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Entry
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- #259600 - MULTICENTRIC OSTEOLYSIS, NODULOSIS, AND ARTHROPATHY; MONA
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- OMIM
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<p>
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<span class="h4">#259600</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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<li role="presentation">
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<a href="/clinicalSynopsis/259600"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div style="display: table-cell;">Clinical Resources</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://clinicaltrials.gov/search?cond=MULTICENTRIC OSTEOLYSIS, NODULOSIS, AND ARTHROPATHY" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22539&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK373578/" 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/7136" 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://medlineplus.gov/genetics/condition/multicentric-osteolysis-nodulosis-and-arthropathy" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=371428" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/3d0bc7df-95da-48d1-87af-fd450a7ca509/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:259600" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 716868003<br />
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<strong>ORPHA:</strong> 371428<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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259600
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</span>
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</span>
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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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MULTICENTRIC OSTEOLYSIS, NODULOSIS, AND ARTHROPATHY; MONA
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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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TORG SYNDROME<br />
|
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NODULOSIS-ARTHROPATHY-OSTEOLYSIS SYNDROME<br />
|
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NAO SYNDROME<br />
|
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AL-AQEEL SEWAIRI SYNDROME<br />
|
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OSTEOLYSIS, HEREDITARY MULTICENTRIC<br />
|
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TORG-WINCHESTER SYNDROME, FORMERLY
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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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<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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</th>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/16/442?start=-3&limit=10&highlight=442">
|
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16q12.2
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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Multicentric osteolysis, nodulosis, and arthropathy
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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/259600"> 259600 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<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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<span class="mim-font">
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MMP2
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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/120360"> 120360 </a>
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</span>
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</td>
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</tr>
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</tbody>
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<a href="/clinicalSynopsis/259600" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<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">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/259600" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/259600" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<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 />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- 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 />
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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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<span class="h5 mim-font">
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<strong> SKELETAL </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Osteoporosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64859006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64859006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Z82.62" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Z82.62</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M81.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M81.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/733.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">733.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/V17.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">V17.81</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/733.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">733.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2911643&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2911643</a>, <a href="https://bioportal.bioontology.org/search?q=C0029456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029456</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000939" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000939</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000939" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000939</a>]</span><br />
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</span>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
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<em> Pelvis </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
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|
|
- Flexion contracture (hip) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/202283002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">202283002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0409354&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0409354</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003273" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003273</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M21.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M21.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M21.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M21.20</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001371" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001371</a>]</span><br />
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|
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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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<span class="h5 mim-font">
|
|
<em> Limbs </em>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Flexion contractures (elbows and knees) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850156&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850156</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/88565003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">88565003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/203598005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">203598005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/785817002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">785817002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/385522000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">385522000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M21.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M21.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M21.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M21.20</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001371" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001371</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
|
</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Hands </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Fusiform finger swelling <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850157&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850157</a>]</span><br /> -
|
|
Interphalangeal joint erosions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850158&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850158</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006252</a>]</span><br /> -
|
|
Finger contractures <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1411006&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1411006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001220" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001220</a>]</span><br /> -
|
|
Carpal osteolysis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833734&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833734</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001495" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001495</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001495" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001495</a>]</span><br /> -
|
|
Widened metacarpal shaft <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850159&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850159</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006012" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006012</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006012" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006012</a>]</span><br /> -
|
|
Thin metacarpal cortices <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850160&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850160</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006086" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006086</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006086" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006086</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
|
</div>
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|
|
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Feet </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Pes planus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/23407003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">23407003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/203534009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">203534009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/53226007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">53226007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q66.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q66.5</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M21.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M21.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/754.61" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.61</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/734" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">734</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0016202&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0016202</a>, <a href="https://bioportal.bioontology.org/search?q=C0392477&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0392477</a>, <a href="https://bioportal.bioontology.org/search?q=C0264133&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0264133</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001763</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001763</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=1f893093d35c2d1df583eed57a47b6cb" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Pes_Planus-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=1f893093d35c2d1df583eed57a47b6cb" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
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Pes cavus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/205091006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">205091006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36755004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36755004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86900005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86900005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q66.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q66.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/736.73" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">736.73</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/754.71" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.71</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0728829&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0728829</a>, <a href="https://bioportal.bioontology.org/search?q=C0039273&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0039273</a>, <a href="https://bioportal.bioontology.org/search?q=C2239098&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2239098</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001761" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001761</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001761" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001761</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=2ad12e53b20f47e5685234fa29da6610" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Pes_Cavus-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=2ad12e53b20f47e5685234fa29da6610" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
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Tarsal osteolysis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1833735&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1833735</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006234" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006234</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006234" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006234</a>]</span><br /> -
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Widened metatarsal shaft <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850161&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850161</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001783" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001783</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001783" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001783</a>]</span><br /> -
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Interphalangeal joint erosions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850158&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850158</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006252</a>]</span><br /> -
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Thin metatarsal cortices <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850162&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850162</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008078" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008078</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008078" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008078</a>]</span><br />
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<span class="h5 mim-font">
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<strong> SKIN, NAILS, & HAIR </strong>
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</span>
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<div style="margin-left: 2em;">
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<span class="h5 mim-font">
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<em> Skin </em>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Subcutaneous nodules (interphalangeal joints, knees, feet, elbows, pretibial) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850166&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850166</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95325000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95325000</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001482" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001482</a>]</span><br /> -
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Hyperpigmented erythematous lesions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850167&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850167</a>]</span><br />
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</span>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </strong>
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</span>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Elevated antinuclear antibody (ANA) (speckled pattern) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850163&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850163</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165850001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165850001</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003493" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003493</a>]</span><br /> -
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Elevated IL1-beta <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850164&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850164</a>]</span><br /> -
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Elevated IL6 <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850165&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850165</a>]</span><br />
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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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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Abnormal gait <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22325002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22325002</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/781.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0575081&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0575081</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001288" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001288</a>]</span><br />
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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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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the matrix metalloproteinase 2 gene (MMP2, <a href="/entry/120360#0001">120360.0001</a>)<br />
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</span>
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</div>
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<div>
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<br />
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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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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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because multicentric osteolysis, nodulosis, and arthropathy (MONA) is caused by homozygous or compound heterozygous mutation in the MMP2 gene (<a href="/entry/120360">120360</a>) on chromosome 16q12.</p>
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<br />
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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<p><a href="#15" class="mim-tip-reference" title="Zankl, A., Pachman, L., Poznanski, A., Bonafe, L., Wang, F., Shusterman, Y., Fishman, D. A., Superti-Furga, A. <strong>Torg syndrome is caused by inactivating mutations in MMP2 and is allelic to NAO and Winchester syndrome.</strong> J. Bone Miner. Res. 22: 329-333, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17059372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17059372</a>] [<a href="https://doi.org/10.1359/jbmr.061013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17059372">Zankl et al. (2007)</a> defined what they considered to be a continuous clinical spectrum involving Torg syndrome, Winchester syndrome (<a href="/entry/277950">277950</a>), and NAO syndrome. Torg syndrome is characterized by the presence of multiple, painless, subcutaneous nodules and mild to moderate osteoporosis and osteolysis that is usually limited to the hands and feet. Radiographically, the osteolysis is accompanied by a characteristic widening of the metacarpal and metatarsal bones. Winchester syndrome presents with severe osteolysis in the hands and feet and generalized osteoporosis and bone thinning, similar to NAO, but subcutaneous nodules are characteristically absent. Various additional features including coarse face, corneal opacities, gum hypertrophy, and EKG changes have been reported. NAO syndrome, which has only been described in patients from Saudi Arabia, is generally more severe, with multiple prominent and painful subcutaneous nodules, massive osteolysis in the hands and feet, and generalized osteoporosis. Coarse face and body hirsutism are additional features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17059372" 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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<br />
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<strong>Clinical Features</strong>
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</h4>
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<span class="mim-text-font">
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<p>Among the offspring of double second cousins, <a href="#12" class="mim-tip-reference" title="Torg, J. S., DiGeorge, A. M., Kirkpatrick, J. A., Jr., Trujillo, M. M. <strong>Hereditary multicentric osteolysis with recessive transmission: a new syndrome.</strong> J. Pediat. 75: 243-252, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5795345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5795345</a>] [<a href="https://doi.org/10.1016/s0022-3476(69)80395-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5795345">Torg et al. (1969)</a> described a novel skeletal disorder. In addition to collapse and resorption of the carpal and tarsal bones, there was osteoporosis, cortical thinning, and increased caliber of the tubular and long bones. Clinically, the disorder was characterized by fusiform enlargement of the digits and flexion contractures of the knees, hip, and elbows. The radiologic features mentioned distinguish the disorder from the autosomal dominant form of hereditary osteolysis (<a href="/entry/166300">166300</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5795345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Sauvegrain, J., Gaussin, G., Blondet, P., Legendre, H., Challe, J. Y., D'Aboville, M. <strong>Osteolyse multicentrique a transmission recessive: quatre cas dans une nouvelle famille.</strong> Ann. Radiol. 24: 638-642, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7325547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7325547</a>]" pmid="7325547">Sauvegrain et al. (1981)</a> described what appeared to be the same disorder in 4 members of a family. <a href="#4" class="mim-tip-reference" title="Eisenstein, D. M., Poznanski, A. K., Pachman, L. M. <strong>Torg osteolysis syndrome.</strong> Am. J. Med. Genet. 80: 207-212, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843039</a>]" pmid="9843039">Eisenstein et al. (1998)</a> described a single case of a 9-year-old girl who initially presented at age 4 years with evidence of arthritis in her hands, feet, and large joints. Although she had a partial response to antiinflammatory medications and had some laboratory results consistent with inflammatory disease, radiographs showed carpal and tarsal osteolysis associated with interphalangeal joint erosions. There was also widening of the shafts of the metacarpals and metatarsals with thinning of the cortices. Based on both the clinical progression of her illness and the radiologic characteristics, the diagnosis of Torg osteolysis was proposed by <a href="#4" class="mim-tip-reference" title="Eisenstein, D. M., Poznanski, A. K., Pachman, L. M. <strong>Torg osteolysis syndrome.</strong> Am. J. Med. Genet. 80: 207-212, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843039</a>]" pmid="9843039">Eisenstein et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9843039+7325547" 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="#6" class="mim-tip-reference" title="Lambert, J. C., Jaffray, J. Y., Michalski, J. C., Ortonne, J. P., Paquis, V., Saunieres, A. M. <strong>Biochemical and ultrastructural study of two familial cases of Winchester syndrome.</strong> J. Genet. Hum. 37: 231-236, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2625626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2625626</a>]" pmid="2625626">Lambert et al. (1989)</a> reported 2 affected French sisters, born of consanguineous parents originating from Algeria. <a href="#9" class="mim-tip-reference" title="Rouzier, C., Vanatka, R., Bannwarth, S., Philip, N., Coussement, A., Paquis-Flucklinger, V., Lambert, J.-C. <strong>A novel homozygous MMP2 mutation in a family with Winchester syndrome.</strong> Clin. Genet. 69: 271-276, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16542393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16542393</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00584.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16542393">Rouzier et al. (2006)</a> provided a detailed clinical history and follow-up of the sisters. At age 3 years, the older sister developed painful contracture of the left fifth finger with a progressive extension to other fingers. Later, she presented with flexion contracture of the wrists, elbows, and shoulders. Lower limbs were also affected in a distal-to-proximal manner, and she was wheelchair-bound by age 10 years. Other features included a shortened trunk, coarse facial features, and thickened skin with hypertrichosis on the anterior sides of the legs and ankles. The younger sister had earlier onset at age 6 months and a more severe course. Reexamination of the sisters at ages 35 and 24 years, respectively, showed short stature, increased weight, flexion contractures of the large joints, kyphosis, and very small hands and feet. The skin was thin, and hypertrichosis in the older sister had disappeared. There were no cataracts and intellectual development was normal. Radiographic examination showed obvious progression of osteopenia with generalized cortical thinning, progressive osteolysis of the carpal and tarsal bones, resorptive deformities of the phalanges, and destruction of the interphalangeal and metacarpophalangeal joints. Other radiographic features included slender metatarsal diaphyses, ankylosed knee joints, incurved diaphyses of the femur and fibula, misshapen pelvis, marked excavation of the acetabulum, erosions of the articular surfaces of the hip joint, and biconcave aspect of the vertebral bodies and scoliosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16542393+2625626" 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="Zankl, A., Bonafe, L., Calcaterra, V., Di Rocco, M., Superti-Furga, A. <strong>Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2.</strong> Clin. Genet. 67: 261-266, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15691365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15691365</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00402.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15691365">Zankl et al. (2005)</a> reported an affected child born of consanguineous parents from southern Italy. After a healthy first year of life, the child's height and weight fell below the third percentile. During the second year of life, she developed degenerative changes in the fingers which extended rapidly to other joints, confining her to a wheelchair at age 3 years. During childhood, she developed type I diabetes mellitus (see <a href="/entry/222100">222100</a>) and hypothyroidism. Despite her disabilities, she showed normal mental development and attended a regular school. Clinical examination at age 21 years showed a woman of very short stature, low weight (16 kg), and marked brachydactyly of the hands and feet. She had mild coarse facial features, generalized hypertrichosis, and a serpiginous, erythematous skin lesion on the neck. Subcutaneous nodules were not present. Radiologic evaluation showed severe generalized osteoporosis and osteolytic changes, particularly in the hands and feet. <a href="#14" class="mim-tip-reference" title="Zankl, A., