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<title>
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- #264800 - PSEUDOXANTHOMA ELASTICUM; PXE
- OMIM
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<span class="h4">#264800</span>
<br />
<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/264800"><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="#diagnosis">Diagnosis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
</li>
<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=PSEUDOXANTHOMA ELASTICUM" 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://medlineplus.gov/genetics/condition/pseudoxanthoma-elasticum" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
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</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:2738" 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>
<div><a href="http://www.informatics.jax.org/disease/264800" 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>
<div><a href="https://wormbase.org/resources/disease/DOID:2738" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
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<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:264800" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
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<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;
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<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> 252246005, 72744008<br />
<strong>ORPHA:</strong> 758<br />
<strong>DO:</strong> 2738<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>
264800
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
PSEUDOXANTHOMA ELASTICUM; PXE
</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">
GRONBLAD-STRANDBERG SYNDROME
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
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<div>
<span class="h3 mim-font">
PSEUDOXANTHOMA ELASTICUM, MODIFIER OF SEVERITY OF, INCLUDED
</span>
</div>
<div>
<span class="h4 mim-font">
PXE, MODIFIER OF SEVERITY OF, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/223?start=-3&limit=10&highlight=223">
16p13.11
</a>
</span>
</td>
<td>
<span class="mim-font">
Pseudoxanthoma elasticum
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/264800"> 264800 </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">
ABCC6
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603234"> 603234 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/229?start=-3&limit=10&highlight=229">
16p12.3
</a>
</span>
</td>
<td>
<span class="mim-font">
{Pseudoxanthoma elasticum, modifier of severity of}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/264800"> 264800 </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">
XYLT1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608124"> 608124 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/737?start=-3&limit=10&highlight=737">
17q21.33
</a>
</span>
</td>
<td>
<span class="mim-font">
{Pseudoxanthoma elasticum, modifier of severity of}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/264800"> 264800 </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">
XYLT2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608125"> 608125 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
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<div class="btn-group ">
<a href="/clinicalSynopsis/264800" 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')">
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&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/264800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/264800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p />
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Peau d'orange retinal changes (yellow-mottled retinal hyperpigmentation) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849601&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849601</a>]</span><br /> -
Angioid streaks of the retina (85% of patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002982&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002982</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001102" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001102</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001102" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001102</a>]</span><br /> -
Macular degeneration <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422338006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422338006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267718000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267718000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H35.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H35.30</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/362.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">362.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242383&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242383</a>, <a href="https://bioportal.bioontology.org/search?q=C0024437&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024437</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000608" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000608</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000608" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000608</a>]</span><br /> -
Visual impairment (50-70% of patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246635007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246635007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7973008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7973008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397540003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397540003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042798</a>, <a href="https://bioportal.bioontology.org/search?q=C3665347&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3665347</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000505" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000505</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000505" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000505</a>]</span><br /> -
Central vision loss <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38950008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38950008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H53.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H53.41</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/368.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">368.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0152191&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0152191</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000603" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000603</a>]</span><br /> -
Colloid bodies <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18695008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18695008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0333440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0333440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025115" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025115</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025115" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025115</a>]</span><br /> -
Retinal hemorrhage <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28998008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28998008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H35.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H35.6</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H35.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H35.60</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/362.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">362.81</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0035317&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035317</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000573" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000573</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000573" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000573</a>]</span><br /> -
Choroidal neovascularization <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0600518&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0600518</a>, <a href="https://bioportal.bioontology.org/search?q=C5574745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5574745</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011506" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011506</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011506" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011506</a>]</span><br /> -
Macular degeneration <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422338006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422338006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267718000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267718000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H35.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H35.30</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/362.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">362.50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242383&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242383</a>, <a href="https://bioportal.bioontology.org/search?q=C0024437&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024437</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000608" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000608</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000608" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000608</a>]</span><br /> -
Optic head drusen (yellowish-white irregularities of optic disc) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849604&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849604</a>]</span><br /> -
Owl's eyes (paired hyperpigmented spots) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849605</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Mouth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Mucosal PXE lesions (inner aspect lower lip, cheeks, and palate) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849606&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849606</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Congestive heart failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42343007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42343007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I50.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/428.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">428.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018802&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018802</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001635" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001635</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001635" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001635</a>]</span><br /> -
Calcifications (atrial and ventricular endocardium) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849615&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849615</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18115005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18115005</a>]</span><br /> -
Mitral valve prolapse (uncommon) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/409712001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">409712001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8074002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8074002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026267&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026267</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001634" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001634</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001634" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001634</a>]</span><br /> -
Mitral valve stenosis (uncommon) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/79619009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">79619009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86466006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86466006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I05.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I05.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/394.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">394.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0264766&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0264766</a>, <a href="https://bioportal.bioontology.org/search?q=C0026269&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026269</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001718</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001718</a>]</span><br /> -
Restrictive cardiomyopathy (very rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/415295002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">415295002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/90828009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">90828009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I42.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I42.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0007196&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007196</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001723" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001723</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001723" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001723</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Accelerated atherosclerosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849618&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849618</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004943</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004943</a>]</span><br /> -
Coronary artery disease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/414024009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">414024009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/443502000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">443502000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/53741008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">53741008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I25.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I25.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K76.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K76.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I25.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I25.10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/414.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">414.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1956346&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1956346</a>, <a href="https://bioportal.bioontology.org/search?q=C0010054&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010054</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001677</a>]</span><br /> -
Angina pectoris <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/194828000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">194828000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/225566008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">225566008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I20.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I20.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/413" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">413</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002962&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002962</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001681" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001681</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001681" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001681</a>]</span><br /> -
Intermittent claudication (30%) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/63491006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">63491006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I73.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I73.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021775&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021775</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004417" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004417</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004417" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004417</a>]</span><br /> -
Renovascular hypertension (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/123799005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">123799005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I15.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I15.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020545&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020545</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100817" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100817</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100817" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100817</a>]</span><br /> -
Absent peripheral pulses <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/301161008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">301161008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0577850&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0577850</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
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<strong> ABDOMEN </strong>
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<em> Gastrointestinal </em>
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- Gastrointestinal hemorrhage <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74474003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74474003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K92.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K92.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/578" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">578</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/578.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">578.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0017181&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017181</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002239" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002239</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002239" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002239</a>]</span><br />
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<strong> GENITOURINARY </strong>
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<em> Internal Genitalia (Female) </em>
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- Uterine hemorrhage <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042134</a>]</span><br />
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<em> Kidneys </em>
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- Renal failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/42399005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">42399005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N19" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N19</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/586" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">586</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0035078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0035078</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000083" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000083</a>]</span><br />
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<em> Bladder </em>
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- Bladder hemorrhage <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197887003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197887003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N32.89" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N32.89</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0341750&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0341750</a>]</span><br />
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<strong> SKIN, NAILS, & HAIR </strong>
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<em> Skin </em>
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- Progression of skin lesions - <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849607&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849607</a>]</span><br /> -
1. yellowish, flat papules (neck, antecubital and popliteal fossae, axillae, inguinal, and periumbilical areas) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849608&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849608</a>]</span><br /> -
2. yellowish, flat plaques <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849609&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849609</a>]</span><br /> -
3. lax, wrinkled skin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849610&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849610</a>]</span><br /> -
Extrusion of calcium deposits ('perforating PXE') <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849611&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849611</a>]</span><br /> -
Acneiform lesions (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3550509&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3550509</a>]</span><br /> -
Chronic granulomatous nodules (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849613&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849613</a>]</span><br /> -
Brown macules in a reticulate pattern (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849614&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849614</a>]</span><br />
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<strong> NEUROLOGIC </strong>
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<em> Central Nervous System </em>
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- Stroke <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/230690007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">230690007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I63.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I63.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038454&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038454</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001297" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001297</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Incidence - 1 in 25,000-100,000<br /> -
Sex ratio - 2 females to 1 male<br /> -
Majority of cases diagnosed at age 10-15 years<br /> -
See <a href="/entry/177850">177850</a> for description of heterozygous phenotype<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutations in the ATP-binding cassette, subfamily C, member 6 gene (ABCC6, <a href="/entry/603234#0001">603234.0001</a>)<br />
