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Entry
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- #208000 - ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1; GACI1
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- OMIM
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<p>
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<span class="h4">#208000</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/208000"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS208000"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</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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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div style="display: table-cell;">External Links</div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=10675&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK253403/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/590" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=208000[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=51608" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0050644" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/208000" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0050644" 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 panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:208000" 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>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 51608<br />
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<strong>DO:</strong> 0050644<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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208000
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1; GACI1
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
GACI<br />
|
|
IDIOPATHIC INFANTILE ARTERIAL CALCIFICATION; IIAC<br />
|
|
ARTERIAL CALCIFICATION, IDIOPATHIC INFANTILE<br />
|
|
ARTERIOPATHY, OCCLUSIVE INFANTILE
|
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</span>
|
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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CORONARY SCLEROSIS, MEDIAL, OF INFANCY, INCLUDED
|
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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<th>
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Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/6/859?start=-3&limit=10&highlight=859">
|
|
6q23.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Arterial calcification, generalized, of infancy, 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/208000"> 208000 </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">
|
|
ENPP1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/173335"> 173335 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/208000" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS208000" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/208000" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/208000" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal 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> GROWTH </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Height </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Short stature (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422065006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422065006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237836003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237836003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237837007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237837007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E34.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E34.31</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R62.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R62.52</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.43" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.43</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349588&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349588</a>, <a href="https://bioportal.bioontology.org/search?q=C0013336&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013336</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003510</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Ears </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Deafness, conductive (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44057004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44057004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H90.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H90.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018777&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018777</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000405" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000405</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Angioid retinal streaks (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240894&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240894</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Teeth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Infraocclusion <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4746746&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4746746</a>]</span><br /> -
|
|
Overretained primary teeth <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4746747&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4746747</a>]</span><br /> -
|
|
Ankylosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36504009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36504009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111227009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111227009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M24.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M24.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/718.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">718.50</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/718.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">718.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003090&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003090</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031013</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031013" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031013</a>]</span><br /> -
|
|
Reduced tooth movement with orthodontic treatment <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4746748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4746748</a>]</span><br /> -
|
|
Hypercementosis of cervical cementum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4746749&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4746749</a>]</span><br /> -
|
|
Protruding cervical root morphology (in primary and/or secondary dentition) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4746750&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4746750</a>]</span><br /> -
|
|
Increased cervical cementum thickness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4746751&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4746751</a>]</span><br /> -
|
|
Increased cervical cementum mineral density <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4746752&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4746752</a>]</span><br /> -
|
|
Cementocyte-like cells in cervical cementum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4746753&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4746753</a>]</span><br /> -
|
|
Lacunae in cervical cementum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4746754&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4746754</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Neck </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Pseudoxanthomatous skin lesions (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277905&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277905</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">
|
|
|
|
- Coronary artery calcification <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/445512009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">445512009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1611184&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1611184</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001717" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001717</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001717" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001717</a>]</span><br /> -
|
|
Myocardial infarction <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22298006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22298006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I22" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I22</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/I21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I21</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2926063&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2926063</a>, <a href="https://bioportal.bioontology.org/search?q=C0027051&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027051</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001658" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001658</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001658" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001658</a>]</span><br /> -
|
|
Cardiac dysfunction <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277906&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277906</a>]</span><br /> -
|
|
Heart failure <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/84114007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">84114007</a>, <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" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I50</a>, <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>, <a href="https://purl.bioontology.org/ontology/ICD9CM/428" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">428</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/428.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">428.9</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>, <a href="https://bioportal.bioontology.org/search?q=C0018801&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018801</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 />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Generalized calcification of arteries, including aorta and intraparenchymal arteries <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277907&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277907</a>]</span><br /> -
|
|
Arterial stenosis due to myointimal proliferation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277908&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277908</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/726490008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">726490008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/68109007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">68109007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I77.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I77.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/447.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">447.1</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100545" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100545</a>]</span><br /> -
|
|
Hypertension <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38341003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38341003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/401-405.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">401-405.99</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/997.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">997.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020538&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020538</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span><br /> -
|
|
Panarteritis (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234959&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234959</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
|
|
|
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|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> External Features </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Periumbilical pseudoxanthomatous skin lesions (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277902&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277902</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
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|
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|
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|
|
</div>
|
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|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Periarticular calcification (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237898004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237898004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0342650&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0342650</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025477" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025477</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025477" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025477</a>]</span><br /> -
|
|
Hypophosphatemic rickets (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/66266003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">66266003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/72831007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">72831007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3536983&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3536983</a>, <a href="https://bioportal.bioontology.org/search?q=C1704375&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1704375</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004912" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004912</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004912" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004912</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Pseudoxanthomatous skin lesions (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277905&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277905</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> METABOLIC FEATURES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hypophosphatemia due to decreased renal tubular phosphate reabsorption <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3277913&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3277913</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/4996001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">4996001</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002148" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002148</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Most patients die in infancy<br /> -
|
|
Features of pseudoxanthoma elasticum seen in later childhood in some surviving patients<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the ectonucleotide pyrophosphatase/phosphodiesterase-1 gene (ENPP1, <a href="/entry/173335#0002">173335.0002</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Generalized arterial calcification of infancy
|
|
- <a href="/phenotypicSeries/PS208000">PS208000</a>
|
|
- 2 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/6/859?start=-3&limit=10&highlight=859"> 6q23.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/208000"> Arterial calcification, generalized, of infancy, 1 </a>
|
|
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<p>A number sign (#) is used with this entry because of evidence that generalized arterial calcification of infancy-1 (GACI1) is caused by homozygous or compound heterozygous mutation in the ENPP1 gene (<a href="/entry/173335">173335</a>) on chromosome 6q23.</p><p>Mutation in ENPP1 can also cause an autosomal recessive form of hypophosphatemic rickets (see ARHR2, <a href="/entry/613312">613312</a>).</p>
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<p>Generalized arterial calcification of infancy (GACI) is a severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. GACI is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure (summary by <a href="#20" class="mim-tip-reference" title="Rutsch, F., Ruf, N., Vaingankar, S., Toliat, M. R., Suk, A., Hohne, W., Schauer, G., Lehmann, M., Roscioli, T., Schnabel, D., Epplen, J. T., Knisely, A., and 10 others. <strong>Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification.</strong> Nature Genet. 34: 379-381, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12881724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12881724</a>] [<a href="https://doi.org/10.1038/ng1221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12881724">Rutsch et al., 2003</a> and <a href="#3" class="mim-tip-reference" title="Cheng, K.-S., Chen, M.-R., Ruf, N., Lin, S.-P., Rutsch, F. <strong>Generalized arterial calcification of infancy: different clinical courses in two affected siblings.</strong> Am. J. Med. Genet. 136A: 210-213, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15940697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15940697</a>] [<a href="https://doi.org/10.1002/ajmg.a.30800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15940697">Cheng et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12881724+15940697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Arterial Calcification</em></strong></p><p>
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Generalized arterial calcification of infancy-2 (GACI2; <a href="/entry/614473">614473</a>) is caused by mutation in the ABCC6 gene (<a href="/entry/603234">603234</a>) on chromosome 16p13.</p><p>Homozygous or compound heterozygous mutation in the NT5E gene (<a href="/entry/129190">129190</a>) can cause adult-onset of calcification of arteries and joints (<a href="/entry/211800">211800</a>).</p>
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<p>Generalized arterial calcification has been noted in multiple sibs (<a href="#6" class="mim-tip-reference" title="Hunt, A. C., Leys, D. G. <strong>Generalized arterial calcification in infancy.</strong> Brit. Med. J. 1: 385-386, 1957.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13396267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13396267</a>] [<a href="https://doi.org/10.1136/bmj.1.5015.385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13396267">Hunt and Leys, 1957</a>). It may be fundamentally a defect of elastic fiber. Calcification occurs particularly in the internal elastic lamina. Material with the staining properties of mucopolysaccharide accumulates around the elastic fibers. Fine calcium incrustation of the lamina is the minimal lesion. Later the lamina is ruptured and occlusive changes in the intima take place. Death from myocardial infarction usually occurs in the first 6 months. Calcification in a peripheral artery with EKG changes of occlusive coronary artery disease suggests the diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13396267" 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="Menten, M. L., Fetterman, G. H. <strong>Coronary sclerosis in infancy: report of three autopsied cases, two in siblings.</strong> Am. J. Clin. Path. 18: 805-810, 1948."None>Menten and Fetterman (1948)</a> described 3 male infants, 2 of them brothers, who all died between 7 and 8 weeks of life with cyanosis and respiratory difficulty. Autopsy revealed generalized arteriosclerosis, with medial sclerosis of multiple arteries, including the coronary, pulmonary, gastric, mesenteric, renal, and hepatic arteries; in addition, there was cardiac hypertrophy and coronary artery stenosis with myocardial infarction. The 2 brothers, who had an older sib who died under similar conditions at about the same age, were also noted to have parenchymatous degeneration of the kidneys, and the other patient had glomerulosclerosis. <a href="#12" class="mim-tip-reference" title="Menten, M. L., Fetterman, G. H. <strong>Coronary sclerosis in infancy: report of three autopsied cases, two in siblings.</strong> Am. J. Clin. Path. 18: 805-810, 1948."None>Menten and Fetterman (1948)</a> stated that the disease process, where well advanced, actually involved all 3 arterial coats, and might be termed a 'diffuse' arterial sclerosis.</p><p><a href="#18" class="mim-tip-reference" title="Raphael, S. S., Horne, W. I., Hyde, T. A. <strong>Arterial medial calcification of infancy in brothers.</strong> Canad. Med. Assoc. J. 103: 290-293, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5433908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5433908</a>]" pmid="5433908">Raphael et al. (1970)</a> reported 2 brothers who died in respiratory distress after lengthy hospitalizations at 3 months and 5 months of age, respectively. Autopsy showed left ventricular hypertrophy and calcific changes involving arteries in many organs, consisting of replacement of the elastica by dense, sharply delineated calcific material. Endocardial fibroelastosis was seen on microscopic examination in 1 patient but not the other. No evidence of renal or bone disease was seen in either case. One of the brothers had a twin sib who died at 8 days of age, reportedly of pneumonia, but no autopsy was performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5433908" 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="Witzleben, C. L. <strong>Idiopathic infantile arterial calcification--a misnomer?.</strong> Am. J. Cardiol. 26: 305-309, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4196111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4196111</a>] [<a href="https://doi.org/10.1016/0002-9149(70)90798-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4196111">Witzleben (1970)</a> suggested that calcification has been overemphasized and is really only a secondary phenomenon. 'Infantile coronary sclerosis' is too restrictive in its topographic implications. He suggested 'occlusive infantile arteriopathy' as the preferred term. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4196111" 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="Sholler, G. F., Yu, J. S., Bale, P. M., Hawker, R. E., Celermajer, J. M., Kozlowski, K. <strong>Generalized arterial calcification of infancy: three case reports, including spontaneous regression with long-term survival.</strong> J. Pediat. 105: 257-260, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6747757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6747757</a>] [<a href="https://doi.org/10.1016/s0022-3476(84)80123-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6747757">Sholler et al. (1984)</a> reported 3 unrelated patients. One was 7 years old at the time of report and showed spontaneous regression of calcification. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6747757" 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>One of 2 affected sibs reported by <a href="#1" class="mim-tip-reference" title="Anderson, K. A., Burbach, J. A., Fenton, L. J., Jaqua, R. A., Barlow, J. F. <strong>Idiopathic arterial calcification of infancy in newborn siblings with unusual light and electron microscopic manifestations.</strong> Arch. Path. Lab. Med. 109: 838-842, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3839656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3839656</a>]" pmid="3839656">Anderson et al. (1985)</a> had an extensive acute panarteritis suggesting to the authors that IIAC may be the result of an inflammatory or infectious process. Ultrastructural examination confirmed that the deposits are hydroxyapatite and showed further a content of iron. No matrix vesicles or mitochondrial calcifications that might serve as nucleation sites for crystalline calcium phosphate were found. They raised the possibility that altered iron metabolism may be involved in the pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3839656" 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="#26" class="mim-tip-reference" title="Van Dyck, M., Proesmans, W., VanHollebeke, E., Marchal, G., Moerman, P. <strong>Idiopathic infantile arterial calcification with cardiac, renal and central nervous system involvement.</strong> Europ. J. Pediat. 148: 374-377, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2707283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2707283</a>] [<a href="https://doi.org/10.1007/BF00444138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2707283">Van Dyck et al. (1989)</a> described an infant in whom the diagnosis was made at age 2 weeks and therapy with diphosphonate resulted in complete resolution of vascular calcification. At the age of 2 years the child was 'doing well' but required medical treatment for arterial hypertension. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2707283" 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="#24" class="mim-tip-reference" title="Stuart, G., Wren, C., Bain, H. <strong>Idiopathic infantile arterial calcification in two siblings: failure of treatment with diphosphonate.</strong> Brit. Heart J. 64: 156-159, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2118367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2118367</a>] [<a href="https://doi.org/10.1136/hrt.64.2.156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2118367">Stuart et al. (1990)</a> described the disorder in 2 sibs. In the second-born sib, serial fetal echocardiography showed the development of pericardial effusion and calcification of the great vessels by 33 weeks of gestation. One sib died at 11 weeks and the other at 6 weeks of age. Diphosphonate was of no apparent benefit. Although survival to adulthood has been reported (<a href="#22" class="mim-tip-reference" title="Sholler, G. F., Yu, J. S., Bale, P. M., Hawker, R. E., Celermajer, J. M., Kozlowski, K. <strong>Generalized arterial calcification of infancy: three case reports, including spontaneous regression with long-term survival.</strong> J. Pediat. 105: 257-260, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6747757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6747757</a>] [<a href="https://doi.org/10.1016/s0022-3476(84)80123-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6747757">Sholler et al., 1984</a>; <a href="#10" class="mim-tip-reference" title="Marrott, P. K., Newcombe, K. D., Becroft, D. M. O., Friedlander, D. H. <strong>Idiopathic infantile arterial calcification with survival to adult life.</strong> Pediat. Cardiol. 5: 119-122, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6473121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6473121</a>] [<a href="https://doi.org/10.1007/BF02424963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6473121">Marrott et al., 1984</a>), most patients die in the first 6 months of life. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6747757+2118367+6473121" 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="Rutsch, F., Boyer, P., Nitschke, Y., Ruf, N., Lorenz-Depierieux, B., Wittkampf, T., Weissen-Plenz, G., Fischer, R.-J., Mughal, Z., Gregory, J. W., Davies, J. H., Loirat, C., Strom, T. M., Schnabel, D., Nurnberg, P., Terkeltaub, R., GACI Study Group. <strong>Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.</strong> Circ. Cardiovasc. Genet. 1: 133-140, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20016754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20016754</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20016754[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.108.797704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20016754">Rutsch et al. (2008)</a> performed retrospective observational analysis of 55 GACI patients, 19 (34%) of whom survived infancy. In the 8 surviving patients who were tested, all developed hypophosphatemia due to reduced renal tubular phosphate resorption during childhood. Eleven (65%) of 17 patients treated with bisphosphonates survived, whereas only 8 (31%) of 26 patients who survived the first day of life and were not treated with bisphosphonates survived beyond infancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20016754" 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="#23" class="mim-tip-reference" title="Staretz-Chacham, O., Shukrun, R., Barel, O., Pode-Shakked, B., Pleniceanu, O., Anikster, Y., Shalva, N., Ferreira, C. R., Kadosh, A. B.-H., Richardson, J., Mane, S. M., Hildebrandt, F., Vivante, A. <strong>Novel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome.</strong> Am. J. Med. Genet. 179A: 2112-2118, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31444901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31444901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31444901[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.61334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31444901">Staretz-Chacham et al. (2019)</a> described 3 sibs and an unrelated infant, born to 2 consanguineous Bedouin families, with GACI1. All 4 patients were born prematurely to pregnancies complicated by polyhydramnios, and all had multisystem involvement including thrombocytopenia and cardiac, hepatic, and CNS involvement. The oldest sib from family A (patient A-I) had polycythemia and hypoglycemia with hyperinsulinemia at birth. He developed cholestasis and acholic stools at 10 days of life. He presented with shock at age 2 months with elevated liver enzymes, lactic acidosis, and thrombocytopenia. Echocardiogram showed septal hypertrophy, mitral regurgitation, tricuspid regurgitation, and decreased contractility. Brain MRI showed old strokes, gliotic changes, and occipital necrosis. He died at 2 months of age. The next oldest sib, patient A-I, had respiratory distress and thrombocytopenia at birth. Echocardiogram showed aortic calcifications, cardiac hypertrophy, and pericardial effusions. Head ultrasound showed a left choroid plexus cyst, bilateral ventriculomegaly, and periventricular calcifications. She died at 3 days of life. Patient A-III, the youngest sib, had encephalopathy, distended abdomen, and hypertonia after birth. Laboratory testing showed an elevated GGT. Head ultrasound showed mild ventriculomegaly with lentriculostriate vasculopathy. He had decreased contractility and hyperechogenicity of large blood vessels on echocardiogram. He died at 11 days of life. Patient B-I from family B had severe hypoglycemia and thrombocytopenia after birth. On day 4 of life he developed systemic hypertension. He had renal artery stenosis, with a small right kidney. Head ultrasound showed bilateral ventriculomegaly, and brain MRI showed global ischemia with cystic periventricular leukomalacia. He developed hydrocephalus, requiring a ventriculoperitoneal shunt. Echocardiogram showed hypertrophy of the left chamber. Abdominal CT revealed aortic and iliac artery calcifications. He died at 6 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31444901" 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>
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<a href="#3" class="mim-tip-reference" title="Cheng, K.-S., Chen, M.-R., Ruf, N., Lin, S.-P., Rutsch, F. <strong>Generalized arterial calcification of infancy: different clinical courses in two affected siblings.</strong> Am. J. Med. Genet. 136A: 210-213, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15940697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15940697</a>] [<a href="https://doi.org/10.1002/ajmg.a.30800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15940697">Cheng et al. (2005)</a> studied 2 Taiwanese sibs with generalized arterial calcification of infancy who had markedly different clinical courses despite their identical genotype (see MOLECULAR GENETICS) and similar sonographic and radiographic findings: the male infant died with severe heart failure and hypertension at the age of 6 weeks, whereas the female infant was clinically well upon examination at 18 months of age, with normal growth and psychomotor development and normal blood pressure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15940697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Dlamini, N., Splitt, M., Durkan, A., Siddiqui, A., Padayachee, S., Hobbins, S., Rutsch, F., Wraige, E. <strong>Generalized arterial calcification of infancy: phenotypic spectrum among three siblings including one case without obvious arterial calcifications.</strong> Am. J. Med. Genet. 149A: 456-460, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206175</a>] [<a href="https://doi.org/10.1002/ajmg.a.32646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206175">Dlamini et al. (2009)</a> reported 3 Caucasian sibs with GACI and striking phenotypic variability. The proband was a 5-year-old boy who had left ventricular hypertrophy noted in infancy and developed hypertension at 14 months of age; arch aortogram showed severe stenosis of the celiac axis, superior mesenteric artery, renal arteries, and both internal and external carotid arteries, and coronary angiography showed normal caliber coronary arteries with no calcification. The proband had 2 deceased younger sibs: a female sib was stillborn, in whom ultrasound at 30 weeks' gestation had shown echogenicity of the myocardium and aortic root suggestive of calcification, and a male sib died 12 hours after birth from myocardial infarction, in whom intracardiac calcification was detected prenatally. Review of the proband's radiographs and echocardiography showed no evidence of typical GACI calcification; however, reevaluation by CT scan revealed high-density foci compatible with calcification in the left internal carotid artery siphon, cervical portions of the common carotid and right brachiocephalic arteries, aortic root, and descending aorta. The proband and his male sib were found to be compound heterozygous for the same ENPP1 mutations (see MOLECULAR GENETICS). At 5 years of age, the proband was healthy and developmentally age-appropriate, on antihypertensive and antiplatelet agents. <a href="#4" class="mim-tip-reference" title="Dlamini, N., Splitt, M., Durkan, A., Siddiqui, A., Padayachee, S., Hobbins, S., Rutsch, F., Wraige, E. <strong>Generalized arterial calcification of infancy: phenotypic spectrum among three siblings including one case without obvious arterial calcifications.</strong> Am. J. Med. Genet. 149A: 456-460, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206175</a>] [<a href="https://doi.org/10.1002/ajmg.a.32646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206175">Dlamini et al. (2009)</a> concluded that GACI may be underrecognized and suggested that the diagnosis should be considered in patients with multiple arterial stenoses even in the absence of radiographic calcification. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19206175" 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>Features of Pseudoxanthoma Elasticum in GACI Patients</em></strong></p><p>
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<a href="#16" 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. <strong>Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.</strong> Am. J. Hum. Genet. 90: 25-39, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22209248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22209248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22209248[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22209248">Nitschke et al. (2012)</a> described 3 unrelated GACI patients with homozygous or compound heterozygous ENNP1 mutations (see MOLECULAR GENETICS) who developed clinical features of pseudoxanthoma elasticum in later childhood. One boy with GACI, who was previously studied by <a href="#4" class="mim-tip-reference" title="Dlamini, N., Splitt, M., Durkan, A., Siddiqui, A., Padayachee, S., Hobbins, S., Rutsch, F., Wraige, E. <strong>Generalized arterial calcification of infancy: phenotypic spectrum among three siblings including one case without obvious arterial calcifications.</strong> Am. J. Med. Genet. 149A: 456-460, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206175</a>] [<a href="https://doi.org/10.1002/ajmg.a.32646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206175">Dlamini et al. (2009)</a>, developed at 8 years of age pseudoxanthomatous skin lesions around his umbilicus and on his neck, which were histologically proven to be typical PXE lesions. A 12-year-old French boy, born of consanguineous parents, was diagnosed with GACI in the neonatal period and treated with oral bisphosphonates, resulting in disappearance of the ectopic calcifications. At 9 years of age, he presented with yellowish papules on the neck and periumbilical region and large angiomatous atrophic macules on the anterior chest. He also had abnormal calcifications of the ear cartilage, cervical fusion between C3 and C5, and microcalcifications of the left kidney, but no cardiovascular or ophthalmologic calcifications were detected. He had short stature with progressive genu valgum, and radiologic signs of rickets were present; he was found to have hypophosphatemia with decreased renal phosphate reabsorption, normal vitamin D levels, and normal glomerular filtration rate. Reexamination at 12 years of age showed development of otosclerosis with stapedovestibular ankylosis, resulting in hearing loss. An eye exam showed no angioid streaks. Histopathologic studies of the yellowish neck papules confirmed the diagnosis of PXE, with calcium deposits in elastic fibers that were stained by carboxylated, but not noncarboxylated, anti-MGP (<a href="/entry/154870">154870</a>) antibodies. The patient's mother also presented with yellow papules characteristic for PXE, and his 9-year-old sister had angiomatous linear lesions of the left flank. The other GACI patient with features of PXE was a 5-year-old French girl with short stature, hypophosphatemic rickets, and cardiovascular, pancreatic, hepatic, and renal calcifications, who developed diffuse angiomatous lesions on her back and had angioid streaks in the Bruch membrane of the retina that were typical for PXE. She did not have any pseudoxanthomatous skin lesions. At 4 years of age, she had also developed conductive deafness and required hearing aids. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22209248+19206175" 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>Dental Features in GACI Survivors</em></strong></p><p>
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<a href="#25" class="mim-tip-reference" title="Thumbigere-Math, V., Alqadi, A., Chalmers, N. I., Chavez, M. B., Chu, E. Y., Collins, M. T., Ferreira, C. R., FitzGerald, K., Gafni, R. I., Gahl, W. A., Hsu, K. S., Ramnitz, M. S., Somerman, M. J., Ziegler, S. G., Foster, B. L. <strong>Hypercementosis associated with ENPP1 mutations and GACI.</strong> J. Dent. Res. 97: 432-441, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29244957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29244957</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29244957[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1177/0022034517744773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29244957">Thumbigere-Math et al. (2018)</a> studied the teeth of 5 unrelated patients with GACI, including patients previously reported by <a href="#7" class="mim-tip-reference" title="Li, Q., Schumacher, W., Jablonski, D., Siegel, D., Uitto, J. <strong>Cutaneous features of pseudoxanthoma elasticum in a patient with generalized arterial calcification of infancy due to a homozygous missense mutation in the ENPP1 gene.</strong> Brit. J. Derm. 166: 1107-1111, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22229486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22229486</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22229486[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1365-2133.2012.10811.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22229486">Li et al. (2012)</a>, <a href="#19" class="mim-tip-reference" title="Rutsch, F., Boyer, P., Nitschke, Y., Ruf, N., Lorenz-Depierieux, B., Wittkampf, T., Weissen-Plenz, G., Fischer, R.-J., Mughal, Z., Gregory, J. W., Davies, J. H., Loirat, C., Strom, T. M., Schnabel, D., Nurnberg, P., Terkeltaub, R., GACI Study Group. <strong>Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.</strong> Circ. Cardiovasc. Genet. 1: 133-140, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20016754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20016754</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20016754[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.108.797704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20016754">Rutsch et al. (2008)</a>, and <a href="#5" class="mim-tip-reference" title="Ferreira, C. R., Ziegler, S. G., Gupta, A., Groden, C., Hsu, K. S., Gahl, W. A. <strong>Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy [GACI] without worsening of vascular calcification.</strong> Am. J. Med. Genet. 170A: 1308-1311, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26857895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26857895</a>] [<a href="https://doi.org/10.1002/ajmg.a.37574" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26857895">Ferreira et al. (2016)</a> (patients 2, 4, and 5). All presented significant hypercementosis of cervical cementum, with radiographic evidence of unusually protruding cervical root morphology, in primary and/or secondary dentition. Dental histories of 4 of the patients included evidence for infraocclusion, overretained primary teeth, possible ankylosis, and/or ineffective orthodontic tooth movement, suggesting altered mineral metabolism contributing to disrupted tooth movement and exfoliation. High-resolution micro-CT analyses of extracted primary teeth from 3 of the patients revealed a 4-fold increased cervical cementum thickness and a 23% increase in cementum mineral density compared to age-matched healthy control teeth. There were no differences in enamel or dentin densities between GACI patients and controls. Histologic examination showed markedly expanded cervical cementum in GACI teeth, including cementocyte-like cells and unusual patterns of cementum resorption and repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29244957+20016754+22229486+26857895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Ferreira, C. R., Ziegler, S. G., Gupta, A., Groden, C., Hsu, K. S., Gahl, W. A. <strong>Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy [GACI] without worsening of vascular calcification.</strong> Am. J. Med. Genet. 170A: 1308-1311, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26857895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26857895</a>] [<a href="https://doi.org/10.1002/ajmg.a.37574" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26857895">Ferreira et al. (2016)</a> reported a 22-year-old man who was diagnosed with GACI at age 6 weeks, at which time he was tachycardic with left ventricular hypertrophy and poor systolic function, and had hepatomegaly and splenomegaly. Cardiac catheterization revealed severe attenuation of the left coronary artery with subtotal occlusion of the first obtuse marginal branch and occlusion proximal to the circumflex, and proximal occlusion of the right coronary artery. CT scan showed calcification of the descending aorta as well as the coronary, brachial, renal, splenic, and superior mesenteric arteries. Bisphosphonate treatment ameliorated his cardiac function, and CT scan at 7 months of age showed reduced calcifications. At 13 months, the calcifications had regressed completely except for mild calcification of the aortic annulus, and bisphosphonate treatment was discontinued at 24 months of age. At age 13 years, the patient developed progressive pain in the ankles and knees, and x-rays showed significant anterior bowing and thinning of the lower ends of both femora. He was diagnosed with hypophosphatemic rickets at 14.5 years of age and treated with phosphorus and calcium supplementation. At 22 years of age, multidetector helical CT from neck to legs revealed minimal calcification of the aortic root, inferior portion of the heart, and left popliteal artery, with no calcifications elsewhere, including no nephrocalcinosis. Anterior femoral bowing was noted. Cardiac CT showed no coronary artery calcification. The authors concluded that long-term treatment of rickets in the setting of GACI can be accomplished without worsening of vascular calcifications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26857895" 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>Spontaneous periarticular and aortic calcifications in early life and systemic lowering of nucleotide pyrophosphatase/phosphodiesterase (NPP) activity and inorganic pyrophosphate levels are shared features of the phenotype of idiopathic infantile arterial calcification (IIAC) and of homozygous 'tiptoe walking' (ttw/ttw) mice, which carry a spontaneous nonsense mutation in Enpp1 (<a href="#17" class="mim-tip-reference" title="Okawa, A., Nakamura, I., Goto, S., Moriya, H., Nakamura, Y., Ikegawa, S. <strong>Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine.</strong> Nature Genet. 19: 271-273, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662402</a>] [<a href="https://doi.org/10.1038/956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662402">Okawa et al., 1998</a>; <a href="#21" class="mim-tip-reference" title="Rutsch, F., Vaingankar, S., Johnson, K., Goldfine, I., Maddux, B., Schauerte, P., Kalhoff, H., Sano, K., Boisvert, W. A., Superti-Furga, A., Terkeltaub, R. <strong>PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification.</strong> Am. J. Path. 158: 543-554, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159191</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11159191[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S0002-9440(10)63996-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159191">Rutsch et al., 2001</a>). <a href="#21" class="mim-tip-reference" title="Rutsch, F., Vaingankar, S., Johnson, K., Goldfine, I., Maddux, B., Schauerte, P., Kalhoff, H., Sano, K., Boisvert, W. A., Superti-Furga, A., Terkeltaub, R. <strong>PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification.</strong> Am. J. Path. 158: 543-554, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159191</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11159191[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S0002-9440(10)63996-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159191">Rutsch et al. (2001)</a> found reduced levels of expression of ENNP1 in an individual with IIAC born to consanguineous parents and demonstrated heterozygosity for a mutation at the ENNP1 locus (<a href="/entry/173335#0002">173335.0002</a>). Using a high-density microsatellite marker panel for 6q, the site of the ENPP1 gene, <a href="#20" class="mim-tip-reference" title="Rutsch, F., Ruf, N., Vaingankar, S., Toliat, M. R., Suk, A., Hohne, W., Schauer, G., Lehmann, M., Roscioli, T., Schnabel, D., Epplen, J. T., Knisely, A., and 10 others. <strong>Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification.</strong> Nature Genet. 34: 379-381, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12881724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12881724</a>] [<a href="https://doi.org/10.1038/ng1221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12881724">Rutsch et al. (2003)</a> identified a recombination event in this proband that had obscured homozygosity with respect to the critical region. Screening for mutations in ENPP1 in 11 unrelated families with IIAC found mutations in 8 of them, either in homozygous or compound heterozygous state, compatible with a functional inactivation of both alleles. ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase-1, a cell surface enzyme that generates inorganic pyrophosphate, a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11159191+9662402+12881724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Lorenz-Depiereux, B., Schnabel, D., Tiosano, D., Hausler, G., Strom, T. M. <strong>Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets.</strong> Am. J. Hum. Genet. 86: 267-272, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20137773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20137773</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20137773[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2010.01.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20137773">Lorenz-Depiereux et al. (2010)</a> restudied 1 of the families previously described by <a href="#20" class="mim-tip-reference" title="Rutsch, F., Ruf, N., Vaingankar, S., Toliat, M. R., Suk, A., Hohne, W., Schauer, G., Lehmann, M., Roscioli, T., Schnabel, D., Epplen, J. T., Knisely, A., and 10 others. <strong>Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification.</strong> Nature Genet. 34: 379-381, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12881724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12881724</a>] [<a href="https://doi.org/10.1038/ng1221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12881724">Rutsch et al. (2003)</a> ('family 4') and identified homozygosity for a missense mutation in the ENPP1 gene (<a href="/entry/173335#0011">173335.0011</a>) in a father and son with different phenotypes: the son had generalized arterial calcification of infancy (GACI) and hypophosphatemia, whereas his father had hypophosphatemic rickets (ARHR2; <a href="/entry/613312">613312</a>). Ultrasound examination of large blood vessels in the father showed normal carotid and renal arteries and a normal thoracic and abdominal aorta. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20137773+12881724" 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 Taiwanese brother and sister with GACI who had markedly different clinical courses, <a href="#3" class="mim-tip-reference" title="Cheng, K.-S., Chen, M.-R., Ruf, N., Lin, S.-P., Rutsch, F. <strong>Generalized arterial calcification of infancy: different clinical courses in two affected siblings.</strong> Am. J. Med. Genet. 136A: 210-213, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15940697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15940697</a>] [<a href="https://doi.org/10.1002/ajmg.a.30800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15940697">Cheng et al. (2005)</a> identified compound heterozygosity for missense mutations in the ENPP1 gene (see <a href="/entry/173335#0008">173335.0008</a> and <a href="/entry/173335#0009">173335.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15940697" 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="Rutsch, F., Boyer, P., Nitschke, Y., Ruf, N., Lorenz-Depierieux, B., Wittkampf, T., Weissen-Plenz, G., Fischer, R.-J., Mughal, Z., Gregory, J. W., Davies, J. H., Loirat, C., Strom, T. M., Schnabel, D., Nurnberg, P., Terkeltaub, R., GACI Study Group. <strong>Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.</strong> Circ. Cardiovasc. Genet. 1: 133-140, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20016754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20016754</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20016754[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.108.797704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20016754">Rutsch et al. (2008)</a> identified homozygosity or compound heterozygosity for 40 different mutations in the ENPP1 gene in 41 (75%) of 55 GACI patients. The most frequently detected mutation was P305T (<a href="/entry/173335#0016">173335.0016</a>); <a href="#19" class="mim-tip-reference" title="Rutsch, F., Boyer, P., Nitschke, Y., Ruf, N., Lorenz-Depierieux, B., Wittkampf, T., Weissen-Plenz, G., Fischer, R.-J., Mughal, Z., Gregory, J. W., Davies, J. H., Loirat, C., Strom, T. M., Schnabel, D., Nurnberg, P., Terkeltaub, R., GACI Study Group. <strong>Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.</strong> Circ. Cardiovasc. Genet. 1: 133-140, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20016754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20016754</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20016754[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.108.797704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20016754">Rutsch et al. (2008)</a> noted that P305T was universally lethal when present on both alleles, but stated that no other clear genotype/phenotype correlation was seen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20016754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Caucasian brothers with GACI, 1 deceased of myocardial infarction 12 hours after birth and 1 healthy at 5 years of age, <a href="#4" class="mim-tip-reference" title="Dlamini, N., Splitt, M., Durkan, A., Siddiqui, A., Padayachee, S., Hobbins, S., Rutsch, F., Wraige, E. <strong>Generalized arterial calcification of infancy: phenotypic spectrum among three siblings including one case without obvious arterial calcifications.</strong> Am. J. Med. Genet. 149A: 456-460, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19206175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19206175</a>] [<a href="https://doi.org/10.1002/ajmg.a.32646" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19206175">Dlamini et al. (2009)</a> identified compound heterozygosity for a missense and a 2-bp deletion in the ENPP1 gene (<a href="/entry/173335#0014">173335.0014</a> and <a href="/entry/173335#0015">173335.0015</a>). <a href="#16" 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. <strong>Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.</strong> Am. J. Hum. Genet. 90: 25-39, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22209248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22209248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22209248[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22209248">Nitschke et al. (2012)</a> provided follow-up on the living brother, who at 8 years of age developed pseudoxanthomatous skin lesions that were histologically proven to be typical of pseudoxanthoma elasticum. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22209248+19206175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with GACI, a 12-year-old French boy and an unrelated 5-year-old French girl, who developed features of PXE in later childhood, <a href="#16" 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. <strong>Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.</strong> Am. J. Hum. Genet. 90: 25-39, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22209248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22209248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22209248[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22209248">Nitschke et al. (2012)</a> identified homozygous and compound heterozygous mutations in the ENNP1 gene (see, e.g., <a href="/entry/173335#0017">173335.0017</a>-<a href="/entry/173335#0019">173335.0019</a>, respectively). <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><p>In a 22-year-old man with GACI who underwent bisphosphonate treatment with near-total resolution of arterial calcifications by age 2 years (see CLINICAL MANAGEMENT), <a href="#5" class="mim-tip-reference" title="Ferreira, C. R., Ziegler, S. G., Gupta, A., Groden, C., Hsu, K. S., Gahl, W. A. <strong>Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy [GACI] without worsening of vascular calcification.</strong> Am. J. Med. Genet. 170A: 1308-1311, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26857895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26857895</a>] [<a href="https://doi.org/10.1002/ajmg.a.37574" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26857895">Ferreira et al. (2016)</a> reported compound heterozygosity for missense mutations in the ENPP1 gene, R481Q and Y471C. In adolescence, the patient developed hypophosphatemic rickets, which was treated with phosphorus and calcium supplementation without any worsening of vascular calcifications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26857895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 sibs and an unrelated infant, born to 2 consanguineous Bedouin families, with GACI1, <a href="#23" class="mim-tip-reference" title="Staretz-Chacham, O., Shukrun, R., Barel, O., Pode-Shakked, B., Pleniceanu, O., Anikster, Y., Shalva, N., Ferreira, C. R., Kadosh, A. B.-H., Richardson, J., Mane, S. M., Hildebrandt, F., Vivante, A. <strong>Novel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome.</strong> Am. J. Med. Genet. 179A: 2112-2118, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31444901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31444901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31444901[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.61334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31444901">Staretz-Chacham et al. (2019)</a> identified homozygosity for a missense mutation in the ENPPI gene (G186R; <a href="/entry/173335#0023">173335.0023</a>). All of the patients had thrombocytopenia and cardiac, hepatic, and CNS involvement, and all died in infancy. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31444901" 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>Using high-resolution micro-CT, <a href="#25" class="mim-tip-reference" title="Thumbigere-Math, V., Alqadi, A., Chalmers, N. I., Chavez, M. B., Chu, E. Y., Collins, M. T., Ferreira, C. R., FitzGerald, K., Gafni, R. I., Gahl, W. A., Hsu, K. S., Ramnitz, M. S., Somerman, M. J., Ziegler, S. G., Foster, B. L. <strong>Hypercementosis associated with ENPP1 mutations and GACI.</strong> J. Dent. Res. 97: 432-441, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29244957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29244957</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29244957[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1177/0022034517744773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29244957">Thumbigere-Math et al. (2018)</a> analyzed the mandibular molars of Enpp1-null mice and observed a 4-fold increased cervical cementum thickness and 5-fold increase in volume compared to wildtype mice, as well as a nonsignificant 5% increase in mineral density. Apically located cellular cementum showed significantly increased volume and height on the mesial root surface, but no change in thickness or density in the null mice compared to wildtype. The authors noted that histologically the molars of Enpp1-null mice resembled those of GACI patients, including dramatically expanded cervical cementum with abnormal inclusion of embedded nucleated cementocyte-like cells and lacunae. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29244957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Bird1974" class="mim-tip-reference" title="Bird, T. <strong>Idiopathic arterial calcification in infancy.</strong> Arch. Dis. Child. 49: 82-89, 1974.">Bird (1974)</a>; <a href="#Maayan1984" class="mim-tip-reference" title="Maayan, C., Peleg, O., Eyal, F., Mogle, P., Rosenmann, E., Bar Ziv, J. <strong>Idiopathic infantile arterial calcification: a case report and review of the literature.</strong> Europ. J. Pediat. 142: 211-215, 1984.">Maayan et al. (1984)</a>; <a href="#McKusick1972" class="mim-tip-reference" title="McKusick, V. A. <strong>Heritable Disorders of Connective Tissue. (3rd ed.)</strong> St. Louis: C. V. Mosby (pub.) 1972. Pp. 310-311. Note: Fig. 103.">McKusick (1972)</a>; <a href="#Meradji1978" class="mim-tip-reference" title="Meradji, M., de Villeneuve, V. H., Huber, J., de Bruijn, W. C., Pearse, R. G. <strong>Idiopathic infantile arterial calcification in siblings: radiologic diagnosis and successful treatment.</strong> J. Pediat. 92: 401-405, 1978.">Meradji et al.
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(1978)</a>; <a href="#Milner1984" class="mim-tip-reference" title="Milner, L. S., Heitner, R., Thomson, P. D., Levin, S. E., Rothberg, A. D., Beale, P., Ninin, D. T. <strong>Hypertension as the major problem of idiopathic arterial calcification of infancy.</strong> J. Pediat. 105: 934-938, 1984.">Milner et al. (1984)</a>; <a href="#Moran1959" class="mim-tip-reference" title="Moran, J. J., Becker, S. M. <strong>Idiopathic arterial calcification of infancy: report of 2 cases occurring in siblings, and review of the literature.</strong> Am. J. Clin. Path. 31: 517-529, 1959.">Moran and Becker (1959)</a>
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<strong>Idiopathic arterial calcification of infancy in newborn siblings with unusual light and electron microscopic manifestations.</strong>
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Rutsch, F., Boyer, P., Nitschke, Y., Ruf, N., Lorenz-Depierieux, B., Wittkampf, T., Weissen-Plenz, G., Fischer, R.-J., Mughal, Z., Gregory, J. W., Davies, J. H., Loirat, C., Strom, T. M., Schnabel, D., Nurnberg, P., Terkeltaub, R., GACI Study Group.
|
|
<strong>Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy.</strong>
|
|
Circ. Cardiovasc. Genet. 1: 133-140, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20016754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20016754</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20016754[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=20016754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/CIRCGENETICS.108.797704" target="_blank">Full Text</a>]
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</p>
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</div>
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<a id="20" class="mim-anchor"></a>
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<a id="Rutsch2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rutsch, F., Ruf, N., Vaingankar, S., Toliat, M. R., Suk, A., Hohne, W., Schauer, G., Lehmann, M., Roscioli, T., Schnabel, D., Epplen, J. T., Knisely, A., and 10 others.
|
|
<strong>Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification.</strong>
|
|
Nature Genet. 34: 379-381, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12881724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12881724</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12881724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1221" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Rutsch2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rutsch, F., Vaingankar, S., Johnson, K., Goldfine, I., Maddux, B., Schauerte, P., Kalhoff, H., Sano, K., Boisvert, W. A., Superti-Furga, A., Terkeltaub, R.
|
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<strong>PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification.</strong>
|
|
Am. J. Path. 158: 543-554, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159191</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11159191[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=11159191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/S0002-9440(10)63996-X" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Sholler1984" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sholler, G. F., Yu, J. S., Bale, P. M., Hawker, R. E., Celermajer, J. M., Kozlowski, K.
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<strong>Generalized arterial calcification of infancy: three case reports, including spontaneous regression with long-term survival.</strong>
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J. Pediat. 105: 257-260, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6747757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6747757</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6747757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(84)80123-7" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Staretz-Chacham2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Staretz-Chacham, O., Shukrun, R., Barel, O., Pode-Shakked, B., Pleniceanu, O., Anikster, Y., Shalva, N., Ferreira, C. R., Kadosh, A. B.-H., Richardson, J., Mane, S. M., Hildebrandt, F., Vivante, A.
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<strong>Novel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome.</strong>
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Am. J. Med. Genet. 179A: 2112-2118, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31444901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31444901</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31444901[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=31444901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.61334" target="_blank">Full Text</a>]
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<a id="24" class="mim-anchor"></a>
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<a id="Stuart1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stuart, G., Wren, C., Bain, H.
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<strong>Idiopathic infantile arterial calcification in two siblings: failure of treatment with diphosphonate.</strong>
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Brit. Heart J. 64: 156-159, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2118367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2118367</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2118367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/hrt.64.2.156" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Thumbigere-Math2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thumbigere-Math, V., Alqadi, A., Chalmers, N. I., Chavez, M. B., Chu, E. Y., Collins, M. T., Ferreira, C. R., FitzGerald, K., Gafni, R. I., Gahl, W. A., Hsu, K. S., Ramnitz, M. S., Somerman, M. J., Ziegler, S. G., Foster, B. L.
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<strong>Hypercementosis associated with ENPP1 mutations and GACI.</strong>
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J. Dent. Res. 97: 432-441, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29244957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29244957</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29244957[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=29244957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1177/0022034517744773" target="_blank">Full Text</a>]
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Van Dyck1989" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Van Dyck, M., Proesmans, W., VanHollebeke, E., Marchal, G., Moerman, P.
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<strong>Idiopathic infantile arterial calcification with cardiac, renal and central nervous system involvement.</strong>
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Europ. J. Pediat. 148: 374-377, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2707283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2707283</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2707283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00444138" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Witzleben1970" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Witzleben, C. L.
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<strong>Idiopathic infantile arterial calcification--a misnomer?.</strong>
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Am. J. Cardiol. 26: 305-309, 1970.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4196111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4196111</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4196111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0002-9149(70)90798-8" target="_blank">Full Text</a>]
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 12/09/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 06/28/2018<br>Marla J. F. O'Neill - updated : 2/8/2012<br>Marla J. F. O'Neill - updated : 2/7/2011<br>Marla J. F. O'Neill - updated : 8/27/2010<br>Marla J. F. O'Neill - updated : 7/26/2010<br>Marla J. F. O'Neill - updated : 3/22/2010<br>Marla J. F. O'Neill - updated : 12/28/2005<br>Victor A. McKusick - updated : 8/1/2003
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/3/1986
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</span>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/14/2022
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/25/2021<br>carol : 12/10/2020<br>carol : 12/09/2020<br>alopez : 06/28/2018<br>carol : 12/15/2017<br>carol : 10/14/2016<br>terry : 07/31/2012<br>carol : 2/8/2012<br>wwang : 2/7/2011<br>terry : 2/7/2011<br>wwang : 9/1/2010<br>terry : 8/27/2010<br>wwang : 7/27/2010<br>terry : 7/26/2010<br>carol : 3/22/2010<br>carol : 3/19/2010<br>wwang : 1/3/2006<br>terry : 12/28/2005<br>alopez : 8/5/2003<br>terry : 8/1/2003<br>alopez : 6/10/1997<br>mimadm : 11/12/1995<br>davew : 8/15/1994<br>warfield : 3/7/1994<br>supermim : 3/16/1992<br>carol : 10/8/1990<br>supermim : 3/20/1990
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</span>
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</div>
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 208000
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1; GACI1
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</span>
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</h3>
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</div>
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<div>
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<br />
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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GACI<br />
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IDIOPATHIC INFANTILE ARTERIAL CALCIFICATION; IIAC<br />
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ARTERIAL CALCIFICATION, IDIOPATHIC INFANTILE<br />
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ARTERIOPATHY, OCCLUSIVE INFANTILE
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</span>
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</h4>
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</div>
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<div>
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<br />
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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CORONARY SCLEROSIS, MEDIAL, OF INFANCY, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong>ORPHA:</strong> 51608;
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<strong>DO:</strong> 0050644;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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<th>
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Gene/Locus
|
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</th>
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<th>
|
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Gene/Locus <br /> MIM number
|
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</th>
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</tr>
|
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6q23.2
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Arterial calcification, generalized, of infancy, 1
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<span class="mim-font">
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208000
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Autosomal recessive
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3
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ENPP1
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173335
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that generalized arterial calcification of infancy-1 (GACI1) is caused by homozygous or compound heterozygous mutation in the ENPP1 gene (173335) on chromosome 6q23.</p><p>Mutation in ENPP1 can also cause an autosomal recessive form of hypophosphatemic rickets (see ARHR2, 613312).</p>
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<strong>Description</strong>
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<p>Generalized arterial calcification of infancy (GACI) is a severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. GACI is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure (summary by Rutsch et al., 2003 and Cheng et al., 2005). </p><p><strong><em>Genetic Heterogeneity of Arterial Calcification</em></strong></p><p>
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Generalized arterial calcification of infancy-2 (GACI2; 614473) is caused by mutation in the ABCC6 gene (603234) on chromosome 16p13.</p><p>Homozygous or compound heterozygous mutation in the NT5E gene (129190) can cause adult-onset of calcification of arteries and joints (211800).</p>
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<strong>Clinical Features</strong>
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<p>Generalized arterial calcification has been noted in multiple sibs (Hunt and Leys, 1957). It may be fundamentally a defect of elastic fiber. Calcification occurs particularly in the internal elastic lamina. Material with the staining properties of mucopolysaccharide accumulates around the elastic fibers. Fine calcium incrustation of the lamina is the minimal lesion. Later the lamina is ruptured and occlusive changes in the intima take place. Death from myocardial infarction usually occurs in the first 6 months. Calcification in a peripheral artery with EKG changes of occlusive coronary artery disease suggests the diagnosis. </p><p>Menten and Fetterman (1948) described 3 male infants, 2 of them brothers, who all died between 7 and 8 weeks of life with cyanosis and respiratory difficulty. Autopsy revealed generalized arteriosclerosis, with medial sclerosis of multiple arteries, including the coronary, pulmonary, gastric, mesenteric, renal, and hepatic arteries; in addition, there was cardiac hypertrophy and coronary artery stenosis with myocardial infarction. The 2 brothers, who had an older sib who died under similar conditions at about the same age, were also noted to have parenchymatous degeneration of the kidneys, and the other patient had glomerulosclerosis. Menten and Fetterman (1948) stated that the disease process, where well advanced, actually involved all 3 arterial coats, and might be termed a 'diffuse' arterial sclerosis.</p><p>Raphael et al. (1970) reported 2 brothers who died in respiratory distress after lengthy hospitalizations at 3 months and 5 months of age, respectively. Autopsy showed left ventricular hypertrophy and calcific changes involving arteries in many organs, consisting of replacement of the elastica by dense, sharply delineated calcific material. Endocardial fibroelastosis was seen on microscopic examination in 1 patient but not the other. No evidence of renal or bone disease was seen in either case. One of the brothers had a twin sib who died at 8 days of age, reportedly of pneumonia, but no autopsy was performed. </p><p>Witzleben (1970) suggested that calcification has been overemphasized and is really only a secondary phenomenon. 'Infantile coronary sclerosis' is too restrictive in its topographic implications. He suggested 'occlusive infantile arteriopathy' as the preferred term. </p><p>Sholler et al. (1984) reported 3 unrelated patients. One was 7 years old at the time of report and showed spontaneous regression of calcification. </p><p>One of 2 affected sibs reported by Anderson et al. (1985) had an extensive acute panarteritis suggesting to the authors that IIAC may be the result of an inflammatory or infectious process. Ultrastructural examination confirmed that the deposits are hydroxyapatite and showed further a content of iron. No matrix vesicles or mitochondrial calcifications that might serve as nucleation sites for crystalline calcium phosphate were found. They raised the possibility that altered iron metabolism may be involved in the pathogenesis. </p><p>Van Dyck et al. (1989) described an infant in whom the diagnosis was made at age 2 weeks and therapy with diphosphonate resulted in complete resolution of vascular calcification. At the age of 2 years the child was 'doing well' but required medical treatment for arterial hypertension. </p><p>Stuart et al. (1990) described the disorder in 2 sibs. In the second-born sib, serial fetal echocardiography showed the development of pericardial effusion and calcification of the great vessels by 33 weeks of gestation. One sib died at 11 weeks and the other at 6 weeks of age. Diphosphonate was of no apparent benefit. Although survival to adulthood has been reported (Sholler et al., 1984; Marrott et al., 1984), most patients die in the first 6 months of life. </p><p>Rutsch et al. (2008) performed retrospective observational analysis of 55 GACI patients, 19 (34%) of whom survived infancy. In the 8 surviving patients who were tested, all developed hypophosphatemia due to reduced renal tubular phosphate resorption during childhood. Eleven (65%) of 17 patients treated with bisphosphonates survived, whereas only 8 (31%) of 26 patients who survived the first day of life and were not treated with bisphosphonates survived beyond infancy. </p><p>Staretz-Chacham et al. (2019) described 3 sibs and an unrelated infant, born to 2 consanguineous Bedouin families, with GACI1. All 4 patients were born prematurely to pregnancies complicated by polyhydramnios, and all had multisystem involvement including thrombocytopenia and cardiac, hepatic, and CNS involvement. The oldest sib from family A (patient A-I) had polycythemia and hypoglycemia with hyperinsulinemia at birth. He developed cholestasis and acholic stools at 10 days of life. He presented with shock at age 2 months with elevated liver enzymes, lactic acidosis, and thrombocytopenia. Echocardiogram showed septal hypertrophy, mitral regurgitation, tricuspid regurgitation, and decreased contractility. Brain MRI showed old strokes, gliotic changes, and occipital necrosis. He died at 2 months of age. The next oldest sib, patient A-I, had respiratory distress and thrombocytopenia at birth. Echocardiogram showed aortic calcifications, cardiac hypertrophy, and pericardial effusions. Head ultrasound showed a left choroid plexus cyst, bilateral ventriculomegaly, and periventricular calcifications. She died at 3 days of life. Patient A-III, the youngest sib, had encephalopathy, distended abdomen, and hypertonia after birth. Laboratory testing showed an elevated GGT. Head ultrasound showed mild ventriculomegaly with lentriculostriate vasculopathy. He had decreased contractility and hyperechogenicity of large blood vessels on echocardiogram. He died at 11 days of life. Patient B-I from family B had severe hypoglycemia and thrombocytopenia after birth. On day 4 of life he developed systemic hypertension. He had renal artery stenosis, with a small right kidney. Head ultrasound showed bilateral ventriculomegaly, and brain MRI showed global ischemia with cystic periventricular leukomalacia. He developed hydrocephalus, requiring a ventriculoperitoneal shunt. Echocardiogram showed hypertrophy of the left chamber. Abdominal CT revealed aortic and iliac artery calcifications. He died at 6 months of age. </p><p><strong><em>Intrafamilial Phenotypic Variability</em></strong></p><p>
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Cheng et al. (2005) studied 2 Taiwanese sibs with generalized arterial calcification of infancy who had markedly different clinical courses despite their identical genotype (see MOLECULAR GENETICS) and similar sonographic and radiographic findings: the male infant died with severe heart failure and hypertension at the age of 6 weeks, whereas the female infant was clinically well upon examination at 18 months of age, with normal growth and psychomotor development and normal blood pressure. </p><p>Dlamini et al. (2009) reported 3 Caucasian sibs with GACI and striking phenotypic variability. The proband was a 5-year-old boy who had left ventricular hypertrophy noted in infancy and developed hypertension at 14 months of age; arch aortogram showed severe stenosis of the celiac axis, superior mesenteric artery, renal arteries, and both internal and external carotid arteries, and coronary angiography showed normal caliber coronary arteries with no calcification. The proband had 2 deceased younger sibs: a female sib was stillborn, in whom ultrasound at 30 weeks' gestation had shown echogenicity of the myocardium and aortic root suggestive of calcification, and a male sib died 12 hours after birth from myocardial infarction, in whom intracardiac calcification was detected prenatally. Review of the proband's radiographs and echocardiography showed no evidence of typical GACI calcification; however, reevaluation by CT scan revealed high-density foci compatible with calcification in the left internal carotid artery siphon, cervical portions of the common carotid and right brachiocephalic arteries, aortic root, and descending aorta. The proband and his male sib were found to be compound heterozygous for the same ENPP1 mutations (see MOLECULAR GENETICS). At 5 years of age, the proband was healthy and developmentally age-appropriate, on antihypertensive and antiplatelet agents. Dlamini et al. (2009) concluded that GACI may be underrecognized and suggested that the diagnosis should be considered in patients with multiple arterial stenoses even in the absence of radiographic calcification. </p><p><strong><em>Features of Pseudoxanthoma Elasticum in GACI Patients</em></strong></p><p>
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Nitschke et al. (2012) described 3 unrelated GACI patients with homozygous or compound heterozygous ENNP1 mutations (see MOLECULAR GENETICS) who developed clinical features of pseudoxanthoma elasticum in later childhood. One boy with GACI, who was previously studied by Dlamini et al. (2009), developed at 8 years of age pseudoxanthomatous skin lesions around his umbilicus and on his neck, which were histologically proven to be typical PXE lesions. A 12-year-old French boy, born of consanguineous parents, was diagnosed with GACI in the neonatal period and treated with oral bisphosphonates, resulting in disappearance of the ectopic calcifications. At 9 years of age, he presented with yellowish papules on the neck and periumbilical region and large angiomatous atrophic macules on the anterior chest. He also had abnormal calcifications of the ear cartilage, cervical fusion between C3 and C5, and microcalcifications of the left kidney, but no cardiovascular or ophthalmologic calcifications were detected. He had short stature with progressive genu valgum, and radiologic signs of rickets were present; he was found to have hypophosphatemia with decreased renal phosphate reabsorption, normal vitamin D levels, and normal glomerular filtration rate. Reexamination at 12 years of age showed development of otosclerosis with stapedovestibular ankylosis, resulting in hearing loss. An eye exam showed no angioid streaks. Histopathologic studies of the yellowish neck papules confirmed the diagnosis of PXE, with calcium deposits in elastic fibers that were stained by carboxylated, but not noncarboxylated, anti-MGP (154870) antibodies. The patient's mother also presented with yellow papules characteristic for PXE, and his 9-year-old sister had angiomatous linear lesions of the left flank. The other GACI patient with features of PXE was a 5-year-old French girl with short stature, hypophosphatemic rickets, and cardiovascular, pancreatic, hepatic, and renal calcifications, who developed diffuse angiomatous lesions on her back and had angioid streaks in the Bruch membrane of the retina that were typical for PXE. She did not have any pseudoxanthomatous skin lesions. At 4 years of age, she had also developed conductive deafness and required hearing aids. </p><p><strong><em>Dental Features in GACI Survivors</em></strong></p><p>
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Thumbigere-Math et al. (2018) studied the teeth of 5 unrelated patients with GACI, including patients previously reported by Li et al. (2012), Rutsch et al. (2008), and Ferreira et al. (2016) (patients 2, 4, and 5). All presented significant hypercementosis of cervical cementum, with radiographic evidence of unusually protruding cervical root morphology, in primary and/or secondary dentition. Dental histories of 4 of the patients included evidence for infraocclusion, overretained primary teeth, possible ankylosis, and/or ineffective orthodontic tooth movement, suggesting altered mineral metabolism contributing to disrupted tooth movement and exfoliation. High-resolution micro-CT analyses of extracted primary teeth from 3 of the patients revealed a 4-fold increased cervical cementum thickness and a 23% increase in cementum mineral density compared to age-matched healthy control teeth. There were no differences in enamel or dentin densities between GACI patients and controls. Histologic examination showed markedly expanded cervical cementum in GACI teeth, including cementocyte-like cells and unusual patterns of cementum resorption and repair. </p>
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<strong>Clinical Management</strong>
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<p>Ferreira et al. (2016) reported a 22-year-old man who was diagnosed with GACI at age 6 weeks, at which time he was tachycardic with left ventricular hypertrophy and poor systolic function, and had hepatomegaly and splenomegaly. Cardiac catheterization revealed severe attenuation of the left coronary artery with subtotal occlusion of the first obtuse marginal branch and occlusion proximal to the circumflex, and proximal occlusion of the right coronary artery. CT scan showed calcification of the descending aorta as well as the coronary, brachial, renal, splenic, and superior mesenteric arteries. Bisphosphonate treatment ameliorated his cardiac function, and CT scan at 7 months of age showed reduced calcifications. At 13 months, the calcifications had regressed completely except for mild calcification of the aortic annulus, and bisphosphonate treatment was discontinued at 24 months of age. At age 13 years, the patient developed progressive pain in the ankles and knees, and x-rays showed significant anterior bowing and thinning of the lower ends of both femora. He was diagnosed with hypophosphatemic rickets at 14.5 years of age and treated with phosphorus and calcium supplementation. At 22 years of age, multidetector helical CT from neck to legs revealed minimal calcification of the aortic root, inferior portion of the heart, and left popliteal artery, with no calcifications elsewhere, including no nephrocalcinosis. Anterior femoral bowing was noted. Cardiac CT showed no coronary artery calcification. The authors concluded that long-term treatment of rickets in the setting of GACI can be accomplished without worsening of vascular calcifications. </p>
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<strong>Molecular Genetics</strong>
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<p>Spontaneous periarticular and aortic calcifications in early life and systemic lowering of nucleotide pyrophosphatase/phosphodiesterase (NPP) activity and inorganic pyrophosphate levels are shared features of the phenotype of idiopathic infantile arterial calcification (IIAC) and of homozygous 'tiptoe walking' (ttw/ttw) mice, which carry a spontaneous nonsense mutation in Enpp1 (Okawa et al., 1998; Rutsch et al., 2001). Rutsch et al. (2001) found reduced levels of expression of ENNP1 in an individual with IIAC born to consanguineous parents and demonstrated heterozygosity for a mutation at the ENNP1 locus (173335.0002). Using a high-density microsatellite marker panel for 6q, the site of the ENPP1 gene, Rutsch et al. (2003) identified a recombination event in this proband that had obscured homozygosity with respect to the critical region. Screening for mutations in ENPP1 in 11 unrelated families with IIAC found mutations in 8 of them, either in homozygous or compound heterozygous state, compatible with a functional inactivation of both alleles. ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase-1, a cell surface enzyme that generates inorganic pyrophosphate, a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification. </p><p>Lorenz-Depiereux et al. (2010) restudied 1 of the families previously described by Rutsch et al. (2003) ('family 4') and identified homozygosity for a missense mutation in the ENPP1 gene (173335.0011) in a father and son with different phenotypes: the son had generalized arterial calcification of infancy (GACI) and hypophosphatemia, whereas his father had hypophosphatemic rickets (ARHR2; 613312). Ultrasound examination of large blood vessels in the father showed normal carotid and renal arteries and a normal thoracic and abdominal aorta. </p><p>In a Taiwanese brother and sister with GACI who had markedly different clinical courses, Cheng et al. (2005) identified compound heterozygosity for missense mutations in the ENPP1 gene (see 173335.0008 and 173335.0009). </p><p>Rutsch et al. (2008) identified homozygosity or compound heterozygosity for 40 different mutations in the ENPP1 gene in 41 (75%) of 55 GACI patients. The most frequently detected mutation was P305T (173335.0016); Rutsch et al. (2008) noted that P305T was universally lethal when present on both alleles, but stated that no other clear genotype/phenotype correlation was seen. </p><p>In 2 Caucasian brothers with GACI, 1 deceased of myocardial infarction 12 hours after birth and 1 healthy at 5 years of age, Dlamini et al. (2009) identified compound heterozygosity for a missense and a 2-bp deletion in the ENPP1 gene (173335.0014 and 173335.0015). Nitschke et al. (2012) provided follow-up on the living brother, who at 8 years of age developed pseudoxanthomatous skin lesions that were histologically proven to be typical of pseudoxanthoma elasticum. </p><p>In 2 patients with GACI, a 12-year-old French boy and an unrelated 5-year-old French girl, who developed features of PXE in later childhood, Nitschke et al. (2012) identified homozygous and compound heterozygous mutations in the ENNP1 gene (see, e.g., 173335.0017-173335.0019, respectively). </p><p>In a 22-year-old man with GACI who underwent bisphosphonate treatment with near-total resolution of arterial calcifications by age 2 years (see CLINICAL MANAGEMENT), Ferreira et al. (2016) reported compound heterozygosity for missense mutations in the ENPP1 gene, R481Q and Y471C. In adolescence, the patient developed hypophosphatemic rickets, which was treated with phosphorus and calcium supplementation without any worsening of vascular calcifications. </p><p>In 3 sibs and an unrelated infant, born to 2 consanguineous Bedouin families, with GACI1, Staretz-Chacham et al. (2019) identified homozygosity for a missense mutation in the ENPPI gene (G186R; 173335.0023). All of the patients had thrombocytopenia and cardiac, hepatic, and CNS involvement, and all died in infancy. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. </p>
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<strong>Animal Model</strong>
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<p>Using high-resolution micro-CT, Thumbigere-Math et al. (2018) analyzed the mandibular molars of Enpp1-null mice and observed a 4-fold increased cervical cementum thickness and 5-fold increase in volume compared to wildtype mice, as well as a nonsignificant 5% increase in mineral density. Apically located cellular cementum showed significantly increased volume and height on the mesial root surface, but no change in thickness or density in the null mice compared to wildtype. The authors noted that histologically the molars of Enpp1-null mice resembled those of GACI patients, including dramatically expanded cervical cementum with abnormal inclusion of embedded nucleated cementocyte-like cells and lacunae. </p>
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Bird (1974); Maayan et al. (1984); McKusick (1972); Meradji et al.
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(1978); Milner et al. (1984); Moran and Becker (1959)
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<strong>REFERENCES</strong>
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Anderson, K. A., Burbach, J. A., Fenton, L. J., Jaqua, R. A., Barlow, J. F.
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<strong>Idiopathic arterial calcification of infancy in newborn siblings with unusual light and electron microscopic manifestations.</strong>
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Arch. Path. Lab. Med. 109: 838-842, 1985.
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[PubMed: 3839656]
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Bird, T.
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<strong>Idiopathic arterial calcification in infancy.</strong>
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Arch. Dis. Child. 49: 82-89, 1974.
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[PubMed: 4274089]
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[Full Text: https://doi.org/10.1136/adc.49.2.82]
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Cheng, K.-S., Chen, M.-R., Ruf, N., Lin, S.-P., Rutsch, F.
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<strong>Generalized arterial calcification of infancy: different clinical courses in two affected siblings.</strong>
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Am. J. Med. Genet. 136A: 210-213, 2005.
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[PubMed: 15940697]
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[Full Text: https://doi.org/10.1002/ajmg.a.30800]
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Dlamini, N., Splitt, M., Durkan, A., Siddiqui, A., Padayachee, S., Hobbins, S., Rutsch, F., Wraige, E.
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<strong>Generalized arterial calcification of infancy: phenotypic spectrum among three siblings including one case without obvious arterial calcifications.</strong>
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Am. J. Med. Genet. 149A: 456-460, 2009.
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[PubMed: 19206175]
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[Full Text: https://doi.org/10.1002/ajmg.a.32646]
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Ferreira, C. R., Ziegler, S. G., Gupta, A., Groden, C., Hsu, K. S., Gahl, W. A.
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<strong>Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy [GACI] without worsening of vascular calcification.</strong>
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Am. J. Med. Genet. 170A: 1308-1311, 2016.
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[PubMed: 26857895]
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[Full Text: https://doi.org/10.1002/ajmg.a.37574]
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Hunt, A. C., Leys, D. G.
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<strong>Generalized arterial calcification in infancy.</strong>
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Brit. Med. J. 1: 385-386, 1957.
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[PubMed: 13396267]
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[Full Text: https://doi.org/10.1136/bmj.1.5015.385]
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Li, Q., Schumacher, W., Jablonski, D., Siegel, D., Uitto, J.
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<strong>Cutaneous features of pseudoxanthoma elasticum in a patient with generalized arterial calcification of infancy due to a homozygous missense mutation in the ENPP1 gene.</strong>
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<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
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</div>
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</div>
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</div>
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</div>
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</div>
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</body>
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</html>
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