="h4">#615522</span>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/615522"><strong>Clinical Synopsis</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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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
<div class="panel-body small mim-panel-body">
<div><a href="https://clinicaltrials.gov/search?cond=(COLE DISEASE) OR (ENPP1)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=21785&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>
<div><a href="https://medlineplus.gov/genetics/condition/cole-disease" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=615522[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>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324561" 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>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<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.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 711154007<br />
<strong>ORPHA:</strong> 324561<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
615522
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
COLE DISEASE; COLED
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
GUTTATE HYPOPIGMENTATION AND PUNCTATE PALMOPLANTAR KERATODERMA WITH OR WITHOUT ECTOPIC CALCIFICATION
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/859?start=-3&limit=10&highlight=859">
6q23.2
</a>
</span>
</td>
<td>
<span class="mim-font">
Cole disease
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615522"> 615522 </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">
ENPP1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/173335"> 173335 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/615522" 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>
&nbsp;
<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/615522" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/615522" 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> 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">
- Normal teeth <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/162005007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">162005007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0426482&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0426482</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CHEST </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Breasts </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Microcalcifications on mammography (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809783&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809783</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Spleen </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Splenic calcification (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/442360003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">442360003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1404059&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1404059</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:6000381" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:6000381</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:6000381" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:6000381</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Pelvis </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Calcific tendinopathy of hips (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809785&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809785</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Limbs </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Calcific tendinopathy of shoulders (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809786&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809786</a>]</span><br /> -
Calcific tendinopathy of wrists (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809787&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809787</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Feet </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Calcific tendinopathy of heels (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809788&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809788</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">
- Hypopigmented macules, primarily on extremities <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809789&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809789</a>]</span><br /> -
Punctate palmoplantar keratoderma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/402773000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">402773000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1274216&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1274216</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Skin Histology </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hyperkeratosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254666005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254666005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399955009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399955009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26996000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26996000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0870082&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0870082</a>, <a href="https://bioportal.bioontology.org/search?q=C0022593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000962" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000962</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000962" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000962</a>]</span><br /> -
Hyperorthokeratosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/19128006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">19128006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0334021&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0334021</a>]</span><br /> -
Hypergranulosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3279547&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3279547</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025114" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025114</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025114" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025114</a>]</span><br /> -
Acanthosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/23620008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">23620008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221270&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221270</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025092" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025092</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025092" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025092</a>]</span><br /> -
Reduction in melanin content in keratinocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809790&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809790</a>]</span><br /> -
Normal melanin content in melanocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809791&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809791</a>]</span><br /> -
Normal number of melanocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809792&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809792</a>]</span><br /> -
Small deposits of calcium in papillary dermis (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809793&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809793</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">
- Increased melanosomes in cytoplasm and dendrites of melanocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809794&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809794</a>]</span><br /> -
Paucity of melanosomes in keratinocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809795&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809795</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">
- Normal nails <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/297988008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">297988008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0574760&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0574760</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hair </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Normal hair <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/830002000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">830002000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849203&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849203</a>]</span><br />
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<strong> MUSCLE, SOFT TISSUES </strong>
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- Calcific tendinopathy, early-onset (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3809782&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3809782</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Skin lesions manifest in the first year of life<br /> -
Hair, teeth, and nails are normal<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the ectonucleotide pyrophosphatase/phosphodiesterase-1 gene (ENPP1, <a href="/entry/173335#0020">173335.0020</a>)<br />
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<p>A number sign (#) is used with this entry because of evidence that Cole disease (COLED) is caused by heterozygous mutation in the ENPP1 gene (<a href="/entry/173335">173335</a>) on chromosome 6q23.</p>
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<p>Cole disease (COLED) is a rare autosomal dominant disorder characterized by congenital or early-onset punctate keratoderma associated with irregularly shaped hypopigmented macules, which are typically found over the arms and legs but not the trunk or acral regions. Skin biopsies of palmoplantar lesions show nonspecific changes including hyperorthokeratosis, hypergranulosis, and acanthosis. Hypopigmented areas of skin, however, reveal a reduction in melanin content in keratinocytes but not in melanocytes, as well as hyperkeratosis and a normal number of melanocytes. Ultrastructurally, melanocytes show a disproportionately large number of melanosomes in the cytoplasm and dendrites, whereas keratinocytes show a paucity of these organelles, suggestive of impaired melanosome transfer (summary by <a href="#2" class="mim-tip-reference" title="Eytan, O., Morice-Picard, F., Sarig, O., Ezzedine, K., Isakov, O., Li, Q., Ishida-Yamamoto, A., Shomron, N., Goldsmith, T., Fuchs-Telem, D., Adir, N., Uitto, J., Orlow, S. J., Taieb, A., Sprecher, E. &lt;strong&gt;Cole disease results from mutations in ENPP1.&lt;/strong&gt; Am. J. Hum. Genet. 93: 752-757, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24075184/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24075184&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24075184[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2013.08.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24075184">Eytan et al., 2013</a>). Some patients also exhibit calcinosis cutis or early-onset calcific tendinopathy (<a href="#2" class="mim-tip-reference" title="Eytan, O., Morice-Picard, F., Sarig, O., Ezzedine, K., Isakov, O., Li, Q., Ishida-Yamamoto, A., Shomron, N., Goldsmith, T., Fuchs-Telem, D., Adir, N., Uitto, J., Orlow, S. J., Taieb, A., Sprecher, E. &lt;strong&gt;Cole disease results from mutations in ENPP1.&lt;/strong&gt; Am. J. Hum. Genet. 93: 752-757, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24075184/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24075184&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24075184[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2013.08.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24075184">Eytan et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24075184" 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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<strong>Clinical Features</strong>
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<p><a href="#1" class="mim-tip-reference" title="Cole, L. A. &lt;strong&gt;Hypopigmentation with punctate keratosis of the palms and soles.&lt;/strong&gt; Arch. Derm. 112: 998-1000, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/132904/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;132904&lt;/a&gt;]" pmid="132904">Cole (1976)</a> reported a family in which 6 members over 3 generations had a diffuse variegated pattern of hypopigmentation affecting almost the entire body; all affected members also had punctate keratosis of the palms and soles. The proband was an 18-year-old man who developed a diffuse irregular macular speckled pattern of hypopigmentation at 6 months of age, which remained unchanged and asymptomatic thereafter. Keratotic papules on his palms and soles were first noted at 3 years of age and also remained asymptomatic. Examination revealed moderately dark pigmented normal skin with sharply demarcated irregular macules showing varying degrees of hypopigmentation scattered diffusely over most of the body, with relative sparing of the acral portions of the body, including the head, neck, nipples, elbows, knees, genitalia, hands, and feet; there was no correspondence to a vascular or dermatomal pattern. The hypopigmented areas ranged in size from 1 to 15 mm in diameter, and many of the macules had small 1- to 2-mm islands of darker pigmentation within them. In addition, numerous flat-topped hypopigmented keratotic papules were present on the palms, soles, and dorsolateral aspects of the fingers and toes, varying from 2 to 6 mm in diameter; the papules did not seem to be concentrated over areas of trauma. Mucous membranes, irides, hair, teeth, and nails were all normal. The proband reported that his mother, maternal grandfather, and 3 brothers were similarly affected, although none of the family members were available for examination. Skin biopsy of hypopigmented skin showed focal areas of mild elongation of the rete ridges, with abundant melanin granules in the basal cell layer and other layers of the epidermis, and occasional small collections of melanophages in the upper dermis. The proband's normal skin showed a slight increase in melanin pigment in the basal cell layer, but was otherwise histologically similar to the hypopigmented skin. Biopsy of a palmar papule showed hyperkeratosis overlying a cup-shaped depression in the epidermis. Mild hypergranulosis and acanthosis was present, with an occasional melanocyte in the basal cell layer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=132904" 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="Moore, M. M., Orlow, S. J., Kamino, H., Wang, N., Schaffer, J. V. &lt;strong&gt;Cole disease: guttate hypopigmentation and punctate palmoplantar keratoderma.&lt;/strong&gt; Arch. Derm. 145: 495-497, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19380683/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19380683&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archdermatol.2009.54&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19380683">Moore et al. (2009)</a> described a 2-year-old boy with congenital guttate hypopigmentation on the extremities as well as asymptomatic papules on the soles that first appeared at 3 months of age. There was no family history of similar skin lesions. Examination revealed irregularly shaped 2- to 10-mm hypopigmented macules on the extremities and scattered 2- to 8-mm pinkish-yellow keratotic papules on the soles. Hair, teeth, and nails were normal. Biopsy of hypopigmented skin showed patchy hypomelanosis and normal melanocyte density with rare melanophages in the papillary dermis. Biopsy of the largest plantar papule showed orthokeratosis and acanthosis, with small deposits of calcium in the papillary dermis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19380683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Eytan, O., Morice-Picard, F., Sarig, O., Ezzedine, K., Isakov, O., Li, Q., Ishida-Yamamoto, A., Shomron, N., Goldsmith, T., Fuchs-Telem, D., Adir, N., Uitto, J., Orlow, S. J., Taieb, A., Sprecher, E. &lt;strong&gt;Cole disease results from mutations in ENPP1.&lt;/strong&gt; Am. J. Hum. Genet. 93: 752-757, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24075184/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24075184&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24075184[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2013.08.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24075184">Eytan et al. (2013)</a> reviewed the clinical data for affected members of 2 multiplex French families who had hypopigmented macules primarily over the extremities and hyperkeratotic papules of the palms and soles. In addition to skin manifestations, 2 affected individuals from the first family exhibited early-onset calcific tendinopathy of the shoulders, wrists, hips, and heels, and 1 of the patients also had microcalcifications on mammography and a large splenic calcification. In the second family, 1 of the patients demonstrated calcinosis cutis. Serum phosphate and fasting glucose levels were normal in the patients tested. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24075184" 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 inheritance pattern of Cole disease in 2 French families studied by <a href="#2" class="mim-tip-reference" title="Eytan, O., Morice-Picard, F., Sarig, O., Ezzedine, K., Isakov, O., Li, Q., Ishida-Yamamoto, A., Shomron, N., Goldsmith, T., Fuchs-Telem, D., Adir, N., Uitto, J., Orlow, S. J., Taieb, A., Sprecher, E. &lt;strong&gt;Cole disease results from mutations in ENPP1.&lt;/strong&gt; Am. J. Hum. Genet. 93: 752-757, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24075184/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24075184&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24075184[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2013.08.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24075184">Eytan et al. (2013)</a> was autosomal dominant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24075184" 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 French families with hypopigmented macules primarily over the extremities and hyperkeratotic papules of the palms and soles, as well as in a similarly affected family described by <a href="#3" class="mim-tip-reference" title="Moore, M. M., Orlow, S. J., Kamino, H., Wang, N., Schaffer, J. V. &lt;strong&gt;Cole disease: guttate hypopigmentation and punctate palmoplantar keratoderma.&lt;/strong&gt; Arch. Derm. 145: 495-497, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19380683/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19380683&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archdermatol.2009.54&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19380683">Moore et al. (2009)</a>, <a href="#2" class="mim-tip-reference" title="Eytan, O., Morice-Picard, F., Sarig, O., Ezzedine, K., Isakov, O., Li, Q., Ishida-Yamamoto, A., Shomron, N., Goldsmith, T., Fuchs-Telem, D., Adir, N., Uitto, J., Orlow, S. J., Taieb, A., Sprecher, E. &lt;strong&gt;Cole disease results from mutations in ENPP1.&lt;/strong&gt; Am. J. Hum. Genet. 93: 752-757, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24075184/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24075184&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24075184[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2013.08.007&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24075184">Eytan et al. (2013)</a> performed whole-exome capture and next-generation sequencing and identified 3 different heterozygous missense mutations in the ENPP1 gene (<a href="/entry/173335#0020">173335.0020</a>-<a href="/entry/173335#0022">173335.0022</a>) that segregated with disease in each family, respectively. All 3 mutations involved highly conserved cysteine residues in the somatomedin-B-like-2 (SMB2) domain of ENPP1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19380683+24075184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="Cole1976" class="mim-anchor"></a>
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Cole, L. A.
<strong>Hypopigmentation with punctate keratosis of the palms and soles.</strong>
Arch. Derm. 112: 998-1000, 1976.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/132904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">132904</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=132904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Eytan, O., Morice-Picard, F., Sarig, O., Ezzedine, K., Isakov, O., Li, Q., Ishida-Yamamoto, A., Shomron, N., Goldsmith, T., Fuchs-Telem, D., Adir, N., Uitto, J., Orlow, S. J., Taieb, A., Sprecher, E.
<strong>Cole disease results from mutations in ENPP1.</strong>
Am. J. Hum. Genet. 93: 752-757, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24075184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24075184</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24075184[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24075184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ajhg.2013.08.007" target="_blank">Full Text</a>]
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Moore, M. M., Orlow, S. J., Kamino, H., Wang, N., Schaffer, J. V.
<strong>Cole disease: guttate hypopigmentation and punctate palmoplantar keratoderma.</strong>
Arch. Derm. 145: 495-497, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19380683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19380683</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19380683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1001/archdermatol.2009.54" target="_blank">Full Text</a>]
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<h3>
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<strong>#</strong> 615522
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<span class="mim-font">
COLE DISEASE; COLED
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
GUTTATE HYPOPIGMENTATION AND PUNCTATE PALMOPLANTAR KERATODERMA WITH OR WITHOUT ECTOPIC CALCIFICATION
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<strong>SNOMEDCT:</strong> 711154007; &nbsp;
<strong>ORPHA:</strong> 324561; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
6q23.2
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Cole disease
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615522
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Autosomal dominant
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3
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ENPP1
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173335
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that Cole disease (COLED) is caused by heterozygous mutation in the ENPP1 gene (173335) on chromosome 6q23.</p>
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<strong>Description</strong>
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<p>Cole disease (COLED) is a rare autosomal dominant disorder characterized by congenital or early-onset punctate keratoderma associated with irregularly shaped hypopigmented macules, which are typically found over the arms and legs but not the trunk or acral regions. Skin biopsies of palmoplantar lesions show nonspecific changes including hyperorthokeratosis, hypergranulosis, and acanthosis. Hypopigmented areas of skin, however, reveal a reduction in melanin content in keratinocytes but not in melanocytes, as well as hyperkeratosis and a normal number of melanocytes. Ultrastructurally, melanocytes show a disproportionately large number of melanosomes in the cytoplasm and dendrites, whereas keratinocytes show a paucity of these organelles, suggestive of impaired melanosome transfer (summary by Eytan et al., 2013). Some patients also exhibit calcinosis cutis or early-onset calcific tendinopathy (Eytan et al., 2013). </p>
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<strong>Clinical Features</strong>
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<p>Cole (1976) reported a family in which 6 members over 3 generations had a diffuse variegated pattern of hypopigmentation affecting almost the entire body; all affected members also had punctate keratosis of the palms and soles. The proband was an 18-year-old man who developed a diffuse irregular macular speckled pattern of hypopigmentation at 6 months of age, which remained unchanged and asymptomatic thereafter. Keratotic papules on his palms and soles were first noted at 3 years of age and also remained asymptomatic. Examination revealed moderately dark pigmented normal skin with sharply demarcated irregular macules showing varying degrees of hypopigmentation scattered diffusely over most of the body, with relative sparing of the acral portions of the body, including the head, neck, nipples, elbows, knees, genitalia, hands, and feet; there was no correspondence to a vascular or dermatomal pattern. The hypopigmented areas ranged in size from 1 to 15 mm in diameter, and many of the macules had small 1- to 2-mm islands of darker pigmentation within them. In addition, numerous flat-topped hypopigmented keratotic papules were present on the palms, soles, and dorsolateral aspects of the fingers and toes, varying from 2 to 6 mm in diameter; the papules did not seem to be concentrated over areas of trauma. Mucous membranes, irides, hair, teeth, and nails were all normal. The proband reported that his mother, maternal grandfather, and 3 brothers were similarly affected, although none of the family members were available for examination. Skin biopsy of hypopigmented skin showed focal areas of mild elongation of the rete ridges, with abundant melanin granules in the basal cell layer and other layers of the epidermis, and occasional small collections of melanophages in the upper dermis. The proband's normal skin showed a slight increase in melanin pigment in the basal cell layer, but was otherwise histologically similar to the hypopigmented skin. Biopsy of a palmar papule showed hyperkeratosis overlying a cup-shaped depression in the epidermis. Mild hypergranulosis and acanthosis was present, with an occasional melanocyte in the basal cell layer. </p><p>Moore et al. (2009) described a 2-year-old boy with congenital guttate hypopigmentation on the extremities as well as asymptomatic papules on the soles that first appeared at 3 months of age. There was no family history of similar skin lesions. Examination revealed irregularly shaped 2- to 10-mm hypopigmented macules on the extremities and scattered 2- to 8-mm pinkish-yellow keratotic papules on the soles. Hair, teeth, and nails were normal. Biopsy of hypopigmented skin showed patchy hypomelanosis and normal melanocyte density with rare melanophages in the papillary dermis. Biopsy of the largest plantar papule showed orthokeratosis and acanthosis, with small deposits of calcium in the papillary dermis. </p><p>Eytan et al. (2013) reviewed the clinical data for affected members of 2 multiplex French families who had hypopigmented macules primarily over the extremities and hyperkeratotic papules of the palms and soles. In addition to skin manifestations, 2 affected individuals from the first family exhibited early-onset calcific tendinopathy of the shoulders, wrists, hips, and heels, and 1 of the patients also had microcalcifications on mammography and a large splenic calcification. In the second family, 1 of the patients demonstrated calcinosis cutis. Serum phosphate and fasting glucose levels were normal in the patients tested. </p>
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<strong>Inheritance</strong>
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<p>The inheritance pattern of Cole disease in 2 French families studied by Eytan et al. (2013) was autosomal dominant. </p>
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<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
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<p>In 2 French families with hypopigmented macules primarily over the extremities and hyperkeratotic papules of the palms and soles, as well as in a similarly affected family described by Moore et al. (2009), Eytan et al. (2013) performed whole-exome capture and next-generation sequencing and identified 3 different heterozygous missense mutations in the ENPP1 gene (173335.0020-173335.0022) that segregated with disease in each family, respectively. All 3 mutations involved highly conserved cysteine residues in the somatomedin-B-like-2 (SMB2) domain of ENPP1. </p>
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<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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<div>
<ol>
<li>
<p class="mim-text-font">
Cole, L. A.
<strong>Hypopigmentation with punctate keratosis of the palms and soles.</strong>
Arch. Derm. 112: 998-1000, 1976.
[PubMed: 132904]
</p>
</li>
<li>
<p class="mim-text-font">
Eytan, O., Morice-Picard, F., Sarig, O., Ezzedine, K., Isakov, O., Li, Q., Ishida-Yamamoto, A., Shomron, N., Goldsmith, T., Fuchs-Telem, D., Adir, N., Uitto, J., Orlow, S. J., Taieb, A., Sprecher, E.
<strong>Cole disease results from mutations in ENPP1.</strong>
Am. J. Hum. Genet. 93: 752-757, 2013.
[PubMed: 24075184]
[Full Text: https://doi.org/10.1016/j.ajhg.2013.08.007]
</p>
</li>
<li>
<p class="mim-text-font">
Moore, M. M., Orlow, S. J., Kamino, H., Wang, N., Schaffer, J. V.
<strong>Cole disease: guttate hypopigmentation and punctate palmoplantar keratoderma.</strong>
Arch. Derm. 145: 495-497, 2009.
[PubMed: 19380683]
[Full Text: https://doi.org/10.1001/archdermatol.2009.54]
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