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because in the overwhelming majority of cases of pseudoxanthoma elasticum (PXE), homozygous or compound heterozygous mutations are found in the ABCC6 gene (<a href="/entry/603234">603234</a>), i.e., PXE is an autosomal recessive disorder. However, carriers of heterozygous mutation in ABCC6 manifest partial manifestations of the disorder (<a href="/entry/177850">177850</a>). It is thought that instances in which the disease occurs in 2 generations can be attributed to pseudodominance (<a href="#8" class="mim-tip-reference" title="Bergen, A. A. B. &lt;strong&gt;Pseudoxanthoma elasticum: the end of the autosomal dominant segregation myth. (Commentary)&lt;/strong&gt; J. Invest. Derm. 126: 704-705, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16541094/&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;16541094&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.jid.5700129&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="16541094">Bergen, 2006</a>; <a href="#55" class="mim-tip-reference" title="Ringpfeil, F., McGuigan, K., Fuchsel, L., Kozic, H., Larralde, M., Lebwohl, M., Uitto, J. &lt;strong&gt;Pseudoxanthoma elasticum is a recessive disease characterized by compound heterozygosity.&lt;/strong&gt; J. Invest. Derm. 126: 782-786, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16410789/&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;16410789&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.jid.5700115&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="16410789">Ringpfeil et al., 2006</a>; <a href="#13" class="mim-tip-reference" title="Chassaing, N., Martin, L., Calvas, P., Le Bert, M., Hovnanian, A. &lt;strong&gt;Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations.&lt;/strong&gt; J. Med. Genet. 42: 881-892, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15894595/&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;15894595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2004.030171&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="15894595">Chassaing et al., 2005</a>; <a href="#43" class="mim-tip-reference" title="Miksch, S., Lumsden, A., Guenther, U. P., Foernzler, D., Christen-Zach, S., Daugherty, C., Ramesar, R. S., Lebwohl, M., Hohl, D., Neldner, K. H., Lindpaintner, K., Richards, R. I., Struk, B. &lt;strong&gt;Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.&lt;/strong&gt; Hum. Mutat. 26: 235-248, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16086317/&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;16086317&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20206&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="16086317">Miksch et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16086317+16541094+15894595+16410789" 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>Polymorphisms in the genes encoding xylosyltransferase, XYLT1 (<a href="/entry/608124">608124</a>) and XYLT2 (<a href="/entry/608125">608125</a>), have been reported to modify the severity of PXE.</p>
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<strong>Description</strong>
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<p>Pseudoxanthoma elasticum is an inherited multisystem disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Bruch membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye, including peau d'orange, angioid streaks, and choroidal neovascularizations (CNVs); of the skin, including soft, ivory colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces; and of the cardiovascular system, with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings (summary by <a href="#20" class="mim-tip-reference" title="Finger, R. P., Charbel Issa, P., Ladewig, M. S., Gotting, C., Szliska, C., Scholl, H. P. N., Holz, F. G. &lt;strong&gt;Pseudoxanthoma elasticum: genetics, clinical manifestations and therapeutic approaches.&lt;/strong&gt; Surv. Ophthal. 54: 272-285, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19298904/&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;19298904&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.survophthal.2008.12.006&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="19298904">Finger et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19298904" 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>Generalized arterial calcification of infancy-2 (GACI2; <a href="/entry/614473">614473</a>) is an allelic disorder, also caused by homozygous or compound heterozygous mutation in the ABCC6 gene; it has been suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders (<a href="#46" class="mim-tip-reference" title="Nitschke, Y., Baujat, G., Botschen, U., Wittkampf, T., du Moulin, M., Stella, J., Le Merrer, M., Guest, G., Lambot, K., Tazarourte-Pinturier, M.-F., Chassaing, N., Roche, O., and 19 others. &lt;strong&gt;Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.&lt;/strong&gt; Am. J. Hum. Genet. 90: 25-39, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22209248/&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;22209248&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22209248[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.2011.11.020&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="22209248">Nitschke et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22209248" 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="#53" class="mim-tip-reference" title="Rigal, (NI). &lt;strong&gt;Observation pour servir a l&#x27;histoire de la cheloide diffuse xanthelasmique.&lt;/strong&gt; Ann. Derm. Syph. 21: 491-501, 1881."None>Rigal (1881)</a> is credited with the first description of the skin changes in PXE, and <a href="#5" class="mim-tip-reference" title="Balzer, F. &lt;strong&gt;Recherches sur les caracteres anatomiques du xanthelasma.&lt;/strong&gt; Arch. Physiol. 4: 65-80, 1884."None>Balzer (1884)</a> provided the first autopsy report. The term 'pseudoxanthoma elasticum' was established by <a href="#17" class="mim-tip-reference" title="Darier, J. &lt;strong&gt;Pseudoxanthoma elasticum.&lt;/strong&gt; Monatshefte Prakt. Derm. 23: 609-617, 1896."None>Darier (1896)</a>, who histologically demonstrated an abnormality in elastin. <a href="#25" class="mim-tip-reference" title="Gronblad, E. &lt;strong&gt;Angioid streaks--pseudoxanthoma elasticum.&lt;/strong&gt; Acta Ophthal. 7: 329 only, 1929."None>Gronblad (1929)</a>, a Swedish ophthalmologist, and <a href="#60" class="mim-tip-reference" title="Strandberg, J. &lt;strong&gt;Pseudoxanthoma elasticum.&lt;/strong&gt; Z. Haut Geschlechtskr. 31: 689 only, 1929."None>Strandberg (1929)</a>, a Swedish dermatologist, established the relationship of PXE and angioid streaks in the retina (<a href="#40" class="mim-tip-reference" title="McKusick, V. A. &lt;strong&gt;Heritable Disorders of Connective Tissue. (4th ed.)&lt;/strong&gt; St. Louis: C. V. Mosby (pub.) 1972. Pp. 475-520."None>McKusick, 1972</a>).</p><p><a href="#23" class="mim-tip-reference" title="Goodman, R. M., Smith, E. W., Paton, D., Bergman, R. A., Siegel, C. L., Ottesen, O. E., Shelley, W. M., Pusch, A. L., McKusick, V. A. &lt;strong&gt;Pseudoxanthoma elasticum: a clinical and histopathological study.&lt;/strong&gt; Medicine 42: 297-334, 1963.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14068068/&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;14068068&lt;/a&gt;]" pmid="14068068">Goodman et al. (1963)</a> provided a detailed clinical and histopathologic study of 12 patients with PXE. They noted that the condition had been referred to by several different names since it was first described in 1881. Eight of 12 patients noted skin changes since early childhood, usually on the neck and in the axilla. Changes included accentuated fine lines, redundant skin folds, and lesions consisting of yellowish papules or plaques. Skin changes were also present in the inguinal folds, antecubital and popliteal spaces, and oral, rectal, and vaginal mucosa. Ocular involvement included pigmentary changes, angioid streaks, chorioretinal scarring, and some loss of vision. Five of the 12 patients had gastrointestinal bleeding. Arteriography demonstrated narrowing or occlusion of peripheral arteries with marked collateral circulation, particularly in the upper extremities. Histopathologic studies of skin, heart, and vessels showed calcium deposition in elastic fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14068068" 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="Cartwright, E., Danks, D. M., Jack, I. &lt;strong&gt;Metachromatic fibroblasts in pseudoxanthoma elasticum and Marfan&#x27;s syndrome. (Letter)&lt;/strong&gt; Lancet 293: 533-534, 1969. Note: Originally Volume I.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4179610/&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;4179610&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(69)91634-1&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="4179610">Cartwright et al. (1969)</a> described metachromatic fibroblasts in PXE. By electron microscopy, <a href="#57" class="mim-tip-reference" title="Ross, R., Fialkow, P. J., Altman, L. K. &lt;strong&gt;Fine structure alterations of elastic fibers in pseudoxanthoma elasticum.&lt;/strong&gt; Clin. Genet. 13: 213-223, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/627111/&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;627111&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1978.tb04252.x&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="627111">Ross et al. (1978)</a> demonstrated that the changes in elastic fibers in individuals with PXE involve elastin whereas the microfibrillar component is unchanged. The elastin had a granular appearance, an increased affinity for cations, and often demonstrated increased density presumed to represent foci of calcification. Similar changes were found in clinically unaffected relatives. In 3 families the inheritance was consistent with the autosomal recessive mode and 1 of the presumed heterozygotes showed electron microscopic changes. In 1 kindred (reported also by <a href="#4" class="mim-tip-reference" title="Altman, L. K., Fialkow, P. J., Parker, F., Sagebiel, R. W. &lt;strong&gt;Pseudoxanthoma elasticum: an underdiagnosed genetically heterogeneous disorder with protean manifestations.&lt;/strong&gt; Arch. Intern. Med. 134: 1048-1054, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4433185/&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;4433185&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archinte.134.6.1048&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="4433185">Altman et al., 1974</a>), the inheritance was apparently more complex than either autosomal dominant or recessive. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4433185+627111+4179610" 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="#40" class="mim-tip-reference" title="McKusick, V. A. &lt;strong&gt;Heritable Disorders of Connective Tissue. (4th ed.)&lt;/strong&gt; St. Louis: C. V. Mosby (pub.) 1972. Pp. 475-520."None>McKusick (1972)</a> presented autopsy findings of endocardial thickening in PXE with degeneration and calcification of elastic fibers and with collagenosis similar to that seen in the skin. Reviewing some of the same autopsy cases, <a href="#41" class="mim-tip-reference" title="Mendelsohn, G., Bulkley, B. H., Hutchins, G. M. &lt;strong&gt;Cardiovascular manifestations of pseudoxanthoma elasticum.&lt;/strong&gt; Arch. Path. Lab. Med. 102: 298-302, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/580722/&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;580722&lt;/a&gt;]" pmid="580722">Mendelsohn et al. (1978)</a> emphasized the severe atherosclerosis present in all, resembling that encountered routinely. Fragmentation and degeneration of the elastic laminae of muscular arteries was followed by vascular calcification which could not be distinguished morphologically from Monckeberg arteriosclerosis. There was striking intimal fibroelastotic thickening, particularly in intrarenal arteries. Like <a href="#40" class="mim-tip-reference" title="McKusick, V. A. &lt;strong&gt;Heritable Disorders of Connective Tissue. (4th ed.)&lt;/strong&gt; St. Louis: C. V. Mosby (pub.) 1972. Pp. 475-520."None>McKusick (1972)</a>, <a href="#41" class="mim-tip-reference" title="Mendelsohn, G., Bulkley, B. H., Hutchins, G. M. &lt;strong&gt;Cardiovascular manifestations of pseudoxanthoma elasticum.&lt;/strong&gt; Arch. Path. Lab. Med. 102: 298-302, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/580722/&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;580722&lt;/a&gt;]" pmid="580722">Mendelsohn et al. (1978)</a> emphasized the striking endocardial changes, e.g., in the right atrium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=580722" 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="Elejalde, B. R., Mercedes de Elejalde, M., Samter, T., Burgess, J., Lombardi, J., Gilbert, E. F. &lt;strong&gt;Manifestations of pseudoxanthoma elasticum during pregnancy: a case report and review of the literature.&lt;/strong&gt; Am. J. Med. Genet. 18: 755-762, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6385710/&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;6385710&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320180422&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="6385710">Elejalde et al. (1984)</a> described a 30-year-old woman with PXE who was followed during pregnancy with several fetal ultrasonographic examinations; these showed normal development up to week 26, followed by a marked deceleration of fetal growth. The ultrasonographic appearance of the placenta was abnormal at all times. The baby, born after 36 weeks, was small for gestational age due probably to placental abnormality: the cotyledons were small and more numerous than normal; one-third of the placenta was hypoplastic or atrophic with focal calcification; and striking abnormalities of the elastic lamellae were found in the maternal vessels. <a href="#21" class="mim-tip-reference" title="Fournier, D. &lt;strong&gt;Le pseudoxanthome elastique, un syndrome meconnu: a propos d&#x27;une observation clinique et genetique.&lt;/strong&gt; Schweiz. Rundsch. Med. Prax. 73: 183-191, 1984.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6701427/&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;6701427&lt;/a&gt;]" pmid="6701427">Fournier (1984)</a> reported a well-studied patient with PXE from an isolate in the Swiss Valais canton and by genealogic research demonstrated relatedness of several affected families in the region. Livedo reticularis and microaneurysms of intrarenal arteries were observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6385710+6701427" 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="#12" class="mim-tip-reference" title="Challenor, V. F., Conway, N., Monro, J. L. &lt;strong&gt;The surgical treatment of restrictive cardiomyopathy in pseudoxanthoma elasticum.&lt;/strong&gt; Brit. Heart J. 59: 266-269, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3342167/&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;3342167&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/hrt.59.2.266&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="3342167">Challenor et al. (1988)</a> described a 27-year-old man with PXE who presented with pulmonary edema resulting from restrictive left ventricular cardiomyopathy caused by calcified endocardial bands. The bands were resected as far as possible and the involved mitral valve was replaced by a heterograft. A year later calcification of the heterograft forced its replacement by a St. Jude prosthesis. Relief of symptoms was satisfactory. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3342167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Fukuda, K., Uno, K., Fujii, T., Mukai, M., Handa, S. &lt;strong&gt;Mitral stenosis in pseudoxanthoma elasticum.&lt;/strong&gt; Chest 101: 1706-1707, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1600795/&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;1600795&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1378/chest.101.6.1706&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="1600795">Fukuda et al. (1992)</a> described a 54-year-old woman with PXE who over a year of observation developed tight mitral stenosis without regurgitation after having moderate mitral regurgitation due to mitral valve prolapse. Endocardial changes of characteristic type were demonstrated by myocardial biopsy of the right ventricle. It was thought that the echocardiographic findings differed from those in classic rheumatic mitral stenosis. <a href="#35" class="mim-tip-reference" title="Lebwohl, M., Halperin, J., Phelps, R. G. &lt;strong&gt;Occult pseudoxanthoma elasticum in patients with premature cardiovascular disease.&lt;/strong&gt; New Eng. J. Med. 329: 1237-1239, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8413390/&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;8413390&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199310213291705&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="8413390">Lebwohl et al. (1993)</a> described 4 patients who presented with premature cardiovascular disease and had angioid streaks but no clinically discernible skin changes of PXE. Characteristic fragmentation and clumping of elastic fibers in the middle and deep dermis with calcification of elastic tissue was demonstrated in all 4 patients. Two of the patients were sisters, aged 27 and 39 years. The younger sister had 4-vessel coronary artery bypass surgery. Multiple arterial biopsies showed calcification of the internal elastic laminae. A 41-year-old brother was subsequently found to have angioid streaks. The father, who died at the age of 69, had a history of retinal hemorrhage. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1600795+8413390" 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 nationwide study in South Africa and Zimbabwe, <a href="#63" class="mim-tip-reference" title="Viljoen, D. L., Pope, F. M., Beighton, P. &lt;strong&gt;Heterogeneity of pseudoxanthoma elasticum: delineation of a new form?&lt;/strong&gt; Clin. Genet. 32: 100-105, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3652487/&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;3652487&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1987.tb03333.x&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="3652487">Viljoen et al. (1987)</a> identified 64 patients with PXE. In the opinion of these workers, 39 of the patients comprised a distinct clinical subgroup of PXE characterized by autosomal recessive inheritance and severe visual impairment out of proportion to the degree of involvement of the skin. In 40% of individuals, severe hypertension and occasionally angina or claudication were also present. The 39 affected individuals were found exclusively among persons of Afrikaner descent. <a href="#63" class="mim-tip-reference" title="Viljoen, D. L., Pope, F. M., Beighton, P. &lt;strong&gt;Heterogeneity of pseudoxanthoma elasticum: delineation of a new form?&lt;/strong&gt; Clin. Genet. 32: 100-105, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3652487/&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;3652487&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1987.tb03333.x&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="3652487">Viljoen et al. (1987)</a> noted that the 'Afrikaner' form and other forms of PXE are indistinguishable on histology, electron microscopy, or biochemistry, and that clinical differences may not be significant. For example, <a href="#39" class="mim-tip-reference" title="McKusick, V. A. &lt;strong&gt;Heritable Disorders of Connective Tissue. (2nd ed.)&lt;/strong&gt; St. Louis: C. V. Mosby (pub.) 1960. P. 221. Note: Fig. 78."None>McKusick (1960)</a> had pointed out the occurrence of inconspicuous skin changes despite severe ocular changes. <a href="#18" class="mim-tip-reference" title="De Paepe, A., Viljoen, D., Matton, M., Beighton, P., Lenaerts, V., Vossaert, K., De Bie, S., Voet, D., De Laey, J.-J., Kint, A. &lt;strong&gt;Pseudoxanthoma elasticum: similar autosomal recessive subtype in Belgian and Afrikaner families.&lt;/strong&gt; Am. J. Med. Genet. 38: 16-20, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2012127/&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;2012127&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320380105&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="2012127">De Paepe et al. (1991)</a> reported on the clinical and genetic characteristics of 26 Belgian and 32 Afrikaner families with PXE. The phenotype in both groups was characterized by severe ophthalmologic manifestations with milder, variable cutaneous and vascular symptoms. The authors reiterated the suggestion that the PXE phenotype in these Belgian and Afrikaner families is distinct from previously described PXE phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2012127+3652487" 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>There have been isolated case reports of arterial and skin calcification in mammograms of patients with pseudoxanthoma elasticum, and unpublished anecdotes of many women with PXE undergoing breast biopsy for evaluation of microcalcifications. <a href="#6" class="mim-tip-reference" title="Bercovitch, L., Schepps, B., Koelliker, S., Magro, C., Terry, S., Lebwohl, M. &lt;strong&gt;Mammographic findings in pseudoxanthoma elasticum.&lt;/strong&gt; J. Am. Acad. Derm. 48: 359-366, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12637915/&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;12637915&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1067/mjd.2003.173&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="12637915">Bercovitch et al. (2003)</a> systematically evaluated mammography and breast pathology in 51 women with confirmed PXE and compared them with those of a control sample of 109 women without PXE. Breast density, skin thickening, skin microcalcifications, vascular calcification, breast microcalcifications and macrocalcifications, and masses were evaluated specifically. The PXE and control groups were similar in age and indications for mammography. <a href="#6" class="mim-tip-reference" title="Bercovitch, L., Schepps, B., Koelliker, S., Magro, C., Terry, S., Lebwohl, M. &lt;strong&gt;Mammographic findings in pseudoxanthoma elasticum.&lt;/strong&gt; J. Am. Acad. Derm. 48: 359-366, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12637915/&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;12637915&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1067/mjd.2003.173&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="12637915">Bercovitch et al. (2003)</a> found a statistically significant increase in skin thickening, vascular calcification, and breast microcalcifications in the PXE group (P less than 0.001 each). Breast density, masses, macrocalcifications, and skin calcification did not differ statistically in the 2 groups, but no control patient had axillary calcification, or both vascular calcification and microcalcifications (p less than 0.001). About 1 in 7 of the patients with PXE demonstrated at least 3 of the following: microcalcifications, skin calcifications, vascular calcification, and skin thickening; however, none of the control group did. Histopathologic findings of breast tissue showed calcification of dermal elastic fibers, subcutaneous arteries, and elastic fibers of the deep fascia and interlobular septae of the fat adjacent to breast parenchyma. <a href="#6" class="mim-tip-reference" title="Bercovitch, L., Schepps, B., Koelliker, S., Magro, C., Terry, S., Lebwohl, M. &lt;strong&gt;Mammographic findings in pseudoxanthoma elasticum.&lt;/strong&gt; J. Am. Acad. Derm. 48: 359-366, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12637915/&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;12637915&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1067/mjd.2003.173&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="12637915">Bercovitch et al. (2003)</a> concluded that breast microcalcification and arterial calcification are not rare in the normal population and are not of diagnostic value. However, the presence of both of these findings, especially with skin thickening or axillary skin calcification, should suggest a diagnosis of PXE. The majority of breast calcifications in PXE are benign. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12637915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Orssaud, C., Roche, O., Dufier, J.-L., Germain, D. P. &lt;strong&gt;Visual impairment in pseudoxanthoma elasticum: a survey of 40 patients.&lt;/strong&gt; Ophthalmic Genet. 36: 327-332, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24749718/&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;24749718&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3109/13816810.2014.886268&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="24749718">Orssaud et al. (2015)</a> reviewed the nature and age of onset of ophthalmologic manifestations in 40 consecutive patients with PXE. The mean age of patients was 53.32 years. Best corrected visual acuity (BCVA) was equal to or less than 20/50 in at least 1 eye in 73.3% of patients over the age of 52 and in 20% of patients younger than age 52. Angioid streaks were observed in 38 patients (93.75%). Macular involvement was observed for the first time at a mean age of 44.28 years. Neovascularization was observed in 17 patients (mean age, 51.70 years), all with poor BCVA. The authors noted that in addition to the well-known findings of peau d'orange and comet lesions, other PXE features include chorioretinal atrophy, subretinal fluid independent of CNV, pattern dystrophy-like changes, debris accumulation under the RPE, reticular drusen, and a decreased fluorescence on late-phase indocyanine green angiography. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24749718" 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="#38" class="mim-tip-reference" title="Legrand, A., Cornez, L., Samkari, W., Mazzella, J.-M., Venisse, A., Boccio, V., Auribault, K., Keren, B., Benistan, K., Germain, D. P., Frank, M., Jeunemaitre, X., Albuisson, J. &lt;strong&gt;Mutation spectrum in the ABCC6 gene and genotype-phenotype correlations in a French cohort with pseudoxanthoma elasticum.&lt;/strong&gt; Genet. Med. 19: 909-917, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28102862/&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;28102862&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2016.213&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="28102862">Legrand et al. (2017)</a> performed a molecular analysis on 458 French PXE probands who were clinically evaluated using the Phenodex score (PS). Among the 220 cases with a complete PS score, there was a higher prevalence of eye features in Caucasian patients (p = 0.03) and more severe eye and vascular phenotype in patients with loss-of-function variants (p = 0.02 and 0.05, respectively). Nephrolithiases and strokes, absent from the PS, were prevalent features of the disorder (11% and 10%, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28102862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Intrafamilial Phenotypic Variability</em></strong></p><p>
<a href="#31" class="mim-tip-reference" title="Le Boulanger, G., Labreze, C., Croue, A., Schurgers, L. J., Chassaing, N., Wittkampf, T., Rutsch, F., Martin, L. &lt;strong&gt;An unusual severe vascular case of pseudoxanthoma elasticum presenting as generalized arterial calcification of infancy.&lt;/strong&gt; Am. J. Med. Genet. 152A: 118-123, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20034067/&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;20034067&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33162&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="20034067">Le Boulanger et al. (2010)</a> studied a nonconsanguineous French family in which an older brother developed uncomplicated PXE in adolescence, whereas a younger brother died of a condition 'strikingly reminiscent' of generalized arterial calcification of infancy (GACI2; <a href="/entry/614473">614473</a>) at 15 months of age. The younger brother had a myocardial infarction complicated by heart failure at 6 months of age, and skin biopsy at 1 year of age for evaluation of a possible connective tissue disorder showed elastic fiber dystrophy, with clumped and fragmented fibers in the mid dermis, as well as calcifications on the elastic fibers and sporadically in vessel walls of the subcutis. At 15 months of age, he had a second, fatal MI, and autopsy showed fibrosis of the coronary arteries with calcifications involving the intima, internal elastic lamina, and media. At 28 years of age, the older brother presented for evaluation of yellowish papules on his neck; he had no cardiovascular symptoms and cardiac examination and echocardiography were normal. Skin samples from the brother with PXE showed heavy staining of mineralized mid-dermal elastic fibers, with active MGP (<a href="/entry/154870">154870</a>) and fetuin-A (<a href="/entry/138680">138680</a>) antibodies, and fetuin-A also showed striking staining of the subepidermal area. All arteries in autopsy samples from the brother with GACI showed the same immunohistochemical profile, as well as calcifications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20034067" 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="diagnosis" class="mim-anchor"></a>
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<strong>Diagnosis</strong>
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<p><a href="#37" class="mim-tip-reference" title="Lebwohl, M., Phelps, R. G., Yannuzzi, L., Chang, S., Schwartz, I., Fuchs, W. &lt;strong&gt;Diagnosis of pseudoxanthoma elasticum by scar biopsy in patients without characteristic skin lesions.&lt;/strong&gt; New Eng. J. Med. 317: 347-350, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3600730/&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;3600730&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198708063170604&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="3600730">Lebwohl et al. (1987)</a> biopsied scars as well as flexural skin from 10 patients with angioid streaks but without cutaneous findings indicative of PXE. In 6 of the 10 patients, scar biopsies showed fragmentation and clumping of elastic tissue in the deep dermis. Three patients also had histologic changes of PXE in biopsy specimens of flexural skin that appeared normal. The authors concluded that scar biopsies may be useful in diagnosis when PXE is suspected despite the absence of typical skin lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3600730" 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 report of a consensus conference on PXE, <a href="#36" class="mim-tip-reference" title="Lebwohl, M., Neldner, K., Pope, F. M., De Paepe, A., Christiano, A. M., Boyd, C. D., Uitto, J., McKusick, V. A. &lt;strong&gt;Classification of pseudoxanthoma elasticum: report of a consensus conference.&lt;/strong&gt; J. Am. Acad. Derm. 30: 103-107, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8277008/&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;8277008&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0190-9622(08)81894-4&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="8277008">Lebwohl et al. (1994)</a> stated that histologic evidence of calcified elastic fibers is essential for diagnosis. The group proposed a provisional classification system of PXE patients who may lack one or more of the 3 major criteria: skin, eye, or cardiovascular involvement. However, the group also noted that in time, all patients with PXE tend to merge into a single classic phenotype with all 3 features, and that separation into subtypes based on phenotype is difficult. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8277008" 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="#61" class="mim-tip-reference" title="Struk, B., Neldner, K. H., Rao, V. S., St Jean, P., Lindpaintner, K. &lt;strong&gt;Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1.&lt;/strong&gt; Hum. Molec. Genet. 6: 1823-1828, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9302259/&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;9302259&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/6.11.1823&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="9302259">Struk et al. (1997)</a> noted that the 'gold standard' for diagnosis of PXE is positive von Kossa staining showing calcification and fracture of elastic fibers in biopsy material from affected skin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302259" 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="#49" class="mim-tip-reference" title="Plomp, A. S., Toonstra, J., Bergen, A. A. B., van Dijk, M. R., de Jong, P. T. V. M. &lt;strong&gt;Proposal for updating the pseudoxanthoma elasticum classification system and a review of the clinical findings.&lt;/strong&gt; Am. J. Med. Genet. 152A: 1049-1058, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20358627/&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;20358627&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33329&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="20358627">Plomp et al. (2010)</a> reviewed the major clinical signs of PXE and proposed an updated classification system for the disorder, including revised diagnostic criteria. Diagnostic criteria included skin findings confirmed by skin biopsy, ocular findings corroborated by funduscopy, and mutation analysis of the ABCC6 gene. Additional minor criteria included the findings of 'comets' in the retina or 'pigmented wing' signs in the retina. Patients can be classified as having a definite, probable, or possible diagnosis based on the number of signs present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20358627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Differential Diagnosis</em></strong></p><p>
The occurrence of angioid streaks in homozygous thalassemia and in sickle cell anemia has been attributed to the deposition of iron in Bruch membrane behind the retina. Severe ophthalmologic complications like those of PXE may occur in some cases (<a href="#3" class="mim-tip-reference" title="Aessopos, A., Stamatelos, G., Savvides, P., Kavouklis, E., Gabriel, L., Rombos, I., Karagiorga, M., Kaklamanis, P. &lt;strong&gt;Angioid streaks in homozygous beta thalassemia.&lt;/strong&gt; Am. J. Ophthal. 108: 356-359, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2801854/&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;2801854&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0002-9394(14)73300-8&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="2801854">Aessopos et al., 1989</a>). Angioid streaks in hemochromatosis are presumably also a reflection of iron deposits. The occurrence of angioid streaks with Paget disease of bone (<a href="/entry/167250">167250</a>) and with tumoral calcinosis with hyperphosphatemia (<a href="/entry/211900">211900</a>) may be related to the deposition of calcium in a relatively normal Bruch membrane. Angioid streaks are said to occur with lead poisoning (<a href="#14" class="mim-tip-reference" title="Clarkson, J. G., Altman, R. D. &lt;strong&gt;Angioid streaks.&lt;/strong&gt; Surv. Ophthalmol. 26: 235-246, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7046115/&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;7046115&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0039-6257(82)90158-8&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="7046115">Clarkson and Altman, 1982</a>). <a href="#2" class="mim-tip-reference" title="Aessopos, A., Savvides, P., Stamatelos, G., Rombos, I., Tassiopoulos, T., Karagiorga, M., Kaklamanis, P., Fessas, P. &lt;strong&gt;Pseudoxanthoma elasticum-like skin lesions and angioid streaks in beta-thalassemia.&lt;/strong&gt; Am. J. Hemat. 41: 159-164, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1415189/&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;1415189&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajh.2830410304&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="1415189">Aessopos et al. (1992)</a> suggested that beta-thalassemia must be considered in the differential diagnosis of PXE because of the occurrence of PXE-like skin lesions as well as angioid streaks. In 62 patients with homozygous beta-thalassemia major and 38 with beta-thalassemia intermedia, they found diagnostic skin lesions in 16 patients. Angioid streaks were found in 20 of the 100 patients, and both PXE skin lesions and angioid streaks were found in 10 of the patients; in all, 26 had either one or both of these manifestations. A positive correlation was found between the presence of one or both types of lesion and age of the patients; there were no differences in regard to ferritin and hematocrit levels, number of transfused units, chelation therapy, and splenic status between patients with or without the findings of PXE. One might wonder about iron loading as the mechanism of the PXE-like changes. Angioid streaks were described in homozygous sickle cell disease by <a href="#44" class="mim-tip-reference" title="Nagpal, K. C., Asdourian, G., Goldbaum, M., Apple, D., Goldberg, M. F. &lt;strong&gt;Angioid streaks and sickle haemoglobinopathies.&lt;/strong&gt; Brit. J. Ophthal. 60: 31-34, 1976.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1268158/&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;1268158&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/bjo.60.1.31&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="1268158">Nagpal et al. (1976)</a>, <a href="#26" class="mim-tip-reference" title="Hamilton, A. M., Pope, F. M., Condon, P. I., Slavin, G., Sowter, C., Ford, S., Hayes, R. J., Serjeant, G. R. &lt;strong&gt;Angioid streaks in Jamaican patients with homozygous sickle cell disease.&lt;/strong&gt; Brit. J. Ophthal. 65: 341-347, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7248242/&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;7248242&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/bjo.65.5.341&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="7248242">Hamilton et al. (1981)</a>, and others. <a href="#1" class="mim-tip-reference" title="Aessopos, A., Farmakis, D., Loukopoulos, D. &lt;strong&gt;Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta-thalassemia and the sickling syndromes.&lt;/strong&gt; Blood 99: 30-35, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11756149/&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;11756149&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood.v99.1.30&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="11756149">Aessopos et al. (2002)</a> reviewed elastic tissue abnormalities resembling PXE in beta-thalassemia and sickling syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7248242+7046115+11756149+2801854+1268158+1415189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Hamlin, N., Beck, K., Bacchelli, B., Cianciulli, P., Pasquali-Ronchetti, I., Le Saux, O. &lt;strong&gt;Acquired pseudoxanthoma elasticum-like syndrome in beta-thalassaemia patients.&lt;/strong&gt; Brit. J. Haemat. 122: 852-854, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12930400/&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;12930400&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1046/j.1365-2141.2003.04484.x&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="12930400">Hamlin et al. (2003)</a> reported the clinical and histopathologic manifestations of 10 beta-thalassemia patients with PXE-like skin lesions in combination with ocular and/or vascular symptoms and calcified elastic fibers. No disease-causing variant was found in the ABCC6 (<a href="/entry/603234">603234</a>) gene, indicating that this was a phenocopy of PXE. <a href="#27" class="mim-tip-reference" title="Hamlin, N., Beck, K., Bacchelli, B., Cianciulli, P., Pasquali-Ronchetti, I., Le Saux, O. &lt;strong&gt;Acquired pseudoxanthoma elasticum-like syndrome in beta-thalassaemia patients.&lt;/strong&gt; Brit. J. Haemat. 122: 852-854, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12930400/&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;12930400&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1046/j.1365-2141.2003.04484.x&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="12930400">Hamlin et al. (2003)</a> discussed the hypothesis that as iron loading progresses in beta-thalassemic patients, the capacity for the transport and storage of iron may be exceeded, and a fraction of iron that is not bound to transferrin or ferritin may promote the generation of free radicals, which are in turn propagators of oxidation-related damage to various organs and tissues, including elastin-rich tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12930400" 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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<div>
<a id="inheritance" class="mim-anchor"></a>
<h4 href="#mimInheritanceFold" id="mimInheritanceToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimInheritanceToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
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<strong>Inheritance</strong>
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<div id="mimInheritanceFold" class="collapse in mimTextToggleFold">
<span class="mim-text-font">
<p>The assessment of inheritance in PXE has been complicated by clinical heterogeneity and variable age of onset (<a href="#45" class="mim-tip-reference" title="Neldner, K. H. &lt;strong&gt;Pseudoxanthoma elasticum.&lt;/strong&gt; Clin. Derm. 6: 83-92, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3359381/&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;3359381&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0738-081x(88)90003-x&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="3359381">Neldner, 1988</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3359381" 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="#43" class="mim-tip-reference" title="Miksch, S., Lumsden, A., Guenther, U. P., Foernzler, D., Christen-Zach, S., Daugherty, C., Ramesar, R. S., Lebwohl, M., Hohl, D., Neldner, K. H., Lindpaintner, K., Richards, R. I., Struk, B. &lt;strong&gt;Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.&lt;/strong&gt; Hum. Mutat. 26: 235-248, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16086317/&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;16086317&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20206&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="16086317">Miksch et al. (2005)</a> performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. Their mutation analysis confirmed an earlier haplotype-based analysis and conclusions regarding a recessive-only mode of inheritance in PXE (<a href="#10" class="mim-tip-reference" title="Cai, L., Struk, B., Adams, M. D., Ji, W., Haaf, T., Kang, H.-L., Dho, S. H., Xu, X., Ringpfeil, F., Nancarrow, J., Zach, S., Schaen, L., and 19 others. &lt;strong&gt;A 500-kb region on chromosome 16p13.1 contains the pseudoxanthoma elasticum locus: high resolution mapping and genomic structure.&lt;/strong&gt; J. Molec. Med. 78: 36-46, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10759028/&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;10759028&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s001090000079&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="10759028">Cai et al., 2000</a>) through the identification of 2 mutated alleles in all individuals with PXE who appear in either consecutive or alternating generations of the same family. Their study demonstrated that the full phenotypic expression of the disorder requires 2 defective allelic copies of ABCC6 and that pseudodominance is the mode of transmission in presumed autosomal dominant families (i.e., the second parental disease allele 'marries into' the family). The apparent frequency of this mechanism was approximately 7.5% in their family cohort. <a href="#43" class="mim-tip-reference" title="Miksch, S., Lumsden, A., Guenther, U. P., Foernzler, D., Christen-Zach, S., Daugherty, C., Ramesar, R. S., Lebwohl, M., Hohl, D., Neldner, K. H., Lindpaintner, K., Richards, R. I., Struk, B. &lt;strong&gt;Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.&lt;/strong&gt; Hum. Mutat. 26: 235-248, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16086317/&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;16086317&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20206&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="16086317">Miksch et al. (2005)</a> stated that in their families no heterozygote for a large deletion showed any apparent clinical sign of PXE according to category I diagnostic criteria. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16086317+10759028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine the exact mode of inheritance of PXE, <a href="#55" class="mim-tip-reference" title="Ringpfeil, F., McGuigan, K., Fuchsel, L., Kozic, H., Larralde, M., Lebwohl, M., Uitto, J. &lt;strong&gt;Pseudoxanthoma elasticum is a recessive disease characterized by compound heterozygosity.&lt;/strong&gt; J. Invest. Derm. 126: 782-786, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16410789/&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;16410789&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.jid.5700115&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="16410789">Ringpfeil et al. (2006)</a> identified 7 pedigrees with affected individuals in 2 different generations and sequenced the entire coding region of ABCC6 in affected persons and in presumed carriers with a limited phenotype, as well as unaffected family members. Two allelic mutations were identified in each individual with unambiguous diagnosis of PXE, as well as in those with only minimal clinical signs suggestive of PXE but with positive skin biopsy. Missense mutations were frequently detected in the latter cases. <a href="#55" class="mim-tip-reference" title="Ringpfeil, F., McGuigan, K., Fuchsel, L., Kozic, H., Larralde, M., Lebwohl, M., Uitto, J. &lt;strong&gt;Pseudoxanthoma elasticum is a recessive disease characterized by compound heterozygosity.&lt;/strong&gt; J. Invest. Derm. 126: 782-786, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16410789/&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;16410789&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.jid.5700115&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="16410789">Ringpfeil et al. (2006)</a> concluded that PXE is inherited as an autosomal recessive trait and that those instances in which the disease occurs in 2 generations can be attributed to pseudodominance. <a href="#8" class="mim-tip-reference" title="Bergen, A. A. B. &lt;strong&gt;Pseudoxanthoma elasticum: the end of the autosomal dominant segregation myth. (Commentary)&lt;/strong&gt; J. Invest. Derm. 126: 704-705, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16541094/&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;16541094&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.jid.5700129&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="16541094">Bergen (2006)</a> maintained that this and other work such as that of <a href="#13" class="mim-tip-reference" title="Chassaing, N., Martin, L., Calvas, P., Le Bert, M., Hovnanian, A. &lt;strong&gt;Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations.&lt;/strong&gt; J. Med. Genet. 42: 881-892, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15894595/&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;15894595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2004.030171&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="15894595">Chassaing et al. (2005)</a> and <a href="#43" class="mim-tip-reference" title="Miksch, S., Lumsden, A., Guenther, U. P., Foernzler, D., Christen-Zach, S., Daugherty, C., Ramesar, R. S., Lebwohl, M., Hohl, D., Neldner, K. H., Lindpaintner, K., Richards, R. I., Struk, B. &lt;strong&gt;Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.&lt;/strong&gt; Hum. Mutat. 26: 235-248, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16086317/&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;16086317&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20206&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="16086317">Miksch et al. (2005)</a> puts an end to the 'autosomal dominant segregation myth' (see HISTORY). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16086317+16541094+15894595+16410789" 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="pathogenesis" class="mim-anchor"></a>
<h4 href="#mimPathogenesisFold" id="mimPathogenesisToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimPathogenesisToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Pathogenesis</strong>
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</h4>
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<p>Since the ABCC6 gene (<a href="/entry/603234">603234</a>) is expressed primarily, if not exclusively, in the liver and kidneys, <a href="#56" class="mim-tip-reference" title="Ringpfeil, F., Pulkkinen, L., Uitto, J. &lt;strong&gt;Molecular genetics of pseudoxanthoma elasticum.&lt;/strong&gt; Exp. Derm. 10: 221-228, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11493310/&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;11493310&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1034/j.1600-0625.2001.100401.x&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="11493310">Ringpfeil et al. (2001)</a> suggested that PXE is a primary metabolic disorder with secondary involvement of elastic fibers, a situation comparable to the secondary involvement of connective tissue elements in homocystinuria (<a href="/entry/236200">236200</a>) and alkaptonuria (<a href="/entry/203500">203500</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11493310" 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>ABCC6 is a member of the large ATP-dependent transmembrane transporter family. <a href="#13" class="mim-tip-reference" title="Chassaing, N., Martin, L., Calvas, P., Le Bert, M., Hovnanian, A. &lt;strong&gt;Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations.&lt;/strong&gt; J. Med. Genet. 42: 881-892, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15894595/&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;15894595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2004.030171&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="15894595">Chassaing et al. (2005)</a> commented that the association of PXE to ABCC6 efflux transport alterations raised a number of pathophysiology hypotheses, among them the idea that PXE is a systemic metabolic disease resulting from lack or accumulation over time in the bloodstream of molecules interacting with the synthesis, turnover, and/or maintenance of extracellular matrix (ECM). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15894595" 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>Findings in mouse models (see ANIMAL MODEL) have also indicated that PXE is a systemic metabolic disease (<a href="#30" class="mim-tip-reference" title="Jiang, Q., Endo, M., Dibra, F., Wang, K., Uitto, J. &lt;strong&gt;Pseudoxanthoma elasticum is a metabolic disease.&lt;/strong&gt; J. Invest. Derm. 129: 348-354, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18685618/&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;18685618&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18685618[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/10.1038/jid.2008.212&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="18685618">Jiang et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18685618" 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="mapping" class="mim-anchor"></a>
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<strong>Mapping</strong>
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<p>In an abstract presented at the Fifth International Workshop on Human Chromosome 16, on 3-4 March 1997 in Toronto, and in a subsequent full publication, <a href="#61" class="mim-tip-reference" title="Struk, B., Neldner, K. H., Rao, V. S., St Jean, P., Lindpaintner, K. &lt;strong&gt;Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1.&lt;/strong&gt; Hum. Molec. Genet. 6: 1823-1828, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9302259/&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;9302259&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/6.11.1823&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="9302259">Struk et al. (1997)</a> reported a genomewide screen on a collection of 38 families with 2 or more sibs with PXE. They used allele-sharing algorithms, followed by high-resolution mapping and analysis by conventional linkage algorithms in recessive and dominant families. Excess allele-sharing was found on the short arm of chromosome 16 and confirmed by maximum-likelihood linkage analysis, localizing the disease gene in recessive families to a 3.0-cM region on 16p13.1 with a maximum 2-point lod score of 19.0. In dominant families, linkage to the same region with a maximum 2-point lod score of 3.6 was observed. <a href="#61" class="mim-tip-reference" title="Struk, B., Neldner, K. H., Rao, V. S., St Jean, P., Lindpaintner, K. &lt;strong&gt;Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1.&lt;/strong&gt; Hum. Molec. Genet. 6: 1823-1828, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9302259/&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;9302259&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/6.11.1823&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="9302259">Struk et al. (1997)</a> predicted that allelic heterogeneity with different variants of a single disease gene residing on 16p13.1 accounts for both recessive and dominant forms of PXE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302259" 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 family from a genetically isolated population in the Netherlands suffering from autosomal recessive PXE, <a href="#62" class="mim-tip-reference" title="van Soest, S., Swart, J., Tijmes, N., Sandkuijl, L. A., Rommers, J., Bergen, A. A. B. &lt;strong&gt;A locus for autosomal recessive pseudoxanthoma elasticum, with penetrance of vascular symptoms in carriers, maps to chromosome 16p13.1.&lt;/strong&gt; Genome Res. 7: 830-834, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9267806/&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;9267806&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=9267806[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/10.1101/gr.7.8.830&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="9267806">van Soest et al. (1997)</a> combined homozygosity mapping and genome scanning to map the PXE1 locus to 16p13.1. Initially, homozygosity was found in 2 or 3 patients with up to 20 markers, among which was D16S292 located in 16p13.1. Refined and more extensive family screening of the latter region showed close linkage without recombination with the marker D16S764 (maximum lod = 6.27). Despite clear autosomal recessive inheritance of the ocular symptoms in this disorder, vascular symptoms appeared in 40 to 50% of the heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9267806" 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="#33" class="mim-tip-reference" title="Le Saux, O., Urban, Z., Goring, H. H. H., Csiszar, K., Pope, F. M., Richards, A., Pasquali-Ronchetti, I., Terry, S., Bercovitch, L., Lebwohl, M. G., Breuning, M., van den Berg, P., Kornet, L., Doggett, N., Ott, J., de Jong, P. T. V. M., Bergen, A. A. B., Boyd, C. D. &lt;strong&gt;Pseudoxanthoma elasticum maps to an 820-kb region of the p13.1 region of chromosome 16.&lt;/strong&gt; Genomics 62: 1-10, 1999. Note: Erratum: Genomics 63: 439 only, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10585762/&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;10585762&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/geno.1999.5925&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="10585762">Le Saux et al. (1999)</a> performed linkage analysis on 21 families with PXE using 10 polymorphic markers located on 16p13.1. They localized the gene to an 8-cM region of 16p13.1 between markers D16S500 and D16S3041 with a maximum lod score of 8.1 at a recombination fraction of 0.04 for marker D16S3017. They found no evidence of locus heterogeneity. Haplotype studies of 36 PXE families identified several recombinations that further confined the PXE gene to a region of less than 1 cM between markers D16S3060 and D16S79. The PXE locus was identified within a single YAC clone and several overlapping BAC recombinants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10585762" 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="molecularGenetics" class="mim-anchor"></a>
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<p>In several families with PXE, <a href="#54" class="mim-tip-reference" title="Ringpfeil, F., Lebwohl, M.G., Christiano, A. M., Uitto, J. &lt;strong&gt;Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter.&lt;/strong&gt; Proc. Nat. Acad. Sci. 97: 6001-6006, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10811882/&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;10811882&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10811882[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/10.1073/pnas.100041297&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="10811882">Ringpfeil et al. (2000)</a>, <a href="#7" class="mim-tip-reference" title="Bergen, A. A. B., Plomp, A. S., Schuurman, E. J., Terry, S., Breuning, M., Dauwerse, H., Swart, J., Kool, M., van Soest, S., Baas, F., ten Brink, J. B., de Jong, P. T. V. M. &lt;strong&gt;Mutations in ABCC6 cause pseudoxanthoma elasticum.&lt;/strong&gt; Nature Genet. 25: 228-231, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10835643/&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;10835643&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/76109&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="10835643">Bergen et al. (2000)</a>, and <a href="#34" class="mim-tip-reference" title="Le Saux, O., Urban, Z., Tschuch, C., Csiszar, K., Bacchelli, B., Quaglino, D., Pasquali-Ronchetti, I., Pope, F. M., Richards, A., Terry, S., Bercovitch, L., de Paepe, A., Boyd, C. D. &lt;strong&gt;Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum.&lt;/strong&gt; Nature Genet. 25: 223-227, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10835642/&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;10835642&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/76102&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="10835642">Le Saux et al. (2000)</a> identified mutations in the ABCC6 gene. Of 4 families with autosomal recessive inheritance of PXE reported by <a href="#54" class="mim-tip-reference" title="Ringpfeil, F., Lebwohl, M.G., Christiano, A. M., Uitto, J. &lt;strong&gt;Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter.&lt;/strong&gt; Proc. Nat. Acad. Sci. 97: 6001-6006, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10811882/&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;10811882&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10811882[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/10.1073/pnas.100041297&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="10811882">Ringpfeil et al. (2000)</a>, 1 was compound heterozygous for mutations in the ABCC6 gene (see, e.g., R1141X, <a href="/entry/603234#0001">603234.0001</a>), 1 family was hemizygous for the R1141X mutation, and 2 families were homozygous for mutations. Of 4 so-called sporadic cases, 1 was compound heterozygous and 3 appeared heterozygous for mutations in the ABCC6 gene. <a href="#7" class="mim-tip-reference" title="Bergen, A. A. B., Plomp, A. S., Schuurman, E. J., Terry, S., Breuning, M., Dauwerse, H., Swart, J., Kool, M., van Soest, S., Baas, F., ten Brink, J. B., de Jong, P. T. V. M. &lt;strong&gt;Mutations in ABCC6 cause pseudoxanthoma elasticum.&lt;/strong&gt; Nature Genet. 25: 228-231, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10835643/&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;10835643&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/76109&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="10835643">Bergen et al. (2000)</a> identified mutations in the ABCC6 gene in 2 sporadic patients with PXE (see, e.g., <a href="/entry/603234#0009">603234.0009</a>), 4 families with PXE that appeared to be autosomal dominant (see, e.g., <a href="/entry/603234#0008">603234.0008</a>), and 1 family with autosomal recessive PXE (<a href="/entry/603234#0007">603234.0007</a>). <a href="#34" class="mim-tip-reference" title="Le Saux, O., Urban, Z., Tschuch, C., Csiszar, K., Bacchelli, B., Quaglino, D., Pasquali-Ronchetti, I., Pope, F. M., Richards, A., Terry, S., Bercovitch, L., de Paepe, A., Boyd, C. D. &lt;strong&gt;Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum.&lt;/strong&gt; Nature Genet. 25: 223-227, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10835642/&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;10835642&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/76102&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="10835642">Le Saux et al. (2000)</a> identified mutations in the ABCC6 gene in 5 families with autosomal recessive PXE and in 1 sporadic case (see, e.g., <a href="/entry/603234#0001">603234.0001</a> and <a href="/entry/603234#0002">603234.0002</a>). The R1141X mutation (<a href="/entry/603234#0001">603234.0001</a>) was found in families segregating autosomal recessive PXE and in families with expressing heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10811882+10835643+10835642" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using multiplex ligation-dependent probe amplification (MLPA) to analyze 35 PXE patients with incomplete ABCC6 genotypes after exonic sequencing, <a href="#16" class="mim-tip-reference" title="Costrop, L. M. F., Vanakker, O. O. M., Van Laer, L., Le Saux, O., Martin, L., Chassaing, N., Guerra, D., Pasquali-Ronchetti, I., Coucke, P. J., De Paepe, A. &lt;strong&gt;Novel deletions causing pseudoxanthoma elasticum underscore the genomic instability of the ABCC6 region.&lt;/strong&gt; J. Hum. Genet. 55: 112-117, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20075945/&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;20075945&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/jhg.2009.132&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="20075945">Costrop et al. (2010)</a> identified 6 multiexon deletions and 4 single-exon deletions and were thus able to characterized 25% of the unidentified disease alleles. The findings illustrated the instability of the ABCC6 genomic region and stressed the importance of screening for deletions in the molecular diagnosis of PXE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20075945" 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 28-year-old French man with pseudoxanthoma elasticum who had a younger brother who died of generalized arterial calcification of infancy (GACI2; <a href="/entry/614473">614473</a>) at age 15 months, <a href="#31" class="mim-tip-reference" title="Le Boulanger, G., Labreze, C., Croue, A., Schurgers, L. J., Chassaing, N., Wittkampf, T., Rutsch, F., Martin, L. &lt;strong&gt;An unusual severe vascular case of pseudoxanthoma elasticum presenting as generalized arterial calcification of infancy.&lt;/strong&gt; Am. J. Med. Genet. 152A: 118-123, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20034067/&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;20034067&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33162&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="20034067">Le Boulanger et al. (2010)</a> identified compound heterozygosity for missense mutations in the ABCC6 gene (<a href="/entry/603234#0025">603234.0025</a> and <a href="/entry/603234#0026">603234.0026</a>), which were also found in heterozygosity in each of his unaffected parents, respectively. No disease-causing mutations were found in the ENPP1 gene (<a href="/entry/173335">173335</a>), which is known to cause GACI1 (<a href="/entry/208000">208000</a>). Although no DNA material was available from the deceased younger brother, his disease was presumed to be related to the familial ABCC6 mutations. <a href="#31" class="mim-tip-reference" title="Le Boulanger, G., Labreze, C., Croue, A., Schurgers, L. J., Chassaing, N., Wittkampf, T., Rutsch, F., Martin, L. &lt;strong&gt;An unusual severe vascular case of pseudoxanthoma elasticum presenting as generalized arterial calcification of infancy.&lt;/strong&gt; Am. J. Med. Genet. 152A: 118-123, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20034067/&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;20034067&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33162&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="20034067">Le Boulanger et al. (2010)</a> concluded that GACI may represent an atypical and severe end of the vascular phenotypic spectrum of PXE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20034067" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>PXE-Associated Retinopathy</em></strong></p><p>
Choroidal neovascularization (CNV) in PXE-associated retinopathy is believed to be mediated by the action of VEGF (<a href="/entry/192240">192240</a>). <a href="#65" class="mim-tip-reference" title="Zarbock, R., Hendig, D., Szliska, C., Kleesiek, K., Gotting, C. &lt;strong&gt;Vascular endothelial growth factor gene polymorphisms as prognostic markers for ocular manifestations in pseudoxanthoma elasticum.&lt;/strong&gt; Hum. Molec. Genet. 18: 3344-3351, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19483196/&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;19483196&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp259&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="19483196">Zarbock et al. (2009)</a> evaluated the distribution of 10 SNPs in the promoter and coding region of the VEGFA gene in DNA samples from 163 German patients affected by PXE and in 163 healthy control subjects. Haplotype analysis identified an 8-SNP haplotype CTGGCCCC that was associated with PXE. Furthermore, 5 SNPs showed significant association with severe retinopathy. The most significant single SNP association was -460C-T (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs833061;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs833061</a>, OR = 3.83, 95% CI 2.01-7.31, corrected p = 0.0003). Logistic regression analysis identified the <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs833061;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs833061</a> and 674C-T variant (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1413711;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1413711</a>; OR = 3.21, 95% CI 1.70-6.02, corrected p = 0.004) as independent risk factors for development of severe retinopathy. <a href="#65" class="mim-tip-reference" title="Zarbock, R., Hendig, D., Szliska, C., Kleesiek, K., Gotting, C. &lt;strong&gt;Vascular endothelial growth factor gene polymorphisms as prognostic markers for ocular manifestations in pseudoxanthoma elasticum.&lt;/strong&gt; Hum. Molec. Genet. 18: 3344-3351, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19483196/&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;19483196&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp259&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="19483196">Zarbock et al. (2009)</a> suggested an involvement of VEGF in the pathogenesis of ocular PXE manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19483196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifier Genes</em></strong></p><p>
<a href="#59" class="mim-tip-reference" title="Schon, S., Schulz, V., Prante, C., Hendig, D., Szliska, C., Kuhn, J., Kleesiek, K., Gotting, C. &lt;strong&gt;Polymorphisms in the xylosyltransferase genes cause higher serum XT-1 activity in patients with pseudoxanthoma elasticum (PXE) and are involved in a severe disease course.&lt;/strong&gt; J. Med. Genet. 43: 745-749, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16571645/&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;16571645&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2006.040972&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="16571645">Schon et al. (2006)</a> reported that polymorphisms in the XYLT1 and XYLT2 genes (<a href="/entry/608124#0001">608124.0001</a> and <a href="/entry/608125#0001">608125.0001</a>, respectively) modify the severity of PXE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16571645" 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="#61" class="mim-tip-reference" title="Struk, B., Neldner, K. H., Rao, V. S., St Jean, P., Lindpaintner, K. &lt;strong&gt;Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1.&lt;/strong&gt; Hum. Molec. Genet. 6: 1823-1828, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9302259/&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;9302259&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/6.11.1823&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="9302259">Struk et al. (1997)</a> estimated that the prevalence of PXE, both the recessive and dominant forms, is 1 in 70,000 to 100,000. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302259" 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 cohort of 122 unrelated PXE patients from various countries, <a href="#32" class="mim-tip-reference" title="Le Saux, O., Beck, K., Sachsinger, C., Silvestri, C., Treiber, C., Goring, H. H. H., Johnson, E. W., De Paepe, A., Pope, F. M., Pasquali-Ronchetti, I., Bercovitch, L., Terry, S., Boyd, C. D. &lt;strong&gt;A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum.&lt;/strong&gt; Am. J. Hum. Genet. 69: 749-764, 2001. Note: Erratum: Am. J. Hum. Genet. 69: 1413 only, 2001; Erratum: Am. J. Hum. Genet. 71: 448 only, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11536079/&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;11536079&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11536079[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/10.1086/323704&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="11536079">Le Saux et al. (2001)</a> identified a G1321S missense mutation in the ABCC6 gene (<a href="/entry/603234#0021">603234.0021</a>). The G1321S mutation was detected in heterozygosity in 1 of 74 United States alleles, for an allele frequency of 1.4%, but was not found in the European population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11536079" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Hu, X., Peek, R., Plomp, A., ten Brink, J., Scheffer, G., van Soest, S., Leys, A., de Jong, P. T. V. M., Bergen, A. A. B. &lt;strong&gt;Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum.&lt;/strong&gt; Invest. Ophthal. Vis. Sci. 44: 1824-1829, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12714611/&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;12714611&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1167/iovs.02-0981&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="12714611">Hu et al. (2003)</a> demonstrated a founder effect for the R1141X mutation (<a href="/entry/603234#0001">603234.0001</a>) in the Netherlands. They identified the mutation in 19 alleles in 16 Dutch patients with PXE, in heterozygous, homozygous, or compound heterozygous form. Expression of the normal allele in heterozygotes was predominant; no or very low expression was found in homozygotes. The mutation induced instability of the aberrant mRNA. <a href="#28" class="mim-tip-reference" title="Hu, X., Peek, R., Plomp, A., ten Brink, J., Scheffer, G., van Soest, S., Leys, A., de Jong, P. T. V. M., Bergen, A. A. B. &lt;strong&gt;Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum.&lt;/strong&gt; Invest. Ophthal. Vis. Sci. 44: 1824-1829, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12714611/&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;12714611&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1167/iovs.02-0981&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="12714611">Hu et al. (2003)</a> suggested that the PXE phenotype of the R1141X mutation most likely results from complete loss of function or functional haploinsufficiency of ABCC6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12714611" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#24" class="mim-tip-reference" title="Gorgels, T. G. M. F., Hu, X., Scheffer, G. L., van der Wal, A. C., Toonstra, J., de Jong, P. T. V. M., van Kuppevelt, T. H., Levelt, C. N., de Wolf, A., Loves, W. J. P., Scheper, R. J., Peek, R., Bergen, A. A. B. &lt;strong&gt;Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum.&lt;/strong&gt; Hum. Molec. Genet. 14: 1763-1773, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15888484/&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;15888484&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddi183&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="15888484">Gorgels et al. (2005)</a> generated Abcc6 -/- mice and showed by light and electron microscopy that Abcc6 -/- mice spontaneously developed calcification of elastic fibers in blood vessel walls and in Bruch membrane in the eye. No clear abnormalities were seen in the dermal extracellular matrix. Calcification of blood vessels was most prominent in small arteries in the cortex of the kidney, but in old mice, it occurred also in other organs and in the aorta and vena cava. Monoclonal antibodies against mouse Abcc6 localized the protein to the basolateral membranes of hepatocytes and the basal membrane in renal proximal tubules, but failed to show the protein at the pathogenic sites. Abcc6 -/- mice developed a 25% reduction in plasma HDL cholesterol and an increase in plasma creatinine levels, which may be due to impaired kidney function. No changes in serum mineral balance were found. <a href="#24" class="mim-tip-reference" title="Gorgels, T. G. M. F., Hu, X., Scheffer, G. L., van der Wal, A. C., Toonstra, J., de Jong, P. T. V. M., van Kuppevelt, T. H., Levelt, C. N., de Wolf, A., Loves, W. J. P., Scheper, R. J., Peek, R., Bergen, A. A. B. &lt;strong&gt;Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum.&lt;/strong&gt; Hum. Molec. Genet. 14: 1763-1773, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15888484/&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;15888484&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddi183&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="15888484">Gorgels et al. (2005)</a> concluded that the phenotype of the Abcc6 -/- mouse shares calcification of elastic fibers with human PXE pathology, and supports the hypothesis that PXE is a systemic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15888484" 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="#30" class="mim-tip-reference" title="Jiang, Q., Endo, M., Dibra, F., Wang, K., Uitto, J. &lt;strong&gt;Pseudoxanthoma elasticum is a metabolic disease.&lt;/strong&gt; J. Invest. Derm. 129: 348-354, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18685618/&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;18685618&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18685618[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/10.1038/jid.2008.212&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="18685618">Jiang et al. (2009)</a> found that grafting of wildtype mouse muzzle skin onto the back of Abcc6-knockout mice resulted in abnormal mineralization of vibrissae consistent with PXE, whereas grafting of Abcc6-knockout mouse muzzle skin onto wildtype mice did not. The data implied that PXE does not result from localized defect based on resident cellular abnormalities but from a change of metabolite(s) in serum. These findings implicate circulatory factors as a critical component of the mineralization process and supported the notion that PXE is a secondary mineralization of connective tissues. In addition, the findings suggested that the abnormal mineralization process could possibly be countered or even reversed by changes in the homeostatic milieu. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18685618" 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><strong><em>Autosomal Dominant Inheritance</em></strong></p><p>
<a href="#50" class="mim-tip-reference" title="Pope, F. M. &lt;strong&gt;Two types of autosomal recessive pseudoxanthoma elasticum.&lt;/strong&gt; Arch. Derm. 110: 209-212, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4855282/&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;4855282&lt;/a&gt;]" pmid="4855282">Pope (1974)</a> suggested that there are 2 dominant and 2 recessive forms of PXE (see below). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4855282" 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="#45" class="mim-tip-reference" title="Neldner, K. H. &lt;strong&gt;Pseudoxanthoma elasticum.&lt;/strong&gt; Clin. Derm. 6: 83-92, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3359381/&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;3359381&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0738-081x(88)90003-x&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="3359381">Neldner (1988)</a> concluded that 97% of his patients had autosomal recessive inheritance. His conclusion did not allow for new mutation dominant cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3359381" 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 report of a consensus conference, <a href="#36" class="mim-tip-reference" title="Lebwohl, M., Neldner, K., Pope, F. M., De Paepe, A., Christiano, A. M., Boyd, C. D., Uitto, J., McKusick, V. A. &lt;strong&gt;Classification of pseudoxanthoma elasticum: report of a consensus conference.&lt;/strong&gt; J. Am. Acad. Derm. 30: 103-107, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8277008/&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;8277008&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0190-9622(08)81894-4&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="8277008">Lebwohl et al. (1994)</a> stated that both autosomal dominant and autosomal recessive forms of PXE exist, and that no clinical features can distinguish between the 2 disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8277008" 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="#61" class="mim-tip-reference" title="Struk, B., Neldner, K. H., Rao, V. S., St Jean, P., Lindpaintner, K. &lt;strong&gt;Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1.&lt;/strong&gt; Hum. Molec. Genet. 6: 1823-1828, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9302259/&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;9302259&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/6.11.1823&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="9302259">Struk et al. (1997)</a> stated that an autosomal dominant pattern of transmission of PXE occurs in approximately 10% of affected families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302259" 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="#48" class="mim-tip-reference" title="Plomp, A. S., Hu, X., de Jong, P. T. V. M., Bergen, A. A. B. &lt;strong&gt;Does autosomal dominant pseudoxanthoma elasticum exist?&lt;/strong&gt; Am. J. Med. Genet. 126A: 403-412, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15098239/&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;15098239&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20632&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="15098239">Plomp et al. (2004)</a> reviewed the literature on autosomal dominant PXE. They studied in detail, both clinically and by DNA studies, a selection of potentially autosomal dominant pedigrees from a patient population comprising 59 probands and their relatives. Individuals were considered to have definite PXE if they had 2 of the following 3 criteria: characteristic ophthalmologic signs, characteristic dermatologic signs, and positive skin biopsy. In the literature, <a href="#48" class="mim-tip-reference" title="Plomp, A. S., Hu, X., de Jong, P. T. V. M., Bergen, A. A. B. &lt;strong&gt;Does autosomal dominant pseudoxanthoma elasticum exist?&lt;/strong&gt; Am. J. Med. Genet. 126A: 403-412, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15098239/&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;15098239&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20632&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="15098239">Plomp et al. (2004)</a> found only 3 families with definite PXE in 2 successive generations and no families with definite PXE in 3 or more generations. Their own data set included 3 putative autosomal dominant families. Extensive DNA studies revealed a mutation in only 1 ABCC6 allele in the patients of these 3 families. Only 1 of the families showed definite PXE in 2 generations. Linkage studies revealed that pseudodominance was unlikely in this family. In the other 2 families, autosomal dominant PXE could not be confirmed after extensive clinical examinations and application of the criteria, since definite PXE was not present in 2 or more generations. <a href="#48" class="mim-tip-reference" title="Plomp, A. S., Hu, X., de Jong, P. T. V. M., Bergen, A. A. B. &lt;strong&gt;Does autosomal dominant pseudoxanthoma elasticum exist?&lt;/strong&gt; Am. J. Med. Genet. 126A: 403-412, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15098239/&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;15098239&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20632&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="15098239">Plomp et al. (2004)</a> concluded that the inheritance pattern in PXE is autosomal recessive in the overwhelming majority of families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15098239" 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="#29" class="mim-tip-reference" title="Hu, X., Plomp, A., Gorgels, T., Ten Brink, J., Loves, W., Mannens, M., De Jong, P. T. V. M., Bergen, A. A. B. &lt;strong&gt;Efficient molecular diagnostic strategy for ABCC6 in pseudoxanthoma elasticum.&lt;/strong&gt; Genet. Test. 8: 292-300, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15727254/&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;15727254&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1089/gte.2004.8.292&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="15727254">Hu et al. (2004)</a> cited the investigation of <a href="#48" class="mim-tip-reference" title="Plomp, A. S., Hu, X., de Jong, P. T. V. M., Bergen, A. A. B. &lt;strong&gt;Does autosomal dominant pseudoxanthoma elasticum exist?&lt;/strong&gt; Am. J. Med. Genet. 126A: 403-412, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15098239/&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;15098239&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20632&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="15098239">Plomp et al. (2004)</a> as indicating that autosomal dominant inheritance of PXE can be expected in approximately 2% of cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15098239+15727254" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Classification</em></strong></p><p>
<a href="#50" class="mim-tip-reference" title="Pope, F. M. &lt;strong&gt;Two types of autosomal recessive pseudoxanthoma elasticum.&lt;/strong&gt; Arch. Derm. 110: 209-212, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4855282/&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;4855282&lt;/a&gt;]" pmid="4855282">Pope (1974)</a> suggested that there are 2 dominant and 2 recessive forms of PXE. The type I recessive form was characterized by moderate vascular and retinal degeneration accompanied by cutaneous lesions. The type II recessive form was characterized by generalized skin changes with no blood vessel or ocular manifestations, and was considered rare, being present in 3 of 121 probands. Individuals with the type I dominant form had severe retinal and cardiovascular degeneration, accompanied by the cutaneous features. Those with the type II dominant form had mild cardiovascular and retinal changes together with hyperextensible joints, blue sclerae, and a high arched palate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4855282" 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>On the basis of his own extensive experience and that reported in the literature, <a href="#45" class="mim-tip-reference" title="Neldner, K. H. &lt;strong&gt;Pseudoxanthoma elasticum.&lt;/strong&gt; Clin. Derm. 6: 83-92, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3359381/&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;3359381&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0738-081x(88)90003-x&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="3359381">Neldner (1988)</a> provided a critique of the Pope 4-subtype classification. Whereas only 47% of 121 patients studied by Pope in the U.K. were thought to have the recessive form, the more general experience is that the recessive form of PXE is by far the more frequent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3359381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Other Inheritance</em></strong></p><p>
<a href="#9" class="mim-tip-reference" title="Berlyne, G. M., Bulmer, M. G., Platt, R. L. &lt;strong&gt;The genetics of pseudoxanthoma elasticum.&lt;/strong&gt; Quart. J. Med. 30: 201-212, 1961."None>Berlyne et al. (1961)</a> suggested that PXE may be inherited as a partial X-linked recessive (i.e., that the gene may be on a part of the X chromosome homologous with part of the Y chromosome). If such were the case, patients in any one sibship would tend always to be of the same sex. This mode of inheritance was not supported by later work.</p>
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<a href="#Coffman1959" class="mim-tip-reference" title="Coffman, J. D., Sommers, S. C. &lt;strong&gt;Familial pseudoxanthoma elasticum and valvular heart disease.&lt;/strong&gt; Circulation 19: 242-250, 1959.">Coffman and Sommers (1959)</a>; <a href="#Messis1970" class="mim-tip-reference" title="Messis, C. P., Budzilovich, G. N. &lt;strong&gt;Pseudoxanthoma elasticum: report of an autopsied case with cerebral involvement.&lt;/strong&gt; Neurology 20: 703-709, 1970.">Messis and Budzilovich (1970)</a>; <a href="#Pope1975" class="mim-tip-reference" title="Pope, F. M. &lt;strong&gt;Historical evidence for the genetic heterogeneity of pseudoxanthoma elasticum.&lt;/strong&gt; Brit. J. Derm. 92: 493-509, 1975.">Pope
(1975)</a>; <a href="#Renie1984" class="mim-tip-reference" title="Renie, W. A., Pyeritz, R. E., Combs, J., Fine, S. L. &lt;strong&gt;Pseudoxanthoma elasticum: high calcium intake in early life correlates with severity.&lt;/strong&gt; Am. J. Med. Genet. 19: 235-244, 1984.">Renie et al. (1984)</a>; <a href="#Sandberg1981" class="mim-tip-reference" title="Sandberg, L. B., Soskel, N. T., Leslie, J. G. &lt;strong&gt;Elastin structure, biosynthesis, and relation to disease states.&lt;/strong&gt; New Eng. J. Med. 304: 566-579, 1981.">Sandberg et al. (1981)</a>; <a href="#Viljoen1988" class="mim-tip-reference" title="Viljoen, D. &lt;strong&gt;Pseudoxanthoma elasticum (Gronblad-Strandberg syndrome).&lt;/strong&gt; J. Med. Genet. 25: 488-490, 1988.">Viljoen (1988)</a>
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Aessopos, A., Farmakis, D., Loukopoulos, D.
<strong>Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta-thalassemia and the sickling syndromes.</strong>
Blood 99: 30-35, 2002.
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[<a href="https://doi.org/10.1182/blood.v99.1.30" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0002-9394(14)73300-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archinte.134.6.1048" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1067/mjd.2003.173" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.jid.5700129" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s001090000079" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(69)91634-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/hrt.59.2.266" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2004.030171" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0039-6257(82)90158-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.cir.19.2.242" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320180422" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.survophthal.2008.12.006" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi183" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/bjo.65.5.341" target="_blank">Full Text</a>]
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Hamlin, N., Beck, K., Bacchelli, B., Cianciulli, P., Pasquali-Ronchetti, I., Le Saux, O.
<strong>Acquired pseudoxanthoma elasticum-like syndrome in beta-thalassaemia patients.</strong>
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[<a href="https://doi.org/10.1046/j.1365-2141.2003.04484.x" target="_blank">Full Text</a>]
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Hu, X., Peek, R., Plomp, A., ten Brink, J., Scheffer, G., van Soest, S., Leys, A., de Jong, P. T. V. M., Bergen, A. A. B.
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[<a href="https://doi.org/10.1167/iovs.02-0981" target="_blank">Full Text</a>]
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<strong>Efficient molecular diagnostic strategy for ABCC6 in pseudoxanthoma elasticum.</strong>
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[<a href="https://doi.org/10.1089/gte.2004.8.292" target="_blank">Full Text</a>]
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<strong>Pseudoxanthoma elasticum is a metabolic disease.</strong>
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[<a href="https://doi.org/10.1038/jid.2008.212" target="_blank">Full Text</a>]
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Le Boulanger, G., Labreze, C., Croue, A., Schurgers, L. J., Chassaing, N., Wittkampf, T., Rutsch, F., Martin, L.
<strong>An unusual severe vascular case of pseudoxanthoma elasticum presenting as generalized arterial calcification of infancy.</strong>
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[<a href="https://doi.org/10.1002/ajmg.a.33162" target="_blank">Full Text</a>]
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Le Saux, O., Beck, K., Sachsinger, C., Silvestri, C., Treiber, C., Goring, H. H. H., Johnson, E. W., De Paepe, A., Pope, F. M., Pasquali-Ronchetti, I., Bercovitch, L., Terry, S., Boyd, C. D.
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[<a href="https://doi.org/10.1086/323704" target="_blank">Full Text</a>]
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Le Saux, O., Urban, Z., Goring, H. H. H., Csiszar, K., Pope, F. M., Richards, A., Pasquali-Ronchetti, I., Terry, S., Bercovitch, L., Lebwohl, M. G., Breuning, M., van den Berg, P., Kornet, L., Doggett, N., Ott, J., de Jong, P. T. V. M., Bergen, A. A. B., Boyd, C. D.
<strong>Pseudoxanthoma elasticum maps to an 820-kb region of the p13.1 region of chromosome 16.</strong>
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[<a href="https://doi.org/10.1006/geno.1999.5925" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/76102" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199310213291705" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0190-9622(08)81894-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198708063170604" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/gim.2016.213" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.20.7.703" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20206" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0738-081x(88)90003-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20632" target="_blank">Full Text</a>]
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<p class="mim-text-font">
Plomp, A. S., Toonstra, J., Bergen, A. A. B., van Dijk, M. R., de Jong, P. T. V. M.
<strong>Proposal for updating the pseudoxanthoma elasticum classification system and a review of the clinical findings.</strong>
Am. J. Med. Genet. 152A: 1049-1058, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20358627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20358627</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20358627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.33329" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="50" class="mim-anchor"></a>
<a id="Pope1974" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Pope, F. M.
<strong>Two types of autosomal recessive pseudoxanthoma elasticum.</strong>
Arch. Derm. 110: 209-212, 1974.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4855282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4855282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4855282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="51" class="mim-anchor"></a>
<a id="Pope1975" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Pope, F. M.
<strong>Historical evidence for the genetic heterogeneity of pseudoxanthoma elasticum.</strong>
Brit. J. Derm. 92: 493-509, 1975.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1100089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1100089</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1100089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1365-2133.1975.tb03117.x" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="52" class="mim-anchor"></a>
<a id="Renie1984" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Renie, W. A., Pyeritz, R. E., Combs, J., Fine, S. L.
<strong>Pseudoxanthoma elasticum: high calcium intake in early life correlates with severity.</strong>
Am. J. Med. Genet. 19: 235-244, 1984.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6507474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6507474</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6507474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320190205" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="53" class="mim-anchor"></a>
<a id="Rigal1881" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rigal, (NI).
<strong>Observation pour servir a l'histoire de la cheloide diffuse xanthelasmique.</strong>
Ann. Derm. Syph. 21: 491-501, 1881.
</p>
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<li>
<a id="54" class="mim-anchor"></a>
<a id="Ringpfeil2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ringpfeil, F., Lebwohl, M.G., Christiano, A. M., Uitto, J.
