3332 lines
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Entry
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- #146300 - HYPOPHOSPHATASIA, ADULT; HPPA
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- OMIM
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<p>
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<span class="h4">#146300</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/146300"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></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="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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<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><a href="https://clinicaltrials.gov/search?cond=HYPOPHOSPHATASIA, ADULT" 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="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=19535&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Adult hypophosphatasia </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=19536&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Odontohypophosphatasia </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=162&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Hypophosphatasia </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1150/" 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/7639" 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=146300[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="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=247676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Adult hypophosphatasia</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=247685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Odontohypophosphatasia</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Hypophosphatasia</a></div>
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</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="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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</a>
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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:0110913" 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/146300" 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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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 20756002, 708672004<br />
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<strong>ORPHA:</strong> 247676, 247685, 436<br />
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<strong>DO:</strong> 0110913<br />
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">ICD+</a>
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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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146300
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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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HYPOPHOSPHATASIA, ADULT; HPPA
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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HYPOPHOSPHATASIA, MILD
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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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ODONTOHYPOPHOSPHATASIA, INCLUDED; HPPO, INCLUDED
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</span>
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</div>
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<div>
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<br />
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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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<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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</tr>
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</thead>
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<tbody>
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|
<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/251?start=-3&limit=10&highlight=251">
|
|
1p36.12
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Hypophosphatasia, adult
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/146300"> 146300 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
ALPL
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/171760"> 171760 </a>
|
|
</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/251?start=-3&limit=10&highlight=251">
|
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1p36.12
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Odontohypophosphatasia
|
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|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/146300"> 146300 </a>
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
ALPL
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/171760"> 171760 </a>
|
|
</span>
|
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</td>
|
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/146300" 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>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/146300" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/146300" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
|
</div>
|
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|
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br /> -
|
|
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>
|
|
|
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|
|
|
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|
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|
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|
|
<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> Teeth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Premature loss of primary teeth <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/234974002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">234974002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0399385&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0399385</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006323" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006323</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0006480" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006480</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006323" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006323</a>]</span><br /> -
|
|
Premature loss of secondary teeth <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969738&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969738</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006357" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006357</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006357" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006357</a>]</span><br /> -
|
|
Severe dental caries <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851048&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851048</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80967001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80967001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K02</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K02.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K02.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/521.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">521.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/521.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">521.00</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000670" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000670</a>]</span><br /> -
|
|
Decreased alveolar bone <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969739&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969739</a>]</span><br /> -
|
|
Enlarged pulp chamber <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843977</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Recurrent fractures (hypophosphatasia only) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969740&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969740</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/788192009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">788192009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771485007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771485007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/5468008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">5468008</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002757" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002757</a>]</span><br /> -
|
|
Pathologic fractures (hypophosphatasia only) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969741&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969741</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22640007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22640007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/268029009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">268029009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M84.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M84.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/733.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">733.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/V13.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">V13.51</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/733.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">733.1</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002756" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002756</a>]</span><br /> -
|
|
Osteomalacia (hypophosphatasia only) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969742&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969742</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/4598005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">4598005</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/268.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">268.2</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002749" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002749</a>]</span><br /> -
|
|
Rickets (hypophosphatasia only) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969743&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969743</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/41345002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">41345002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E55.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E55.0</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002748" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002748</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Limbs </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Long bone pseudofractures (hypophosphatasia only) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969744&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969744</a>]</span><br /> -
|
|
Calcium pyrophosphate arthropathy (hypophosphatasia only) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969745</a>]</span><br /> -
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Chondrocalcinosis (hypophosphatasia only) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969746&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969746</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/239838005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">239838005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/201637001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">201637001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/239832006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">239832006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M11.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M11.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/712.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">712.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/712.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">712.3</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/712.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">712.20</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000934" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000934</a>]</span><br />
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- Metatarsal stress fracture (hypophosphatasia only) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1969747&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1969747</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/733.94" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">733.94</a>]</span><br />
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<strong> LABORATORY ABNORMALITIES </strong>
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- Decreased serum alkaline phosphatase <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860130&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860130</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003282" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003282</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003282" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003282</a>]</span><br /> -
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Elevated urinary phosphoethanolamine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1840329&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1840329</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- No skeletal abnormalities in odontohypophosphatasia<br /> -
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Rickets and premature primary tooth loss occur in childhood<br /> -
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Fractures and dental caries and premature secondary tooth loss occur in adulthood<br /> -
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Can be asymptomatic<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in alkaline phosphatase gene (ALPL, <a href="/entry/171760#0003">171760.0003</a>)<br />
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that adult hypophosphatasia (HPPA) is caused by heterozygous or compound heterozygous mutation in the gene encoding tissue-nonspecific alkaline phosphatase (ALPL; <a href="/entry/171760">171760</a>) on chromosome 1p36.</p><p><a href="#7" class="mim-tip-reference" title="Fraser, D. <strong>Hypophosphatasia.</strong> Am. J. Med. 22: 730-746, 1957.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13410963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13410963</a>] [<a href="https://doi.org/10.1016/0002-9343(57)90124-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13410963">Fraser (1957)</a> classified forms of hypophosphatasia (HPP) according to age of onset: perinatal (see <a href="/entry/241500">241500</a>), infantile (<a href="/entry/241500">241500</a>), childhood (<a href="/entry/241510">241510</a>), and adult. <a href="#29" class="mim-tip-reference" title="Whyte, M. P. <strong>Personal Communication.</strong> St. Louis, Mo. 7/21/1988."None>Whyte (1988)</a> indicated a fifth form of hypophosphatasia with primarily only dental manifestations, referred to as odontohypophosphatasia (HPPO). All of these forms are allelic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13410963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Clinical Features</strong>
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<p>In the family reported by <a href="#20" class="mim-tip-reference" title="Silverman, J. L. <strong>Apparent dominant inheritance of hypophosphatasia.</strong> Ann. Intern. Med. 110: 191-198, 1962."None>Silverman (1962)</a>, a father and 2 sons had hypophosphatasia. The paternal grandmother may have been affected. No evidence of heterozygosity was obtained in the propositus' wife or 2 unaffected children. Clinical features were early loss of teeth, bowed legs diagnosed as rickets and requiring osteotomy, and beaten-copper appearance of skull x-ray. The propositus had served in the U.S. Air Force. <a href="#4" class="mim-tip-reference" title="Danovitch, S. H., Baer, P. N., Laster, L. <strong>Intestinal alkaline phosphatase activity in familial hypophosphatasia.</strong> New Eng. J. Med. 278: 1253-1260, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4296721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4296721</a>] [<a href="https://doi.org/10.1056/NEJM196806062782303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4296721">Danovitch et al. (1968)</a> also suggested dominant inheritance as the mechanism in the family they studied. Three female cousins, the daughters of 3 sisters, and their mothers had low serum alkaline phosphatase and elevated urinary phosphoethanolamine. Two of the cousins had premature loss of primary teeth. Intestinal alkaline phosphatase was normal. <a href="#12" class="mim-tip-reference" title="Jardon, O. M., Burney, D. W., Fink, R. L. <strong>Hypophosphatasia in an adult.</strong> J. Bone Joint Surg. Am. 52: 1477-1484, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4319245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4319245</a>]" pmid="4319245">Jardon et al. (1970)</a> described a woman who was asymptomatic until age 50 years. She showed pseudofracture of the proximal femur and calcification of paraspinous ligaments like those in adults with hypophosphatemic rickets (see <a href="/entry/307800">307800</a>). <a href="#1" class="mim-tip-reference" title="Bixler, D., Poland, C., III, Brandt, I. K., Nicholas, N. J. <strong>Autosomal dominant hypophosphatasia without skeletal disease. (Abstract)</strong> Am. J. Hum. Genet. 26: 14A only, 1974."None>Bixler et al. (1974)</a> observed affected persons in 3 generations. <a href="#2" class="mim-tip-reference" title="Bixler, D. <strong>Heritable disorders affecting cementum and the periodontal structure. In: Stewart, R. E.; Prescott, G. H. (eds.): Oral Facial Genetics.</strong> St. Louis: C. V. Mosby (pub.) 1976. Pp. 276-277."None>Bixler (1976)</a> referred to 4 kindreds showing autosomal dominant inheritance, and a fifth described to him by another worker. Electrophoretic abnormality of isozymes were described by <a href="#10" class="mim-tip-reference" title="Hosenfeld, D., Hosenfeld, A. <strong>Qualitative and quantitative examinations of the isoenzymes of serum alkaline phosphatase in hypophosphatasia.</strong> Klin. Padiatr. 185: 437-443, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4798670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4798670</a>]" pmid="4798670">Hosenfeld and Hosenfeld (1973)</a>. The diagnosis often can be made first by the dentist who is asked to explain a child's early loss of deciduous incisors, usually before 3 years of age. Males were less severely affected in the kindred reported by <a href="#27" class="mim-tip-reference" title="Whyte, M. P., Teitelbaum, S. L., Murphy, W. A., Avioli, L. V. <strong>Adult hypophosphatasia: clinical, laboratory, and genetic investigation of a large kindred with review of the literature.</strong> Medicine 58: 329-347, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/481194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">481194</a>]" pmid="481194">Whyte et al. (1979)</a>. Expression is so mild in many of the persons presumed to have the dominant disorder that the mating of 2 such individuals might present as the phenotype of infantile hypophosphatasia (<a href="/entry/241500">241500</a>) in an offspring. 'A correct diagnosis is important, since vitamin D therapy, appropriate for most forms of osteomalacia, is of no benefit in hypophosphatasia and has led to inordinate hypercalcemia with resultant kidney damage' (<a href="#22" class="mim-tip-reference" title="Weinstein, R. S., Whyte, M. P. <strong>Heterogeneity of adult hypophosphatasia: report of severe and mild cases.</strong> Arch. Intern. Med. 141: 727-731, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7235780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7235780</a>]" pmid="7235780">Weinstein and Whyte, 1981</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=481194+7235780+4296721+4319245+4798670" 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="#25" class="mim-tip-reference" title="Whyte, M. P., Murphy, W. A., Fallon, M. D. <strong>Adult hypophosphatasia with chondrocalcinosis and arthropathy: variable penetrance of hypophosphatasemia in a large Oklahoma kindred.</strong> Am. J. Med. 72: 631-641, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7072744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7072744</a>] [<a href="https://doi.org/10.1016/0002-9343(82)90474-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7072744">Whyte et al. (1982)</a> described a family in which 3 sisters had chondrocalcinosis and arthropathy as a complication. <a href="#25" class="mim-tip-reference" title="Whyte, M. P., Murphy, W. A., Fallon, M. D. <strong>Adult hypophosphatasia with chondrocalcinosis and arthropathy: variable penetrance of hypophosphatasemia in a large Oklahoma kindred.</strong> Am. J. Med. 72: 631-641, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7072744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7072744</a>] [<a href="https://doi.org/10.1016/0002-9343(82)90474-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7072744">Whyte et al. (1982)</a> showed that cultured skin fibroblasts are low in alkaline phosphatase; thus, since the enzyme deficiency is not limited to bone, the disorder is not a selective abiotrophy of osteoblasts. <a href="#23" class="mim-tip-reference" title="Whyte, M. P., Mahuren, J. D., Vrabel, L. A., Coburn, S. P. <strong>Markedly increased circulating pyridoxal-5-prime-phosphate levels in hypophosphatasia: alkaline phosphatase acts in vitamin B6 metabolism.</strong> J. Clin. Invest. 76: 752-756, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4031070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4031070</a>] [<a href="https://doi.org/10.1172/JCI112031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4031070">Whyte et al. (1985)</a> found markedly increased circulating concentrations of pyridoxal-5-prime-phosphate (PLP) in all clinical forms of hypophosphatasia. The findings indicated that tissue-nonspecific alkaline phosphatase acts in vitamin B6 metabolism. The enzyme appears to function as an ectoenzyme to regulate extracellular but not intracellular levels of PLP substrate. Assays of circulating PLP concentration may be misleading in assessing vitamin B6 nutrition in disorders associated with altered alkaline phosphatase activity. The degree of plasma PLP elevation generally reflected the clinical severity of the disorder (<a href="#29" class="mim-tip-reference" title="Whyte, M. P. <strong>Personal Communication.</strong> St. Louis, Mo. 7/21/1988."None>Whyte, 1988</a>). A small oral dose of pyridoxine (which is converted to PLP) has been shown to discriminate patients from normals and may be useful for heterozygote detection (<a href="#29" class="mim-tip-reference" title="Whyte, M. P. <strong>Personal Communication.</strong> St. Louis, Mo. 7/21/1988."None>Whyte, 1988</a>). The elevation of PLP was observed in all forms of hypophosphatasia, which <a href="#29" class="mim-tip-reference" title="Whyte, M. P. <strong>Personal Communication.</strong> St. Louis, Mo. 7/21/1988."None>Whyte (1988)</a> indicated as 5 in number: perinatal, infantile (<a href="/entry/241500">241500</a>), childhood (<a href="/entry/241510">241510</a>), adult, and a form with primarily only dental manifestations, which is referred to as odontohypophosphatasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4031070+7072744" 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="#15" class="mim-tip-reference" title="Macfarlane, J. D., Kroon, H. M., van der Harten, J. J. <strong>Phenotypically dissimilar hypophosphatasia in two sibships.</strong> Am. J. Med. Genet. 42: 117-121, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1308350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1308350</a>] [<a href="https://doi.org/10.1002/ajmg.1320420124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1308350">Macfarlane et al. (1992)</a> were impressed with the difference in severity in 2 sisters with hypophosphatasia. Both had early loss of primary teeth, but only 1 of them had clinical or radiologic manifestations: joint pains and peri- and intraarticular calcifications of joints of the hands, feet, and knees and calcification of the anterior spinous ligament in the lumbar area. The parents shared a common ancestor '6 generations back.' <a href="#3" class="mim-tip-reference" title="Chapple, I. L. C., Thorpe, G. H. G., Smith, J. M., Saxby, M. S., Glenwright, H. D., Green, A., Perry, G. M., Grundy, M., Shaw, L., Matthews, J. B. <strong>Hypophosphatasia: a family study involving a case diagnosed from gingival crevicular fluid.</strong> J. Oral Path. Med. 21: 426-431, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1432739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1432739</a>] [<a href="https://doi.org/10.1111/j.1600-0714.1992.tb01033.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1432739">Chapple et al. (1992)</a> described a family with affected members in 3 generations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1308350+1432739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Hu, J. C.-C., Plaetke, R., Mornet, E., Zhang, C., Sun, X., Thomas, H. F., Simmer, J. P. <strong>Characterization of a family with dominant hypophosphatasia.</strong> Europ. J. Oral Sci. 108: 189-194, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10872988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10872988</a>] [<a href="https://doi.org/10.1034/j.1600-0722.2000.108003189.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10872988">Hu et al. (2000)</a> described a 4-generation Texas family segregating autosomal dominant hypophosphatasia in both children and adults. The probands were a 6-year-old girl and her twin brother, who exhibited enamel hypoplasia and the premature loss of fully rooted anterior teeth at age 3.5 years; histologic examination of a tooth demonstrated a complete absence of cementum on the root surface. Lateral cephalometric radiograph showed multiple radiolucent spots with wormian bone in the occipital region, and enlarged pulp chambers in the mandibular canines and first primary molars were evident in the panorex. Radiographs of the long bones and chest revealed no additional skeletal abnormalities. Serum PLP and urine phosphoethanolamine (PEA) were abnormally high in both of the twins and a definitive diagnosis of hypophosphatasia was made, which was supported by findings in other members of the kindred. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10872988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Lia-Baldini, A. S., Muller, F., Taillandier, A., Gibrat, J. F., Mouchard, M., Robin, B., Simon-Bouy, B., Serre, J. L., Aylsworth, A. S., Bieth, E., Delanote, S., Freisinger, P., Hu, J. C.-C., Krohn, H.-P., Nunes, M. E., Mornet, E. <strong>A molecular approach to dominance in hypophosphatasia.</strong> Hum. Genet. 109: 99-108, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479741</a>] [<a href="https://doi.org/10.1007/s004390100546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479741">Lia-Baldini et al. (2001)</a> reported a 15-month-old girl with a phenotype suggestive of childhood hypophosphatasia, whose father had recurrent dental caries in his third decade despite being raised with fluoridated water, which the authors suggested represented odontohypophosphatasia. A paternal aunt had died at 7 days of apparent neonatal hypophosphatasia, with x-rays showing poorly mineralized ribs and skull, and the paternal grandmother lost all her permanent teeth in her third decade and subsequently developed osteoporosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Unger, S., Mornet, E., Mundlos, S., Blaser, S., Cole, D. E. C. <strong>Severe cleidocranial dysplasia can mimic hypophosphatasia.</strong> Europ. J. Pediat. 161: 623-626, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12424591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12424591</a>] [<a href="https://doi.org/10.1007/s00431-002-0978-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12424591">Unger et al. (2002)</a> and <a href="#17" class="mim-tip-reference" title="Morava, E., Karteszi, J., Weisenbach, J., Caliebe, A., Mundlos, S., Mehes, K. <strong>Cleidocranial dysplasia with decreased bone density and biochemical findings of hypophosphatasia.</strong> Europ. J. Pediat. 161: 619-622, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12424590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12424590</a>] [<a href="https://doi.org/10.1007/s00431-002-0977-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12424590">Morava et al. (2002)</a> reported 3 patients with cleidocranial dysplasia (CCD; <a href="/entry/119600">119600</a>) and secondary hypophosphatasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12424591+12424590" 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>In Utero Manifestations</em></strong></p><p>
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<a href="#16" class="mim-tip-reference" title="Moore, C. A., Curry, C. J. R., Henthorn, P. S., Smith, J. A., Smith, J. C., O'Lague, P., Coburn, S. P., Weaver, D. D., Whyte, M. P. <strong>Mild autosomal dominant hypophosphatasia: in utero presentation in two families.</strong> Am. J. Med. Genet. 86: 410-415, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508980</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19991029)86:5<410::aid-ajmg3>3.0.co;2-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508980">Moore et al. (1999)</a> described 2 families with mild hypophosphatasia, apparently transmitted as an autosomal dominant trait, in which ultrasonography detected 4 affected fetuses with severe long bone bowing. In contrast to the progressive deterioration typical of both the perinatal and infantile forms of hypophosphatasia, these skeletal defects improved spontaneously during infancy and early childhood. Biochemical evidence of hypophosphatasia was present in both families, and in 1 family, a mutation in the ALPL gene was identified (<a href="/entry/171760#0009">171760.0009</a>). The authors noted that the prognosis for this condition was considerably better than for more severe forms of hypophosphatasia and for many other disorders that cause long bone bowing in utero. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508980" 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="Pauli, R. M., Modaff, P., Sipes, S. L., Whyte, M. P. <strong>Mild hypophosphatasia mimicking severe osteogenesis imperfecta in utero: bent but not broken.</strong> Am. J. Med. Genet. 86: 434-438, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508985</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19991029)86:5<434::aid-ajmg8>3.0.co;2-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508985">Pauli et al. (1999)</a> described an additional case with hypophosphatasia presenting with prenatal findings suggestive of a very severe bone dysplasia but with a subsequently benign course. Repeat late-gestation ultrasonography documented that improvement was already occurring prior to delivery. The authors emphasized the need to add spontaneously improving hypophosphatasia to the list of disorders presenting with in utero bony angulation or bowing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#24" class="mim-tip-reference" title="Whyte, M. P., Mumm, S., Deal, C. <strong>Adult hypophosphatasia treated with teriparatide.</strong> J. Clin. Endocr. Metab. 92: 1203-1208, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17213282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17213282</a>] [<a href="https://doi.org/10.1210/jc.2006-1902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17213282">Whyte et al. (2007)</a> reported treatment of a middle-aged woman who sustained a slowly healing metatarsal stress fracture (MTSF) and then 2 enlarging MTSFs and a spontaneous proximal femur fracture. She carried a heterozygous ALPL missense mutation (D378V; <a href="/entry/171760#0009">171760.0009</a>). Pain persisted at all fracture sites. Hypophosphatasia was diagnosed as a result of low ALP activity and elevated inorganic phosphate and pyridoxal 5-prime-phosphate concentrations in serum. Teriparatide (TPTD) (recombinant human PTH 1-34), 20 micrograms, was injected subcutaneously daily in an attempt to enhance osteoblast synthesis of tissue-nonspecific ALP (TNSALP). Six weeks later, all fracture pain improved, and resolved after 4 months. Radiographs of the enlarging MTSFs showed repair after 2-4 months. The femur fracture partially mended after 2 months and then healed. Additionally, hypophosphatasemia and hyperphosphatemia corrected, and biochemical markers of bone remodeling increased as long as TPTD (given for 18 months) was continued. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17213282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Kishnani, P. S., del Angel, G., Zhou, S., Rush, E. T. <strong>Investigation of ALPL variant states and clinical outcomes: an analysis of adults and adolescents with hypophosphatasia treated with asfotase alfa.</strong> Molec. Genet. Metab. 133: 113-121, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33814268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33814268</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.03.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33814268">Kishnani et al. (2021)</a> reported outcomes of a phase 2 efficacy and safety study of asfotase alfa in 19 adolescents and adults with childhood or adult hypophosphatasia, including 14 patients with autosomal recessive disease and 5 patients with autosomal dominant disease. Median inorganic phosphate (PPi) and PLP concentrations were normalized over 5 years of treatment in patients with both recessive and dominant disease. Median predicted distance walked on the 6-minute walk test remained within the normal range for patients with dominant disease over 4 years of treatment, and improved from below normal to normal in patients with autosomal recessive disease. Pain scores also improved in both recessive and dominant groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33814268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 65-year-old woman with adult hypophosphatasia, <a href="#8" class="mim-tip-reference" title="Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P. <strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong> Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1409720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1409720</a>] [<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1409720">Henthorn et al. (1992)</a> identified compound heterozygosity for missense mutations in the ALPL gene (<a href="/entry/171760#0003">171760.0003</a> and <a href="/entry/171760#0008">171760.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1409720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Mornet, E. <strong>Personal Communication.</strong> Paris, France 6/3/1999."None>Mornet (1999)</a> tested 2 large families with adult hypophosphatasia. In 1 family, hypophosphatasia was dominantly inherited and was due to a missense mutation in the ALPL gene; in the other family, adult hypophosphatasia was recessively transmitted and was due to compound heterozygosity for a missense mutation and a splicing mutation in the ALPL gene.</p><p>In a 4-generation Texas family segregating autosomal dominant hypophosphatasia in both children and adults, <a href="#11" class="mim-tip-reference" title="Hu, J. C.-C., Plaetke, R., Mornet, E., Zhang, C., Sun, X., Thomas, H. F., Simmer, J. P. <strong>Characterization of a family with dominant hypophosphatasia.</strong> Europ. J. Oral Sci. 108: 189-194, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10872988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10872988</a>] [<a href="https://doi.org/10.1034/j.1600-0722.2000.108003189.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10872988">Hu et al. (2000)</a> identified a heterozygous missense mutation in the ALPL gene (<a href="/entry/171760#0015">171760.0015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10872988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 15-month-old girl and her father, who had phenotypes suggestive of childhood hypophosphatasia and odontohypophosphatasia, respectively, <a href="#14" class="mim-tip-reference" title="Lia-Baldini, A. S., Muller, F., Taillandier, A., Gibrat, J. F., Mouchard, M., Robin, B., Simon-Bouy, B., Serre, J. L., Aylsworth, A. S., Bieth, E., Delanote, S., Freisinger, P., Hu, J. C.-C., Krohn, H.-P., Nunes, M. E., Mornet, E. <strong>A molecular approach to dominance in hypophosphatasia.</strong> Hum. Genet. 109: 99-108, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479741</a>] [<a href="https://doi.org/10.1007/s004390100546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479741">Lia-Baldini et al. (2001)</a> identified heterozygosity for a missense mutation in the ALPL gene (<a href="/entry/171760#0021">171760.0021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479741" 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 mother and son with odontohypophosphatasia, low serum alkaline phosphatase, and no evidence of fractures, <a href="#9" class="mim-tip-reference" title="Herasse, M., Spentchian, M., Taillandier, A., Keppler-Noreuil, K., Fliorito, A. N. M., Bergoffen, J., Wallerstein, R., Muti, C., Simon-Bouy, B., Mornet, E. <strong>Molecular study of three cases of odontohypophosphatasia resulting from heterozygosity for mutations in the tissue non-specific alkaline phosphatase gene.</strong> J. Med. Genet. 40: 605-609, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920074</a>] [<a href="https://doi.org/10.1136/jmg.40.8.605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920074">Herasse et al. (2003)</a> identified heterozygosity for a missense mutation in the ALPL gene (<a href="/entry/171760#0018">171760.0018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a study of 44 adolescents and adults with childhood or adult hypophosphatasia, <a href="#13" class="mim-tip-reference" title="Kishnani, P. S., del Angel, G., Zhou, S., Rush, E. T. <strong>Investigation of ALPL variant states and clinical outcomes: an analysis of adults and adolescents with hypophosphatasia treated with asfotase alfa.</strong> Molec. Genet. Metab. 133: 113-121, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33814268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33814268</a>] [<a href="https://doi.org/10.1016/j.ymgme.2021.03.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33814268">Kishnani et al. (2021)</a> compared clinical characteristics between patients with autosomal recessive disease (30 patients) and autosomal dominant disease (14 patients). Median age of onset of symptoms in patients with recessive disease was 1 year, with a range of 0-4 years, and the median age of onset of symptoms in patients with dominant disease was 4 years, with a range of 0 to 36 years. Baseline inorganic phosphate (PPi) and pyridoxal 5-prime phosphate (PLP) concentrations were significantly higher in patients with recessive disease compared to dominant disease. A large percentage of both groups experienced bone pain, abnormal gait, and fractures. Abnormally shaped head or chest, bowing of the limbs, and delayed walking were more common in patients with recessive disease. Patients with dominant disease had a higher number of fractures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33814268" 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="https://doi.org/10.1136/ard.40.2.164" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.89.20.9924" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.40.8.605" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00431-002-0977-x" target="_blank">Full Text</a>]
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</p>
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<a id="18" class="mim-anchor"></a>
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<a id="Mornet1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mornet, E.
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<strong>Personal Communication.</strong>
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|
Paris, France 6/3/1999.
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Pauli1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pauli, R. M., Modaff, P., Sipes, S. L., Whyte, M. P.
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<strong>Mild hypophosphatasia mimicking severe osteogenesis imperfecta in utero: bent but not broken.</strong>
|
|
Am. J. Med. Genet. 86: 434-438, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508985</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508985" 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/(sici)1096-8628(19991029)86:5<434::aid-ajmg8>3.0.co;2-c" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Silverman1962" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Silverman, J. L.
|
|
<strong>Apparent dominant inheritance of hypophosphatasia.</strong>
|
|
Ann. Intern. Med. 110: 191-198, 1962.
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</p>
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</div>
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</li>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Unger2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Unger, S., Mornet, E., Mundlos, S., Blaser, S., Cole, D. E. C.
|
|
<strong>Severe cleidocranial dysplasia can mimic hypophosphatasia.</strong>
|
|
Europ. J. Pediat. 161: 623-626, 2002.
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|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12424591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12424591</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12424591" 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/s00431-002-0978-9" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Weinstein1981" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weinstein, R. S., Whyte, M. P.
|
|
<strong>Heterogeneity of adult hypophosphatasia: report of severe and mild cases.</strong>
|
|
Arch. Intern. Med. 141: 727-731, 1981.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7235780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7235780</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7235780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Whyte1985" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Whyte, M. P., Mahuren, J. D., Vrabel, L. A., Coburn, S. P.
|
|
<strong>Markedly increased circulating pyridoxal-5-prime-phosphate levels in hypophosphatasia: alkaline phosphatase acts in vitamin B6 metabolism.</strong>
|
|
J. Clin. Invest. 76: 752-756, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4031070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4031070</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4031070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI112031" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Whyte2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Whyte, M. P., Mumm, S., Deal, C.
|
|
<strong>Adult hypophosphatasia treated with teriparatide.</strong>
|
|
J. Clin. Endocr. Metab. 92: 1203-1208, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17213282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17213282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17213282" 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/10.1210/jc.2006-1902" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Whyte1982" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Whyte, M. P., Murphy, W. A., Fallon, M. D.
|
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<strong>Adult hypophosphatasia with chondrocalcinosis and arthropathy: variable penetrance of hypophosphatasemia in a large Oklahoma kindred.</strong>
|
|
Am. J. Med. 72: 631-641, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7072744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7072744</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7072744" 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/10.1016/0002-9343(82)90474-0" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Whyte1978" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Whyte, M. P., Teitelbaum, S. L., Murphy, W. A., Avioli, L. V.
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<strong>Adult hypophosphatasia: dominant inheritance in a large kindred.</strong>
|
|
Trans. Assoc. Am. Phys. 91: 144-155, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/754388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">754388</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=754388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Whyte1979" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
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Whyte, M. P., Teitelbaum, S. L., Murphy, W. A., Avioli, L. V.
|
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<strong>Adult hypophosphatasia: clinical, laboratory, and genetic investigation of a large kindred with review of the literature.</strong>
|
|
Medicine 58: 329-347, 1979.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/481194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">481194</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=481194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Whyte1982" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Whyte, M. P., Vrabel, L. A., Schwartz, T. D.
|
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<strong>Adult hypophosphatasia: generalized deficiency of alkaline phosphatase activity demonstrated with cultured skin fibroblasts.</strong>
|
|
Trans. Assoc. Am. Phys. 95: 253-263, 1982.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7182980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7182980</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7182980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="29" class="mim-anchor"></a>
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<a id="Whyte1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
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Whyte, M. P.
|
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<strong>Personal Communication.</strong>
|
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St. Louis, Mo. 7/21/1988.
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</p>
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</div>
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</li>
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</ol>
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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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<div>
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<a id="contributors" 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="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 : 06/04/2021
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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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John A. Phillips, III - updated : 3/24/2008<br>Cassandra L. Kniffin - updated : 8/11/2004<br>Victor A. McKusick - updated : 10/1/2003<br>Sonja A. Rasmussen - updated : 12/15/1999<br>Victor A. McKusick - updated : 6/8/1999
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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 : 6/2/1986
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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="editHistory" 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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<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 : 06/07/2021
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</span>
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</div>
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</div>
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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 : 06/06/2021<br>carol : 06/04/2021<br>carol : 04/12/2021<br>carol : 12/06/2019<br>carol : 12/05/2019<br>terry : 03/20/2012<br>terry : 1/13/2011<br>wwang : 10/17/2008<br>carol : 9/17/2008<br>carol : 3/24/2008<br>carol : 3/24/2008<br>carol : 9/1/2005<br>carol : 8/11/2004<br>ckniffin : 8/11/2004<br>carol : 10/24/2003<br>tkritzer : 10/6/2003<br>tkritzer : 10/1/2003<br>mgross : 12/20/1999<br>mgross : 12/15/1999<br>mgross : 12/1/1999<br>mgross : 12/1/1999<br>carol : 9/14/1999<br>jlewis : 6/15/1999<br>terry : 6/8/1999<br>mimadm : 11/5/1994<br>carol : 5/24/1994<br>warfield : 4/12/1994<br>pfoster : 2/25/1994<br>carol : 1/19/1993<br>carol : 12/21/1992
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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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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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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> 146300
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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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HYPOPHOSPHATASIA, ADULT; HPPA
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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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<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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HYPOPHOSPHATASIA, MILD
|
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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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<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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ODONTOHYPOPHOSPHATASIA, INCLUDED; HPPO, 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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 20756002, 708672004;
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<strong>ORPHA:</strong> 247676, 247685, 436;
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<strong>DO:</strong> 0110913;
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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>
|
|
Location
|
|
</th>
|
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<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
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</thead>
|
|
<tbody>
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|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
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1p36.12
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</span>
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</td>
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<td>
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<span class="mim-font">
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Hypophosphatasia, adult
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</span>
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</td>
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<td>
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<span class="mim-font">
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146300
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
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ALPL
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</span>
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</td>
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<td>
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<span class="mim-font">
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171760
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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1p36.12
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</span>
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</td>
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<td>
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<span class="mim-font">
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Odontohypophosphatasia
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</span>
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</td>
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<td>
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<span class="mim-font">
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146300
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<td>
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<span class="mim-font">
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ALPL
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</span>
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</td>
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<td>
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<span class="mim-font">
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171760
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that adult hypophosphatasia (HPPA) is caused by heterozygous or compound heterozygous mutation in the gene encoding tissue-nonspecific alkaline phosphatase (ALPL; 171760) on chromosome 1p36.</p><p>Fraser (1957) classified forms of hypophosphatasia (HPP) according to age of onset: perinatal (see 241500), infantile (241500), childhood (241510), and adult. Whyte (1988) indicated a fifth form of hypophosphatasia with primarily only dental manifestations, referred to as odontohypophosphatasia (HPPO). All of these forms are allelic. </p>
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</span>
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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>Clinical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In the family reported by Silverman (1962), a father and 2 sons had hypophosphatasia. The paternal grandmother may have been affected. No evidence of heterozygosity was obtained in the propositus' wife or 2 unaffected children. Clinical features were early loss of teeth, bowed legs diagnosed as rickets and requiring osteotomy, and beaten-copper appearance of skull x-ray. The propositus had served in the U.S. Air Force. Danovitch et al. (1968) also suggested dominant inheritance as the mechanism in the family they studied. Three female cousins, the daughters of 3 sisters, and their mothers had low serum alkaline phosphatase and elevated urinary phosphoethanolamine. Two of the cousins had premature loss of primary teeth. Intestinal alkaline phosphatase was normal. Jardon et al. (1970) described a woman who was asymptomatic until age 50 years. She showed pseudofracture of the proximal femur and calcification of paraspinous ligaments like those in adults with hypophosphatemic rickets (see 307800). Bixler et al. (1974) observed affected persons in 3 generations. Bixler (1976) referred to 4 kindreds showing autosomal dominant inheritance, and a fifth described to him by another worker. Electrophoretic abnormality of isozymes were described by Hosenfeld and Hosenfeld (1973). The diagnosis often can be made first by the dentist who is asked to explain a child's early loss of deciduous incisors, usually before 3 years of age. Males were less severely affected in the kindred reported by Whyte et al. (1979). Expression is so mild in many of the persons presumed to have the dominant disorder that the mating of 2 such individuals might present as the phenotype of infantile hypophosphatasia (241500) in an offspring. 'A correct diagnosis is important, since vitamin D therapy, appropriate for most forms of osteomalacia, is of no benefit in hypophosphatasia and has led to inordinate hypercalcemia with resultant kidney damage' (Weinstein and Whyte, 1981). </p><p>Whyte et al. (1982) described a family in which 3 sisters had chondrocalcinosis and arthropathy as a complication. Whyte et al. (1982) showed that cultured skin fibroblasts are low in alkaline phosphatase; thus, since the enzyme deficiency is not limited to bone, the disorder is not a selective abiotrophy of osteoblasts. Whyte et al. (1985) found markedly increased circulating concentrations of pyridoxal-5-prime-phosphate (PLP) in all clinical forms of hypophosphatasia. The findings indicated that tissue-nonspecific alkaline phosphatase acts in vitamin B6 metabolism. The enzyme appears to function as an ectoenzyme to regulate extracellular but not intracellular levels of PLP substrate. Assays of circulating PLP concentration may be misleading in assessing vitamin B6 nutrition in disorders associated with altered alkaline phosphatase activity. The degree of plasma PLP elevation generally reflected the clinical severity of the disorder (Whyte, 1988). A small oral dose of pyridoxine (which is converted to PLP) has been shown to discriminate patients from normals and may be useful for heterozygote detection (Whyte, 1988). The elevation of PLP was observed in all forms of hypophosphatasia, which Whyte (1988) indicated as 5 in number: perinatal, infantile (241500), childhood (241510), adult, and a form with primarily only dental manifestations, which is referred to as odontohypophosphatasia. </p><p>Macfarlane et al. (1992) were impressed with the difference in severity in 2 sisters with hypophosphatasia. Both had early loss of primary teeth, but only 1 of them had clinical or radiologic manifestations: joint pains and peri- and intraarticular calcifications of joints of the hands, feet, and knees and calcification of the anterior spinous ligament in the lumbar area. The parents shared a common ancestor '6 generations back.' Chapple et al. (1992) described a family with affected members in 3 generations. </p><p>Hu et al. (2000) described a 4-generation Texas family segregating autosomal dominant hypophosphatasia in both children and adults. The probands were a 6-year-old girl and her twin brother, who exhibited enamel hypoplasia and the premature loss of fully rooted anterior teeth at age 3.5 years; histologic examination of a tooth demonstrated a complete absence of cementum on the root surface. Lateral cephalometric radiograph showed multiple radiolucent spots with wormian bone in the occipital region, and enlarged pulp chambers in the mandibular canines and first primary molars were evident in the panorex. Radiographs of the long bones and chest revealed no additional skeletal abnormalities. Serum PLP and urine phosphoethanolamine (PEA) were abnormally high in both of the twins and a definitive diagnosis of hypophosphatasia was made, which was supported by findings in other members of the kindred. </p><p>Lia-Baldini et al. (2001) reported a 15-month-old girl with a phenotype suggestive of childhood hypophosphatasia, whose father had recurrent dental caries in his third decade despite being raised with fluoridated water, which the authors suggested represented odontohypophosphatasia. A paternal aunt had died at 7 days of apparent neonatal hypophosphatasia, with x-rays showing poorly mineralized ribs and skull, and the paternal grandmother lost all her permanent teeth in her third decade and subsequently developed osteoporosis. </p><p>Unger et al. (2002) and Morava et al. (2002) reported 3 patients with cleidocranial dysplasia (CCD; 119600) and secondary hypophosphatasia. </p><p><strong><em>In Utero Manifestations</em></strong></p><p>
|
|
Moore et al. (1999) described 2 families with mild hypophosphatasia, apparently transmitted as an autosomal dominant trait, in which ultrasonography detected 4 affected fetuses with severe long bone bowing. In contrast to the progressive deterioration typical of both the perinatal and infantile forms of hypophosphatasia, these skeletal defects improved spontaneously during infancy and early childhood. Biochemical evidence of hypophosphatasia was present in both families, and in 1 family, a mutation in the ALPL gene was identified (171760.0009). The authors noted that the prognosis for this condition was considerably better than for more severe forms of hypophosphatasia and for many other disorders that cause long bone bowing in utero. </p><p>Pauli et al. (1999) described an additional case with hypophosphatasia presenting with prenatal findings suggestive of a very severe bone dysplasia but with a subsequently benign course. Repeat late-gestation ultrasonography documented that improvement was already occurring prior to delivery. The authors emphasized the need to add spontaneously improving hypophosphatasia to the list of disorders presenting with in utero bony angulation or bowing. </p>
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</span>
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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>Clinical Management</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Whyte et al. (2007) reported treatment of a middle-aged woman who sustained a slowly healing metatarsal stress fracture (MTSF) and then 2 enlarging MTSFs and a spontaneous proximal femur fracture. She carried a heterozygous ALPL missense mutation (D378V; 171760.0009). Pain persisted at all fracture sites. Hypophosphatasia was diagnosed as a result of low ALP activity and elevated inorganic phosphate and pyridoxal 5-prime-phosphate concentrations in serum. Teriparatide (TPTD) (recombinant human PTH 1-34), 20 micrograms, was injected subcutaneously daily in an attempt to enhance osteoblast synthesis of tissue-nonspecific ALP (TNSALP). Six weeks later, all fracture pain improved, and resolved after 4 months. Radiographs of the enlarging MTSFs showed repair after 2-4 months. The femur fracture partially mended after 2 months and then healed. Additionally, hypophosphatasemia and hyperphosphatemia corrected, and biochemical markers of bone remodeling increased as long as TPTD (given for 18 months) was continued. </p><p>Kishnani et al. (2021) reported outcomes of a phase 2 efficacy and safety study of asfotase alfa in 19 adolescents and adults with childhood or adult hypophosphatasia, including 14 patients with autosomal recessive disease and 5 patients with autosomal dominant disease. Median inorganic phosphate (PPi) and PLP concentrations were normalized over 5 years of treatment in patients with both recessive and dominant disease. Median predicted distance walked on the 6-minute walk test remained within the normal range for patients with dominant disease over 4 years of treatment, and improved from below normal to normal in patients with autosomal recessive disease. Pain scores also improved in both recessive and dominant groups. </p>
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</span>
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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>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a 65-year-old woman with adult hypophosphatasia, Henthorn et al. (1992) identified compound heterozygosity for missense mutations in the ALPL gene (171760.0003 and 171760.0008). </p><p>Mornet (1999) tested 2 large families with adult hypophosphatasia. In 1 family, hypophosphatasia was dominantly inherited and was due to a missense mutation in the ALPL gene; in the other family, adult hypophosphatasia was recessively transmitted and was due to compound heterozygosity for a missense mutation and a splicing mutation in the ALPL gene.</p><p>In a 4-generation Texas family segregating autosomal dominant hypophosphatasia in both children and adults, Hu et al. (2000) identified a heterozygous missense mutation in the ALPL gene (171760.0015). </p><p>In a 15-month-old girl and her father, who had phenotypes suggestive of childhood hypophosphatasia and odontohypophosphatasia, respectively, Lia-Baldini et al. (2001) identified heterozygosity for a missense mutation in the ALPL gene (171760.0021). </p><p>In a mother and son with odontohypophosphatasia, low serum alkaline phosphatase, and no evidence of fractures, Herasse et al. (2003) identified heterozygosity for a missense mutation in the ALPL gene (171760.0018). </p>
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</span>
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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">
|
|
<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a study of 44 adolescents and adults with childhood or adult hypophosphatasia, Kishnani et al. (2021) compared clinical characteristics between patients with autosomal recessive disease (30 patients) and autosomal dominant disease (14 patients). Median age of onset of symptoms in patients with recessive disease was 1 year, with a range of 0-4 years, and the median age of onset of symptoms in patients with dominant disease was 4 years, with a range of 0 to 36 years. Baseline inorganic phosphate (PPi) and pyridoxal 5-prime phosphate (PLP) concentrations were significantly higher in patients with recessive disease compared to dominant disease. A large percentage of both groups experienced bone pain, abnormal gait, and fractures. Abnormally shaped head or chest, bowing of the limbs, and delayed walking were more common in patients with recessive disease. Patients with dominant disease had a higher number of fractures. </p>
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</span>
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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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<h4>
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<span class="mim-font">
|
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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">
|
|
Eade et al. (1981); Fallon et al. (1984); Whyte et al. (1978); Whyte
|
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et al. (1982)
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</span>
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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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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bixler, D., Poland, C., III, Brandt, I. K., Nicholas, N. J.
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<strong>Autosomal dominant hypophosphatasia without skeletal disease. (Abstract)</strong>
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Am. J. Hum. Genet. 26: 14A only, 1974.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bixler, D.
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<strong>Heritable disorders affecting cementum and the periodontal structure. In: Stewart, R. E.; Prescott, G. H. (eds.): Oral Facial Genetics.</strong>
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St. Louis: C. V. Mosby (pub.) 1976. Pp. 276-277.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Chapple, I. L. C., Thorpe, G. H. G., Smith, J. M., Saxby, M. S., Glenwright, H. D., Green, A., Perry, G. M., Grundy, M., Shaw, L., Matthews, J. B.
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<strong>Hypophosphatasia: a family study involving a case diagnosed from gingival crevicular fluid.</strong>
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J. Oral Path. Med. 21: 426-431, 1992.
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[PubMed: 1432739]
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[Full Text: https://doi.org/10.1111/j.1600-0714.1992.tb01033.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Danovitch, S. H., Baer, P. N., Laster, L.
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<strong>Intestinal alkaline phosphatase activity in familial hypophosphatasia.</strong>
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New Eng. J. Med. 278: 1253-1260, 1968.
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[PubMed: 4296721]
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[Full Text: https://doi.org/10.1056/NEJM196806062782303]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Eade, A. W. T., Swannell, A. J., Williamson, N.
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<strong>Pyrophosphate arthropathy in hypophosphatasia.</strong>
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Ann. Rheum. Dis. 40: 164-170, 1981.
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[PubMed: 6261701]
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[Full Text: https://doi.org/10.1136/ard.40.2.164]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Fallon, M. D., Teitelbaum, S. L., Weinstein, R. S., Goldfischer, S., Brown, D. M., Whyte, M. P.
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<strong>Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms.</strong>
|
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Medicine 63: 12-24, 1984.
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[PubMed: 6690884]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Fraser, D.
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<strong>Hypophosphatasia.</strong>
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Am. J. Med. 22: 730-746, 1957.
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[PubMed: 13410963]
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[Full Text: https://doi.org/10.1016/0002-9343(57)90124-9]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Henthorn, P. S., Raducha, M., Fedde, K. N., Lafferty, M. A., Whyte, M. P.
|
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<strong>Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.</strong>
|
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Proc. Nat. Acad. Sci. 89: 9924-9928, 1992.
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[PubMed: 1409720]
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[Full Text: https://doi.org/10.1073/pnas.89.20.9924]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Herasse, M., Spentchian, M., Taillandier, A., Keppler-Noreuil, K., Fliorito, A. N. M., Bergoffen, J., Wallerstein, R., Muti, C., Simon-Bouy, B., Mornet, E.
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<strong>Molecular study of three cases of odontohypophosphatasia resulting from heterozygosity for mutations in the tissue non-specific alkaline phosphatase gene.</strong>
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J. Med. Genet. 40: 605-609, 2003.
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[PubMed: 12920074]
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[Full Text: https://doi.org/10.1136/jmg.40.8.605]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Hosenfeld, D., Hosenfeld, A.
|
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<strong>Qualitative and quantitative examinations of the isoenzymes of serum alkaline phosphatase in hypophosphatasia.</strong>
|
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Klin. Padiatr. 185: 437-443, 1973.
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[PubMed: 4798670]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hu, J. C.-C., Plaetke, R., Mornet, E., Zhang, C., Sun, X., Thomas, H. F., Simmer, J. P.
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<strong>Characterization of a family with dominant hypophosphatasia.</strong>
|
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Europ. J. Oral Sci. 108: 189-194, 2000.
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[PubMed: 10872988]
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[Full Text: https://doi.org/10.1034/j.1600-0722.2000.108003189.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Jardon, O. M., Burney, D. W., Fink, R. L.
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<strong>Hypophosphatasia in an adult.</strong>
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J. Bone Joint Surg. Am. 52: 1477-1484, 1970.
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[PubMed: 4319245]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Kishnani, P. S., del Angel, G., Zhou, S., Rush, E. T.
|
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<strong>Investigation of ALPL variant states and clinical outcomes: an analysis of adults and adolescents with hypophosphatasia treated with asfotase alfa.</strong>
|
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Molec. Genet. Metab. 133: 113-121, 2021.
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[PubMed: 33814268]
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[Full Text: https://doi.org/10.1016/j.ymgme.2021.03.011]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lia-Baldini, A. S., Muller, F., Taillandier, A., Gibrat, J. F., Mouchard, M., Robin, B., Simon-Bouy, B., Serre, J. L., Aylsworth, A. S., Bieth, E., Delanote, S., Freisinger, P., Hu, J. C.-C., Krohn, H.-P., Nunes, M. E., Mornet, E.
|
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<strong>A molecular approach to dominance in hypophosphatasia.</strong>
|
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Hum. Genet. 109: 99-108, 2001.
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[PubMed: 11479741]
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[Full Text: https://doi.org/10.1007/s004390100546]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Macfarlane, J. D., Kroon, H. M., van der Harten, J. J.
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<strong>Phenotypically dissimilar hypophosphatasia in two sibships.</strong>
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<p class="mim-text-font">
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Moore, C. A., Curry, C. J. R., Henthorn, P. S., Smith, J. A., Smith, J. C., O'Lague, P., Coburn, S. P., Weaver, D. D., Whyte, M. P.
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<strong>Mild autosomal dominant hypophosphatasia: in utero presentation in two families.</strong>
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[PubMed: 10508980]
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Morava, E., Karteszi, J., Weisenbach, J., Caliebe, A., Mundlos, S., Mehes, K.
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<strong>Cleidocranial dysplasia with decreased bone density and biochemical findings of hypophosphatasia.</strong>
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Mornet, E.
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<strong>Personal Communication.</strong>
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Paris, France 6/3/1999.
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Pauli, R. M., Modaff, P., Sipes, S. L., Whyte, M. P.
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<strong>Mild hypophosphatasia mimicking severe osteogenesis imperfecta in utero: bent but not broken.</strong>
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<p class="mim-text-font">
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Silverman, J. L.
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<strong>Apparent dominant inheritance of hypophosphatasia.</strong>
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Ann. Intern. Med. 110: 191-198, 1962.
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Unger, S., Mornet, E., Mundlos, S., Blaser, S., Cole, D. E. C.
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<strong>Severe cleidocranial dysplasia can mimic hypophosphatasia.</strong>
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Europ. J. Pediat. 161: 623-626, 2002.
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[PubMed: 12424591]
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Weinstein, R. S., Whyte, M. P.
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<strong>Heterogeneity of adult hypophosphatasia: report of severe and mild cases.</strong>
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Arch. Intern. Med. 141: 727-731, 1981.
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Whyte, M. P., Mahuren, J. D., Vrabel, L. A., Coburn, S. P.
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<strong>Markedly increased circulating pyridoxal-5-prime-phosphate levels in hypophosphatasia: alkaline phosphatase acts in vitamin B6 metabolism.</strong>
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J. Clin. Invest. 76: 752-756, 1985.
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[PubMed: 4031070]
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<p class="mim-text-font">
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Whyte, M. P., Mumm, S., Deal, C.
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<strong>Adult hypophosphatasia treated with teriparatide.</strong>
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J. Clin. Endocr. Metab. 92: 1203-1208, 2007.
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<p class="mim-text-font">
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Whyte, M. P., Murphy, W. A., Fallon, M. D.
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<strong>Adult hypophosphatasia with chondrocalcinosis and arthropathy: variable penetrance of hypophosphatasemia in a large Oklahoma kindred.</strong>
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Am. J. Med. 72: 631-641, 1982.
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Whyte, M. P., Teitelbaum, S. L., Murphy, W. A., Avioli, L. V.
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<strong>Adult hypophosphatasia: dominant inheritance in a large kindred.</strong>
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Trans. Assoc. Am. Phys. 91: 144-155, 1978.
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[PubMed: 754388]
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<p class="mim-text-font">
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Whyte, M. P., Teitelbaum, S. L., Murphy, W. A., Avioli, L. V.
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<strong>Adult hypophosphatasia: clinical, laboratory, and genetic investigation of a large kindred with review of the literature.</strong>
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[PubMed: 481194]
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<p class="mim-text-font">
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Whyte, M. P., Vrabel, L. A., Schwartz, T. D.
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<strong>Adult hypophosphatasia: generalized deficiency of alkaline phosphatase activity demonstrated with cultured skin fibroblasts.</strong>
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Trans. Assoc. Am. Phys. 95: 253-263, 1982.
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[PubMed: 7182980]
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<p class="mim-text-font">
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Whyte, M. P.
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<strong>Personal Communication.</strong>
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St. Louis, Mo. 7/21/1988.
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