<strong>Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter.</strong>
Proc. Nat. Acad. Sci. 97: 6001-6006, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10811882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10811882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10811882[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=10811882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.100041297" target="_blank">Full Text</a>]
</p>
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<a id="55" class="mim-anchor"></a>
<a id="Ringpfeil2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ringpfeil, F., McGuigan, K., Fuchsel, L., Kozic, H., Larralde, M., Lebwohl, M., Uitto, J.
<strong>Pseudoxanthoma elasticum is a recessive disease characterized by compound heterozygosity.</strong>
J. Invest. Derm. 126: 782-786, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16410789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16410789</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16410789" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/sj.jid.5700115" target="_blank">Full Text</a>]
</p>
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<a id="56" class="mim-anchor"></a>
<a id="Ringpfeil2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ringpfeil, F., Pulkkinen, L., Uitto, J.
<strong>Molecular genetics of pseudoxanthoma elasticum.</strong>
Exp. Derm. 10: 221-228, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11493310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11493310</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11493310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1034/j.1600-0625.2001.100401.x" target="_blank">Full Text</a>]
</p>
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<a id="57" class="mim-anchor"></a>
<a id="Ross1978" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ross, R., Fialkow, P. J., Altman, L. K.
<strong>Fine structure alterations of elastic fibers in pseudoxanthoma elasticum.</strong>
Clin. Genet. 13: 213-223, 1978.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/627111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">627111</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=627111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.1978.tb04252.x" target="_blank">Full Text</a>]
</p>
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<a id="58" class="mim-anchor"></a>
<a id="Sandberg1981" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Sandberg, L. B., Soskel, N. T., Leslie, J. G.
<strong>Elastin structure, biosynthesis, and relation to disease states.</strong>
New Eng. J. Med. 304: 566-579, 1981.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7005671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7005671</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7005671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM198103053041004" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="59" class="mim-anchor"></a>
<a id="Schon2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Schon, S., Schulz, V., Prante, C., Hendig, D., Szliska, C., Kuhn, J., Kleesiek, K., Gotting, C.
<strong>Polymorphisms in the xylosyltransferase genes cause higher serum XT-1 activity in patients with pseudoxanthoma elasticum (PXE) and are involved in a severe disease course.</strong>
J. Med. Genet. 43: 745-749, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16571645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16571645</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16571645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.2006.040972" target="_blank">Full Text</a>]
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<a id="60" class="mim-anchor"></a>
<a id="Strandberg1929" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Strandberg, J.
<strong>Pseudoxanthoma elasticum.</strong>
Z. Haut Geschlechtskr. 31: 689 only, 1929.
</p>
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<a id="61" class="mim-anchor"></a>
<a id="Struk1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Struk, B., Neldner, K. H., Rao, V. S., St Jean, P., Lindpaintner, K.
<strong>Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1.</strong>
Hum. Molec. Genet. 6: 1823-1828, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302259</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/6.11.1823" target="_blank">Full Text</a>]
</p>
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<a id="62" class="mim-anchor"></a>
<a id="van Soest1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
van Soest, S., Swart, J., Tijmes, N., Sandkuijl, L. A., Rommers, J., Bergen, A. A. B.
<strong>A locus for autosomal recessive pseudoxanthoma elasticum, with penetrance of vascular symptoms in carriers, maps to chromosome 16p13.1.</strong>
Genome Res. 7: 830-834, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9267806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9267806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9267806[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=9267806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1101/gr.7.8.830" target="_blank">Full Text</a>]
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<a id="63" class="mim-anchor"></a>
<a id="Viljoen1987" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Viljoen, D. L., Pope, F. M., Beighton, P.
<strong>Heterogeneity of pseudoxanthoma elasticum: delineation of a new form?</strong>
Clin. Genet. 32: 100-105, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3652487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3652487</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3652487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.1987.tb03333.x" target="_blank">Full Text</a>]
</p>
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<a id="64" class="mim-anchor"></a>
<a id="Viljoen1988" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Viljoen, D.
<strong>Pseudoxanthoma elasticum (Gronblad-Strandberg syndrome).</strong>
J. Med. Genet. 25: 488-490, 1988.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3172143/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3172143</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3172143" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.25.7.488" target="_blank">Full Text</a>]
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<a id="65" class="mim-anchor"></a>
<a id="Zarbock2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zarbock, R., Hendig, D., Szliska, C., Kleesiek, K., Gotting, C.
<strong>Vascular endothelial growth factor gene polymorphisms as prognostic markers for ocular manifestations in pseudoxanthoma elasticum.</strong>
Hum. Molec. Genet. 18: 3344-3351, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19483196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19483196</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19483196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/ddp259" target="_blank">Full Text</a>]
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<span class="mim-text-font">
Ada Hamosh - updated : 06/15/2018
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Jane Kelly - updated : 3/1/2016<br>Marla J. F. O'Neill - updated : 2/8/2012<br>Cassandra L. Kniffin - updated : 11/10/2010<br>George E. Tiller - updated : 7/7/2010<br>Cassandra L. Kniffin - updated : 3/25/2010<br>Cassandra L. Kniffin - updated : 10/14/2009<br>George E. Tiller - updated : 10/28/2008<br>Victor A. McKusick - updated : 3/6/2007<br>Victor A. McKusick - edited : 9/21/2005<br>Victor A. McKusick - updated : 5/11/2004<br>Victor A. McKusick - updated : 11/26/2003<br>Cassandra L. Kniffin - reorganized : 10/24/2003<br>Cassandra L. Kniffin - updated : 10/16/2003<br>Jane Kelly - updated : 8/22/2003<br>Gary A. Bellus - updated : 5/20/2003<br>Victor A. McKusick - updated : 2/22/2002<br>Ada Hamosh - updated : 5/22/2000<br>Victor A. McKusick - updated : 12/15/1999<br>Victor A. McKusick - updated : 7/1/1998<br>Victor A. McKusick - updated : 12/10/1997<br>Victor A. McKusick - updated : 11/4/1997<br>Victor A. McKusick - updated : 9/23/1997
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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Victor A. McKusick : 6/4/1986
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carol : 07/03/2024
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alopez : 07/01/2024<br>carol : 05/30/2019<br>alopez : 06/15/2018<br>carol : 07/09/2016<br>carol : 6/14/2016<br>carol : 6/13/2016<br>carol : 3/1/2016<br>carol : 10/12/2015<br>terry : 3/15/2013<br>alopez : 8/8/2012<br>carol : 2/29/2012<br>carol : 2/24/2012<br>carol : 2/8/2012<br>terry : 7/7/2011<br>terry : 3/14/2011<br>terry : 3/11/2011<br>terry : 3/10/2011<br>wwang : 11/15/2010<br>ckniffin : 11/10/2010<br>wwang : 7/20/2010<br>terry : 7/7/2010<br>wwang : 6/18/2010<br>ckniffin : 3/25/2010<br>wwang : 10/30/2009<br>ckniffin : 10/14/2009<br>terry : 3/24/2009<br>wwang : 10/28/2008<br>alopez : 3/13/2007<br>alopez : 3/9/2007<br>alopez : 3/9/2007<br>terry : 3/6/2007<br>terry : 2/16/2006<br>carol : 1/27/2006<br>carol : 1/24/2006<br>carol : 1/12/2006<br>joanna : 12/20/2005<br>alopez : 9/21/2005<br>alopez : 9/21/2005<br>tkritzer : 6/3/2004<br>terry : 5/11/2004<br>terry : 2/19/2004<br>tkritzer : 12/8/2003<br>tkritzer : 12/4/2003<br>terry : 11/26/2003<br>ckniffin : 10/27/2003<br>carol : 10/24/2003<br>ckniffin : 10/16/2003<br>carol : 8/22/2003<br>alopez : 5/20/2003<br>cwells : 3/13/2002<br>cwells : 3/7/2002<br>terry : 2/22/2002<br>carol : 6/14/2000<br>alopez : 5/22/2000<br>alopez : 12/21/1999<br>mcapotos : 12/17/1999<br>terry : 12/15/1999<br>carol : 10/12/1998<br>carol : 7/14/1998<br>dholmes : 7/13/1998<br>terry : 7/1/1998<br>mark : 12/17/1997<br>terry : 12/10/1997<br>mark : 11/19/1997<br>terry : 11/13/1997<br>terry : 11/4/1997<br>terry : 9/26/1997<br>terry : 9/23/1997<br>davew : 8/19/1994<br>mimadm : 5/17/1994<br>terry : 5/2/1994<br>pfoster : 4/22/1994<br>warfield : 4/19/1994<br>carol : 4/15/1994
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<h3>
<span class="mim-font">
<strong>#</strong> 264800
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<h3>
<span class="mim-font">
PSEUDOXANTHOMA ELASTICUM; PXE
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<span class="mim-font">
<em>Alternative titles; symbols</em>
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<h4>
<span class="mim-font">
GRONBLAD-STRANDBERG SYNDROME
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Other entities represented in this entry:
</span>
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<span class="h3 mim-font">
PSEUDOXANTHOMA ELASTICUM, MODIFIER OF SEVERITY OF, INCLUDED
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<span class="h4 mim-font">
PXE, MODIFIER OF SEVERITY OF, INCLUDED
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<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 252246005, 72744008; &nbsp;
<strong>ORPHA:</strong> 758; &nbsp;
<strong>DO:</strong> 2738; &nbsp;
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<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed 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">
16p13.11
</span>
</td>
<td>
<span class="mim-font">
Pseudoxanthoma elasticum
</span>
</td>
<td>
<span class="mim-font">
264800
</span>
</td>
<td>
<span class="mim-font">
Autosomal recessive
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
ABCC6
</span>
</td>
<td>
<span class="mim-font">
603234
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
16p12.3
</span>
</td>
<td>
<span class="mim-font">
{Pseudoxanthoma elasticum, modifier of severity of}
</span>
</td>
<td>
<span class="mim-font">
264800
</span>
</td>
<td>
<span class="mim-font">
Autosomal recessive
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
XYLT1
</span>
</td>
<td>
<span class="mim-font">
608124
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
17q21.33
</span>
</td>
<td>
<span class="mim-font">
{Pseudoxanthoma elasticum, modifier of severity of}
</span>
</td>
<td>
<span class="mim-font">
264800
</span>
</td>
<td>
<span class="mim-font">
Autosomal recessive
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
XYLT2
</span>
</td>
<td>
<span class="mim-font">
608125
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because in the overwhelming majority of cases of pseudoxanthoma elasticum (PXE), homozygous or compound heterozygous mutations are found in the ABCC6 gene (603234), i.e., PXE is an autosomal recessive disorder. However, carriers of heterozygous mutation in ABCC6 manifest partial manifestations of the disorder (177850). It is thought that instances in which the disease occurs in 2 generations can be attributed to pseudodominance (Bergen, 2006; Ringpfeil et al., 2006; Chassaing et al., 2005; Miksch et al., 2005). </p><p>Polymorphisms in the genes encoding xylosyltransferase, XYLT1 (608124) and XYLT2 (608125), have been reported to modify the severity of PXE.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Pseudoxanthoma elasticum is an inherited multisystem disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Bruch membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye, including peau d'orange, angioid streaks, and choroidal neovascularizations (CNVs); of the skin, including soft, ivory colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces; and of the cardiovascular system, with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings (summary by Finger et al., 2009). </p><p>Generalized arterial calcification of infancy-2 (GACI2; 614473) is an allelic disorder, also caused by homozygous or compound heterozygous mutation in the ABCC6 gene; it has been suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders (Nitschke et al., 2012). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Rigal (1881) is credited with the first description of the skin changes in PXE, and Balzer (1884) provided the first autopsy report. The term 'pseudoxanthoma elasticum' was established by Darier (1896), who histologically demonstrated an abnormality in elastin. Gronblad (1929), a Swedish ophthalmologist, and Strandberg (1929), a Swedish dermatologist, established the relationship of PXE and angioid streaks in the retina (McKusick, 1972).</p><p>Goodman et al. (1963) provided a detailed clinical and histopathologic study of 12 patients with PXE. They noted that the condition had been referred to by several different names since it was first described in 1881. Eight of 12 patients noted skin changes since early childhood, usually on the neck and in the axilla. Changes included accentuated fine lines, redundant skin folds, and lesions consisting of yellowish papules or plaques. Skin changes were also present in the inguinal folds, antecubital and popliteal spaces, and oral, rectal, and vaginal mucosa. Ocular involvement included pigmentary changes, angioid streaks, chorioretinal scarring, and some loss of vision. Five of the 12 patients had gastrointestinal bleeding. Arteriography demonstrated narrowing or occlusion of peripheral arteries with marked collateral circulation, particularly in the upper extremities. Histopathologic studies of skin, heart, and vessels showed calcium deposition in elastic fibers. </p><p>Cartwright et al. (1969) described metachromatic fibroblasts in PXE. By electron microscopy, Ross et al. (1978) demonstrated that the changes in elastic fibers in individuals with PXE involve elastin whereas the microfibrillar component is unchanged. The elastin had a granular appearance, an increased affinity for cations, and often demonstrated increased density presumed to represent foci of calcification. Similar changes were found in clinically unaffected relatives. In 3 families the inheritance was consistent with the autosomal recessive mode and 1 of the presumed heterozygotes showed electron microscopic changes. In 1 kindred (reported also by Altman et al., 1974), the inheritance was apparently more complex than either autosomal dominant or recessive. </p><p>McKusick (1972) presented autopsy findings of endocardial thickening in PXE with degeneration and calcification of elastic fibers and with collagenosis similar to that seen in the skin. Reviewing some of the same autopsy cases, Mendelsohn et al. (1978) emphasized the severe atherosclerosis present in all, resembling that encountered routinely. Fragmentation and degeneration of the elastic laminae of muscular arteries was followed by vascular calcification which could not be distinguished morphologically from Monckeberg arteriosclerosis. There was striking intimal fibroelastotic thickening, particularly in intrarenal arteries. Like McKusick (1972), Mendelsohn et al. (1978) emphasized the striking endocardial changes, e.g., in the right atrium. </p><p>Elejalde et al. (1984) described a 30-year-old woman with PXE who was followed during pregnancy with several fetal ultrasonographic examinations; these showed normal development up to week 26, followed by a marked deceleration of fetal growth. The ultrasonographic appearance of the placenta was abnormal at all times. The baby, born after 36 weeks, was small for gestational age due probably to placental abnormality: the cotyledons were small and more numerous than normal; one-third of the placenta was hypoplastic or atrophic with focal calcification; and striking abnormalities of the elastic lamellae were found in the maternal vessels. Fournier (1984) reported a well-studied patient with PXE from an isolate in the Swiss Valais canton and by genealogic research demonstrated relatedness of several affected families in the region. Livedo reticularis and microaneurysms of intrarenal arteries were observed. </p><p>Challenor et al. (1988) described a 27-year-old man with PXE who presented with pulmonary edema resulting from restrictive left ventricular cardiomyopathy caused by calcified endocardial bands. The bands were resected as far as possible and the involved mitral valve was replaced by a heterograft. A year later calcification of the heterograft forced its replacement by a St. Jude prosthesis. Relief of symptoms was satisfactory. </p><p>Fukuda et al. (1992) described a 54-year-old woman with PXE who over a year of observation developed tight mitral stenosis without regurgitation after having moderate mitral regurgitation due to mitral valve prolapse. Endocardial changes of characteristic type were demonstrated by myocardial biopsy of the right ventricle. It was thought that the echocardiographic findings differed from those in classic rheumatic mitral stenosis. Lebwohl et al. (1993) described 4 patients who presented with premature cardiovascular disease and had angioid streaks but no clinically discernible skin changes of PXE. Characteristic fragmentation and clumping of elastic fibers in the middle and deep dermis with calcification of elastic tissue was demonstrated in all 4 patients. Two of the patients were sisters, aged 27 and 39 years. The younger sister had 4-vessel coronary artery bypass surgery. Multiple arterial biopsies showed calcification of the internal elastic laminae. A 41-year-old brother was subsequently found to have angioid streaks. The father, who died at the age of 69, had a history of retinal hemorrhage. </p><p>In a nationwide study in South Africa and Zimbabwe, Viljoen et al. (1987) identified 64 patients with PXE. In the opinion of these workers, 39 of the patients comprised a distinct clinical subgroup of PXE characterized by autosomal recessive inheritance and severe visual impairment out of proportion to the degree of involvement of the skin. In 40% of individuals, severe hypertension and occasionally angina or claudication were also present. The 39 affected individuals were found exclusively among persons of Afrikaner descent. Viljoen et al. (1987) noted that the 'Afrikaner' form and other forms of PXE are indistinguishable on histology, electron microscopy, or biochemistry, and that clinical differences may not be significant. For example, McKusick (1960) had pointed out the occurrence of inconspicuous skin changes despite severe ocular changes. De Paepe et al. (1991) reported on the clinical and genetic characteristics of 26 Belgian and 32 Afrikaner families with PXE. The phenotype in both groups was characterized by severe ophthalmologic manifestations with milder, variable cutaneous and vascular symptoms. The authors reiterated the suggestion that the PXE phenotype in these Belgian and Afrikaner families is distinct from previously described PXE phenotypes. </p><p>There have been isolated case reports of arterial and skin calcification in mammograms of patients with pseudoxanthoma elasticum, and unpublished anecdotes of many women with PXE undergoing breast biopsy for evaluation of microcalcifications. Bercovitch et al. (2003) systematically evaluated mammography and breast pathology in 51 women with confirmed PXE and compared them with those of a control sample of 109 women without PXE. Breast density, skin thickening, skin microcalcifications, vascular calcification, breast microcalcifications and macrocalcifications, and masses were evaluated specifically. The PXE and control groups were similar in age and indications for mammography. Bercovitch et al. (2003) found a statistically significant increase in skin thickening, vascular calcification, and breast microcalcifications in the PXE group (P less than 0.001 each). Breast density, masses, macrocalcifications, and skin calcification did not differ statistically in the 2 groups, but no control patient had axillary calcification, or both vascular calcification and microcalcifications (p less than 0.001). About 1 in 7 of the patients with PXE demonstrated at least 3 of the following: microcalcifications, skin calcifications, vascular calcification, and skin thickening; however, none of the control group did. Histopathologic findings of breast tissue showed calcification of dermal elastic fibers, subcutaneous arteries, and elastic fibers of the deep fascia and interlobular septae of the fat adjacent to breast parenchyma. Bercovitch et al. (2003) concluded that breast microcalcification and arterial calcification are not rare in the normal population and are not of diagnostic value. However, the presence of both of these findings, especially with skin thickening or axillary skin calcification, should suggest a diagnosis of PXE. The majority of breast calcifications in PXE are benign. </p><p>Orssaud et al. (2015) reviewed the nature and age of onset of ophthalmologic manifestations in 40 consecutive patients with PXE. The mean age of patients was 53.32 years. Best corrected visual acuity (BCVA) was equal to or less than 20/50 in at least 1 eye in 73.3% of patients over the age of 52 and in 20% of patients younger than age 52. Angioid streaks were observed in 38 patients (93.75%). Macular involvement was observed for the first time at a mean age of 44.28 years. Neovascularization was observed in 17 patients (mean age, 51.70 years), all with poor BCVA. The authors noted that in addition to the well-known findings of peau d'orange and comet lesions, other PXE features include chorioretinal atrophy, subretinal fluid independent of CNV, pattern dystrophy-like changes, debris accumulation under the RPE, reticular drusen, and a decreased fluorescence on late-phase indocyanine green angiography. </p><p>Legrand et al. (2017) performed a molecular analysis on 458 French PXE probands who were clinically evaluated using the Phenodex score (PS). Among the 220 cases with a complete PS score, there was a higher prevalence of eye features in Caucasian patients (p = 0.03) and more severe eye and vascular phenotype in patients with loss-of-function variants (p = 0.02 and 0.05, respectively). Nephrolithiases and strokes, absent from the PS, were prevalent features of the disorder (11% and 10%, respectively). </p><p><strong><em>Intrafamilial Phenotypic Variability</em></strong></p><p>
Le Boulanger et al. (2010) studied a nonconsanguineous French family in which an older brother developed uncomplicated PXE in adolescence, whereas a younger brother died of a condition 'strikingly reminiscent' of generalized arterial calcification of infancy (GACI2; 614473) at 15 months of age. The younger brother had a myocardial infarction complicated by heart failure at 6 months of age, and skin biopsy at 1 year of age for evaluation of a possible connective tissue disorder showed elastic fiber dystrophy, with clumped and fragmented fibers in the mid dermis, as well as calcifications on the elastic fibers and sporadically in vessel walls of the subcutis. At 15 months of age, he had a second, fatal MI, and autopsy showed fibrosis of the coronary arteries with calcifications involving the intima, internal elastic lamina, and media. At 28 years of age, the older brother presented for evaluation of yellowish papules on his neck; he had no cardiovascular symptoms and cardiac examination and echocardiography were normal. Skin samples from the brother with PXE showed heavy staining of mineralized mid-dermal elastic fibers, with active MGP (154870) and fetuin-A (138680) antibodies, and fetuin-A also showed striking staining of the subepidermal area. All arteries in autopsy samples from the brother with GACI showed the same immunohistochemical profile, as well as calcifications. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Lebwohl et al. (1987) biopsied scars as well as flexural skin from 10 patients with angioid streaks but without cutaneous findings indicative of PXE. In 6 of the 10 patients, scar biopsies showed fragmentation and clumping of elastic tissue in the deep dermis. Three patients also had histologic changes of PXE in biopsy specimens of flexural skin that appeared normal. The authors concluded that scar biopsies may be useful in diagnosis when PXE is suspected despite the absence of typical skin lesions. </p><p>In a report of a consensus conference on PXE, Lebwohl et al. (1994) stated that histologic evidence of calcified elastic fibers is essential for diagnosis. The group proposed a provisional classification system of PXE patients who may lack one or more of the 3 major criteria: skin, eye, or cardiovascular involvement. However, the group also noted that in time, all patients with PXE tend to merge into a single classic phenotype with all 3 features, and that separation into subtypes based on phenotype is difficult. </p><p>Struk et al. (1997) noted that the 'gold standard' for diagnosis of PXE is positive von Kossa staining showing calcification and fracture of elastic fibers in biopsy material from affected skin. </p><p>Plomp et al. (2010) reviewed the major clinical signs of PXE and proposed an updated classification system for the disorder, including revised diagnostic criteria. Diagnostic criteria included skin findings confirmed by skin biopsy, ocular findings corroborated by funduscopy, and mutation analysis of the ABCC6 gene. Additional minor criteria included the findings of 'comets' in the retina or 'pigmented wing' signs in the retina. Patients can be classified as having a definite, probable, or possible diagnosis based on the number of signs present. </p><p><strong><em>Differential Diagnosis</em></strong></p><p>
The occurrence of angioid streaks in homozygous thalassemia and in sickle cell anemia has been attributed to the deposition of iron in Bruch membrane behind the retina. Severe ophthalmologic complications like those of PXE may occur in some cases (Aessopos et al., 1989). Angioid streaks in hemochromatosis are presumably also a reflection of iron deposits. The occurrence of angioid streaks with Paget disease of bone (167250) and with tumoral calcinosis with hyperphosphatemia (211900) may be related to the deposition of calcium in a relatively normal Bruch membrane. Angioid streaks are said to occur with lead poisoning (Clarkson and Altman, 1982). Aessopos et al. (1992) suggested that beta-thalassemia must be considered in the differential diagnosis of PXE because of the occurrence of PXE-like skin lesions as well as angioid streaks. In 62 patients with homozygous beta-thalassemia major and 38 with beta-thalassemia intermedia, they found diagnostic skin lesions in 16 patients. Angioid streaks were found in 20 of the 100 patients, and both PXE skin lesions and angioid streaks were found in 10 of the patients; in all, 26 had either one or both of these manifestations. A positive correlation was found between the presence of one or both types of lesion and age of the patients; there were no differences in regard to ferritin and hematocrit levels, number of transfused units, chelation therapy, and splenic status between patients with or without the findings of PXE. One might wonder about iron loading as the mechanism of the PXE-like changes. Angioid streaks were described in homozygous sickle cell disease by Nagpal et al. (1976), Hamilton et al. (1981), and others. Aessopos et al. (2002) reviewed elastic tissue abnormalities resembling PXE in beta-thalassemia and sickling syndromes. </p><p>Hamlin et al. (2003) reported the clinical and histopathologic manifestations of 10 beta-thalassemia patients with PXE-like skin lesions in combination with ocular and/or vascular symptoms and calcified elastic fibers. No disease-causing variant was found in the ABCC6 (603234) gene, indicating that this was a phenocopy of PXE. Hamlin et al. (2003) discussed the hypothesis that as iron loading progresses in beta-thalassemic patients, the capacity for the transport and storage of iron may be exceeded, and a fraction of iron that is not bound to transferrin or ferritin may promote the generation of free radicals, which are in turn propagators of oxidation-related damage to various organs and tissues, including elastin-rich tissues. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The assessment of inheritance in PXE has been complicated by clinical heterogeneity and variable age of onset (Neldner, 1988). </p><p>Miksch et al. (2005) performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. Their mutation analysis confirmed an earlier haplotype-based analysis and conclusions regarding a recessive-only mode of inheritance in PXE (Cai et al., 2000) through the identification of 2 mutated alleles in all individuals with PXE who appear in either consecutive or alternating generations of the same family. Their study demonstrated that the full phenotypic expression of the disorder requires 2 defective allelic copies of ABCC6 and that pseudodominance is the mode of transmission in presumed autosomal dominant families (i.e., the second parental disease allele 'marries into' the family). The apparent frequency of this mechanism was approximately 7.5% in their family cohort. Miksch et al. (2005) stated that in their families no heterozygote for a large deletion showed any apparent clinical sign of PXE according to category I diagnostic criteria. </p><p>To determine the exact mode of inheritance of PXE, Ringpfeil et al. (2006) identified 7 pedigrees with affected individuals in 2 different generations and sequenced the entire coding region of ABCC6 in affected persons and in presumed carriers with a limited phenotype, as well as unaffected family members. Two allelic mutations were identified in each individual with unambiguous diagnosis of PXE, as well as in those with only minimal clinical signs suggestive of PXE but with positive skin biopsy. Missense mutations were frequently detected in the latter cases. Ringpfeil et al. (2006) concluded that PXE is inherited as an autosomal recessive trait and that those instances in which the disease occurs in 2 generations can be attributed to pseudodominance. Bergen (2006) maintained that this and other work such as that of Chassaing et al. (2005) and Miksch et al. (2005) puts an end to the 'autosomal dominant segregation myth' (see HISTORY). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Since the ABCC6 gene (603234) is expressed primarily, if not exclusively, in the liver and kidneys, Ringpfeil et al. (2001) suggested that PXE is a primary metabolic disorder with secondary involvement of elastic fibers, a situation comparable to the secondary involvement of connective tissue elements in homocystinuria (236200) and alkaptonuria (203500). </p><p>ABCC6 is a member of the large ATP-dependent transmembrane transporter family. Chassaing et al. (2005) commented that the association of PXE to ABCC6 efflux transport alterations raised a number of pathophysiology hypotheses, among them the idea that PXE is a systemic metabolic disease resulting from lack or accumulation over time in the bloodstream of molecules interacting with the synthesis, turnover, and/or maintenance of extracellular matrix (ECM). </p><p>Findings in mouse models (see ANIMAL MODEL) have also indicated that PXE is a systemic metabolic disease (Jiang et al., 2009). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In an abstract presented at the Fifth International Workshop on Human Chromosome 16, on 3-4 March 1997 in Toronto, and in a subsequent full publication, Struk et al. (1997) reported a genomewide screen on a collection of 38 families with 2 or more sibs with PXE. They used allele-sharing algorithms, followed by high-resolution mapping and analysis by conventional linkage algorithms in recessive and dominant families. Excess allele-sharing was found on the short arm of chromosome 16 and confirmed by maximum-likelihood linkage analysis, localizing the disease gene in recessive families to a 3.0-cM region on 16p13.1 with a maximum 2-point lod score of 19.0. In dominant families, linkage to the same region with a maximum 2-point lod score of 3.6 was observed. Struk et al. (1997) predicted that allelic heterogeneity with different variants of a single disease gene residing on 16p13.1 accounts for both recessive and dominant forms of PXE. </p><p>In a family from a genetically isolated population in the Netherlands suffering from autosomal recessive PXE, van Soest et al. (1997) combined homozygosity mapping and genome scanning to map the PXE1 locus to 16p13.1. Initially, homozygosity was found in 2 or 3 patients with up to 20 markers, among which was D16S292 located in 16p13.1. Refined and more extensive family screening of the latter region showed close linkage without recombination with the marker D16S764 (maximum lod = 6.27). Despite clear autosomal recessive inheritance of the ocular symptoms in this disorder, vascular symptoms appeared in 40 to 50% of the heterozygotes. </p><p>Le Saux et al. (1999) performed linkage analysis on 21 families with PXE using 10 polymorphic markers located on 16p13.1. They localized the gene to an 8-cM region of 16p13.1 between markers D16S500 and D16S3041 with a maximum lod score of 8.1 at a recombination fraction of 0.04 for marker D16S3017. They found no evidence of locus heterogeneity. Haplotype studies of 36 PXE families identified several recombinations that further confined the PXE gene to a region of less than 1 cM between markers D16S3060 and D16S79. The PXE locus was identified within a single YAC clone and several overlapping BAC recombinants. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In several families with PXE, Ringpfeil et al. (2000), Bergen et al. (2000), and Le Saux et al. (2000) identified mutations in the ABCC6 gene. Of 4 families with autosomal recessive inheritance of PXE reported by Ringpfeil et al. (2000), 1 was compound heterozygous for mutations in the ABCC6 gene (see, e.g., R1141X, 603234.0001), 1 family was hemizygous for the R1141X mutation, and 2 families were homozygous for mutations. Of 4 so-called sporadic cases, 1 was compound heterozygous and 3 appeared heterozygous for mutations in the ABCC6 gene. Bergen et al. (2000) identified mutations in the ABCC6 gene in 2 sporadic patients with PXE (see, e.g., 603234.0009), 4 families with PXE that appeared to be autosomal dominant (see, e.g., 603234.0008), and 1 family with autosomal recessive PXE (603234.0007). Le Saux et al. (2000) identified mutations in the ABCC6 gene in 5 families with autosomal recessive PXE and in 1 sporadic case (see, e.g., 603234.0001 and 603234.0002). The R1141X mutation (603234.0001) was found in families segregating autosomal recessive PXE and in families with expressing heterozygotes. </p><p>Using multiplex ligation-dependent probe amplification (MLPA) to analyze 35 PXE patients with incomplete ABCC6 genotypes after exonic sequencing, Costrop et al. (2010) identified 6 multiexon deletions and 4 single-exon deletions and were thus able to characterized 25% of the unidentified disease alleles. The findings illustrated the instability of the ABCC6 genomic region and stressed the importance of screening for deletions in the molecular diagnosis of PXE. </p><p>In a 28-year-old French man with pseudoxanthoma elasticum who had a younger brother who died of generalized arterial calcification of infancy (GACI2; 614473) at age 15 months, Le Boulanger et al. (2010) identified compound heterozygosity for missense mutations in the ABCC6 gene (603234.0025 and 603234.0026), which were also found in heterozygosity in each of his unaffected parents, respectively. No disease-causing mutations were found in the ENPP1 gene (173335), which is known to cause GACI1 (208000). Although no DNA material was available from the deceased younger brother, his disease was presumed to be related to the familial ABCC6 mutations. Le Boulanger et al. (2010) concluded that GACI may represent an atypical and severe end of the vascular phenotypic spectrum of PXE. </p><p><strong><em>PXE-Associated Retinopathy</em></strong></p><p>
Choroidal neovascularization (CNV) in PXE-associated retinopathy is believed to be mediated by the action of VEGF (192240). Zarbock et al. (2009) evaluated the distribution of 10 SNPs in the promoter and coding region of the VEGFA gene in DNA samples from 163 German patients affected by PXE and in 163 healthy control subjects. Haplotype analysis identified an 8-SNP haplotype CTGGCCCC that was associated with PXE. Furthermore, 5 SNPs showed significant association with severe retinopathy. The most significant single SNP association was -460C-T (rs833061, OR = 3.83, 95% CI 2.01-7.31, corrected p = 0.0003). Logistic regression analysis identified the rs833061 and 674C-T variant (rs1413711; OR = 3.21, 95% CI 1.70-6.02, corrected p = 0.004) as independent risk factors for development of severe retinopathy. Zarbock et al. (2009) suggested an involvement of VEGF in the pathogenesis of ocular PXE manifestations. </p><p><strong><em>Modifier Genes</em></strong></p><p>
Schon et al. (2006) reported that polymorphisms in the XYLT1 and XYLT2 genes (608124.0001 and 608125.0001, respectively) modify the severity of PXE. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Struk et al. (1997) estimated that the prevalence of PXE, both the recessive and dominant forms, is 1 in 70,000 to 100,000. </p><p>In a cohort of 122 unrelated PXE patients from various countries, Le Saux et al. (2001) identified a G1321S missense mutation in the ABCC6 gene (603234.0021). The G1321S mutation was detected in heterozygosity in 1 of 74 United States alleles, for an allele frequency of 1.4%, but was not found in the European population. </p><p>Hu et al. (2003) demonstrated a founder effect for the R1141X mutation (603234.0001) in the Netherlands. They identified the mutation in 19 alleles in 16 Dutch patients with PXE, in heterozygous, homozygous, or compound heterozygous form. Expression of the normal allele in heterozygotes was predominant; no or very low expression was found in homozygotes. The mutation induced instability of the aberrant mRNA. Hu et al. (2003) suggested that the PXE phenotype of the R1141X mutation most likely results from complete loss of function or functional haploinsufficiency of ABCC6. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Gorgels et al. (2005) generated Abcc6 -/- mice and showed by light and electron microscopy that Abcc6 -/- mice spontaneously developed calcification of elastic fibers in blood vessel walls and in Bruch membrane in the eye. No clear abnormalities were seen in the dermal extracellular matrix. Calcification of blood vessels was most prominent in small arteries in the cortex of the kidney, but in old mice, it occurred also in other organs and in the aorta and vena cava. Monoclonal antibodies against mouse Abcc6 localized the protein to the basolateral membranes of hepatocytes and the basal membrane in renal proximal tubules, but failed to show the protein at the pathogenic sites. Abcc6 -/- mice developed a 25% reduction in plasma HDL cholesterol and an increase in plasma creatinine levels, which may be due to impaired kidney function. No changes in serum mineral balance were found. Gorgels et al. (2005) concluded that the phenotype of the Abcc6 -/- mouse shares calcification of elastic fibers with human PXE pathology, and supports the hypothesis that PXE is a systemic disease. </p><p>Jiang et al. (2009) found that grafting of wildtype mouse muzzle skin onto the back of Abcc6-knockout mice resulted in abnormal mineralization of vibrissae consistent with PXE, whereas grafting of Abcc6-knockout mouse muzzle skin onto wildtype mice did not. The data implied that PXE does not result from localized defect based on resident cellular abnormalities but from a change of metabolite(s) in serum. These findings implicate circulatory factors as a critical component of the mineralization process and supported the notion that PXE is a secondary mineralization of connective tissues. In addition, the findings suggested that the abnormal mineralization process could possibly be countered or even reversed by changes in the homeostatic milieu. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>Autosomal Dominant Inheritance</em></strong></p><p>
Pope (1974) suggested that there are 2 dominant and 2 recessive forms of PXE (see below). </p><p>Neldner (1988) concluded that 97% of his patients had autosomal recessive inheritance. His conclusion did not allow for new mutation dominant cases. </p><p>In a report of a consensus conference, Lebwohl et al. (1994) stated that both autosomal dominant and autosomal recessive forms of PXE exist, and that no clinical features can distinguish between the 2 disorders. </p><p>Struk et al. (1997) stated that an autosomal dominant pattern of transmission of PXE occurs in approximately 10% of affected families. </p><p>Plomp et al. (2004) reviewed the literature on autosomal dominant PXE. They studied in detail, both clinically and by DNA studies, a selection of potentially autosomal dominant pedigrees from a patient population comprising 59 probands and their relatives. Individuals were considered to have definite PXE if they had 2 of the following 3 criteria: characteristic ophthalmologic signs, characteristic dermatologic signs, and positive skin biopsy. In the literature, Plomp et al. (2004) found only 3 families with definite PXE in 2 successive generations and no families with definite PXE in 3 or more generations. Their own data set included 3 putative autosomal dominant families. Extensive DNA studies revealed a mutation in only 1 ABCC6 allele in the patients of these 3 families. Only 1 of the families showed definite PXE in 2 generations. Linkage studies revealed that pseudodominance was unlikely in this family. In the other 2 families, autosomal dominant PXE could not be confirmed after extensive clinical examinations and application of the criteria, since definite PXE was not present in 2 or more generations. Plomp et al. (2004) concluded that the inheritance pattern in PXE is autosomal recessive in the overwhelming majority of families. </p><p>Hu et al. (2004) cited the investigation of Plomp et al. (2004) as indicating that autosomal dominant inheritance of PXE can be expected in approximately 2% of cases. </p><p><strong><em>Classification</em></strong></p><p>
Pope (1974) suggested that there are 2 dominant and 2 recessive forms of PXE. The type I recessive form was characterized by moderate vascular and retinal degeneration accompanied by cutaneous lesions. The type II recessive form was characterized by generalized skin changes with no blood vessel or ocular manifestations, and was considered rare, being present in 3 of 121 probands. Individuals with the type I dominant form had severe retinal and cardiovascular degeneration, accompanied by the cutaneous features. Those with the type II dominant form had mild cardiovascular and retinal changes together with hyperextensible joints, blue sclerae, and a high arched palate. </p><p>On the basis of his own extensive experience and that reported in the literature, Neldner (1988) provided a critique of the Pope 4-subtype classification. Whereas only 47% of 121 patients studied by Pope in the U.K. were thought to have the recessive form, the more general experience is that the recessive form of PXE is by far the more frequent. </p><p><strong><em>Other Inheritance</em></strong></p><p>
Berlyne et al. (1961) suggested that PXE may be inherited as a partial X-linked recessive (i.e., that the gene may be on a part of the X chromosome homologous with part of the Y chromosome). If such were the case, patients in any one sibship would tend always to be of the same sex. This mode of inheritance was not supported by later work.</p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Coffman and Sommers (1959); Messis and Budzilovich (1970); Pope
(1975); Renie et al. (1984); Sandberg et al. (1981); Viljoen (1988)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
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Le Saux, O., Urban, Z., Goring, H. H. H., Csiszar, K., Pope, F. M., Richards, A., Pasquali-Ronchetti, I., Terry, S., Bercovitch, L., Lebwohl, M. G., Breuning, M., van den Berg, P., Kornet, L., Doggett, N., Ott, J., de Jong, P. T. V. M., Bergen, A. A. B., Boyd, C. D.
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Lebwohl, M., Phelps, R. G., Yannuzzi, L., Chang, S., Schwartz, I., Fuchs, W.
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Legrand, A., Cornez, L., Samkari, W., Mazzella, J.-M., Venisse, A., Boccio, V., Auribault, K., Keren, B., Benistan, K., Germain, D. P., Frank, M., Jeunemaitre, X., Albuisson, J.
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McKusick, V. A.
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McKusick, V. A.
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Mendelsohn, G., Bulkley, B. H., Hutchins, G. M.
<strong>Cardiovascular manifestations of pseudoxanthoma elasticum.</strong>
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<p class="mim-text-font">
Messis, C. P., Budzilovich, G. N.
<strong>Pseudoxanthoma elasticum: report of an autopsied case with cerebral involvement.</strong>
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Miksch, S., Lumsden, A., Guenther, U. P., Foernzler, D., Christen-Zach, S., Daugherty, C., Ramesar, R. S., Lebwohl, M., Hohl, D., Neldner, K. H., Lindpaintner, K., Richards, R. I., Struk, B.
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Nagpal, K. C., Asdourian, G., Goldbaum, M., Apple, D., Goldberg, M. F.
<strong>Angioid streaks and sickle haemoglobinopathies.</strong>
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Neldner, K. H.
<strong>Pseudoxanthoma elasticum.</strong>
Clin. Derm. 6: 83-92, 1988.
[PubMed: 3359381]
[Full Text: https://doi.org/10.1016/0738-081x(88)90003-x]
</p>
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<p class="mim-text-font">
Nitschke, Y., Baujat, G., Botschen, U., Wittkampf, T., du Moulin, M., Stella, J., Le Merrer, M., Guest, G., Lambot, K., Tazarourte-Pinturier, M.-F., Chassaing, N., Roche, O., and 19 others.
<strong>Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.</strong>
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[PubMed: 22209248]
[Full Text: https://doi.org/10.1016/j.ajhg.2011.11.020]
</p>
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<li>
<p class="mim-text-font">
Orssaud, C., Roche, O., Dufier, J.-L., Germain, D. P.
<strong>Visual impairment in pseudoxanthoma elasticum: a survey of 40 patients.</strong>
Ophthalmic Genet. 36: 327-332, 2015.
[PubMed: 24749718]
[Full Text: https://doi.org/10.3109/13816810.2014.886268]
</p>
</li>
<li>
<p class="mim-text-font">
Plomp, A. S., Hu, X., de Jong, P. T. V. M., Bergen, A. A. B.
<strong>Does autosomal dominant pseudoxanthoma elasticum exist?</strong>
Am. J. Med. Genet. 126A: 403-412, 2004.
[PubMed: 15098239]
[Full Text: https://doi.org/10.1002/ajmg.a.20632]
</p>
</li>
<li>
<p class="mim-text-font">
Plomp, A. S., Toonstra, J., Bergen, A. A. B., van Dijk, M. R., de Jong, P. T. V. M.
<strong>Proposal for updating the pseudoxanthoma elasticum classification system and a review of the clinical findings.</strong>
Am. J. Med. Genet. 152A: 1049-1058, 2010.
[PubMed: 20358627]
[Full Text: https://doi.org/10.1002/ajmg.a.33329]
</p>
</li>
<li>
<p class="mim-text-font">
Pope, F. M.
<strong>Two types of autosomal recessive pseudoxanthoma elasticum.</strong>
Arch. Derm. 110: 209-212, 1974.
[PubMed: 4855282]
</p>
</li>
<li>
<p class="mim-text-font">
Pope, F. M.
<strong>Historical evidence for the genetic heterogeneity of pseudoxanthoma elasticum.</strong>
Brit. J. Derm. 92: 493-509, 1975.
[PubMed: 1100089]
[Full Text: https://doi.org/10.1111/j.1365-2133.1975.tb03117.x]
</p>
</li>
<li>
<p class="mim-text-font">
Renie, W. A., Pyeritz, R. E., Combs, J., Fine, S. L.
<strong>Pseudoxanthoma elasticum: high calcium intake in early life correlates with severity.</strong>
Am. J. Med. Genet. 19: 235-244, 1984.
[PubMed: 6507474]
[Full Text: https://doi.org/10.1002/ajmg.1320190205]
</p>
</li>
<li>
<p class="mim-text-font">
Rigal, (NI).
<strong>Observation pour servir a l&#x27;histoire de la cheloide diffuse xanthelasmique.</strong>
Ann. Derm. Syph. 21: 491-501, 1881.
</p>
</li>
<li>
<p class="mim-text-font">
Ringpfeil, F., Lebwohl, M.G., Christiano, A. M., Uitto, J.
<strong>Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter.</strong>
Proc. Nat. Acad. Sci. 97: 6001-6006, 2000.
[PubMed: 10811882]
[Full Text: https://doi.org/10.1073/pnas.100041297]
</p>
</li>
<li>
<p class="mim-text-font">
Ringpfeil, F., McGuigan, K., Fuchsel, L., Kozic, H., Larralde, M., Lebwohl, M., Uitto, J.
<strong>Pseudoxanthoma elasticum is a recessive disease characterized by compound heterozygosity.</strong>
J. Invest. Derm. 126: 782-786, 2006.
[PubMed: 16410789]
[Full Text: https://doi.org/10.1038/sj.jid.5700115]
</p>
</li>
<li>
<p class="mim-text-font">
Ringpfeil, F., Pulkkinen, L., Uitto, J.
<strong>Molecular genetics of pseudoxanthoma elasticum.</strong>
Exp. Derm. 10: 221-228, 2001.
[PubMed: 11493310]
[Full Text: https://doi.org/10.1034/j.1600-0625.2001.100401.x]
</p>
</li>
<li>
<p class="mim-text-font">
Ross, R., Fialkow, P. J., Altman, L. K.
<strong>Fine structure alterations of elastic fibers in pseudoxanthoma elasticum.</strong>
Clin. Genet. 13: 213-223, 1978.
[PubMed: 627111]
[Full Text: https://doi.org/10.1111/j.1399-0004.1978.tb04252.x]
</p>
</li>
<li>
<p class="mim-text-font">
Sandberg, L. B., Soskel, N. T., Leslie, J. G.
<strong>Elastin structure, biosynthesis, and relation to disease states.</strong>
New Eng. J. Med. 304: 566-579, 1981.
[PubMed: 7005671]
[Full Text: https://doi.org/10.1056/NEJM198103053041004]
</p>
</li>
<li>
<p class="mim-text-font">
Schon, S., Schulz, V., Prante, C., Hendig, D., Szliska, C., Kuhn, J., Kleesiek, K., Gotting, C.
<strong>Polymorphisms in the xylosyltransferase genes cause higher serum XT-1 activity in patients with pseudoxanthoma elasticum (PXE) and are involved in a severe disease course.</strong>
J. Med. Genet. 43: 745-749, 2006.
[PubMed: 16571645]
[Full Text: https://doi.org/10.1136/jmg.2006.040972]
</p>
</li>
<li>
<p class="mim-text-font">
Strandberg, J.
<strong>Pseudoxanthoma elasticum.</strong>
Z. Haut Geschlechtskr. 31: 689 only, 1929.
</p>
</li>
<li>
<p class="mim-text-font">
Struk, B., Neldner, K. H., Rao, V. S., St Jean, P., Lindpaintner, K.
<strong>Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1.</strong>
Hum. Molec. Genet. 6: 1823-1828, 1997.
[PubMed: 9302259]
[Full Text: https://doi.org/10.1093/hmg/6.11.1823]
</p>
</li>
<li>
<p class="mim-text-font">
van Soest, S., Swart, J., Tijmes, N., Sandkuijl, L. A., Rommers, J., Bergen, A. A. B.
<strong>A locus for autosomal recessive pseudoxanthoma elasticum, with penetrance of vascular symptoms in carriers, maps to chromosome 16p13.1.</strong>
Genome Res. 7: 830-834, 1997.
[PubMed: 9267806]
[Full Text: https://doi.org/10.1101/gr.7.8.830]
</p>
</li>
<li>
<p class="mim-text-font">
Viljoen, D. L., Pope, F. M., Beighton, P.
<strong>Heterogeneity of pseudoxanthoma elasticum: delineation of a new form?</strong>
Clin. Genet. 32: 100-105, 1987.
[PubMed: 3652487]
[Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb03333.x]
</p>
</li>
<li>
<p class="mim-text-font">
Viljoen, D.
<strong>Pseudoxanthoma elasticum (Gronblad-Strandberg syndrome).</strong>
J. Med. Genet. 25: 488-490, 1988.
[PubMed: 3172143]
[Full Text: https://doi.org/10.1136/jmg.25.7.488]
</p>
</li>
<li>
<p class="mim-text-font">
Zarbock, R., Hendig, D., Szliska, C., Kleesiek, K., Gotting, C.
<strong>Vascular endothelial growth factor gene polymorphisms as prognostic markers for ocular manifestations in pseudoxanthoma elasticum.</strong>
Hum. Molec. Genet. 18: 3344-3351, 2009.
[PubMed: 19483196]
[Full Text: https://doi.org/10.1093/hmg/ddp259]
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Ada Hamosh - updated : 06/15/2018<br>Jane Kelly - updated : 3/1/2016<br>Marla J. F. O&#x27;Neill - updated : 2/8/2012<br>Cassandra L. Kniffin - updated : 11/10/2010<br>George E. Tiller - updated : 7/7/2010<br>Cassandra L. Kniffin - updated : 3/25/2010<br>Cassandra L. Kniffin - updated : 10/14/2009<br>George E. Tiller - updated : 10/28/2008<br>Victor A. McKusick - updated : 3/6/2007<br>Victor A. McKusick - edited : 9/21/2005<br>Victor A. McKusick - updated : 5/11/2004<br>Victor A. McKusick - updated : 11/26/2003<br>Cassandra L. Kniffin - reorganized : 10/24/2003<br>Cassandra L. Kniffin - updated : 10/16/2003<br>Jane Kelly - updated : 8/22/2003<br>Gary A. Bellus - updated : 5/20/2003<br>Victor A. McKusick - updated : 2/22/2002<br>Ada Hamosh - updated : 5/22/2000<br>Victor A. McKusick - updated : 12/15/1999<br>Victor A. McKusick - updated : 7/1/1998<br>Victor A. McKusick - updated : 12/10/1997<br>Victor A. McKusick - updated : 11/4/1997<br>Victor A. McKusick - updated : 9/23/1997
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Victor A. McKusick : 6/4/1986
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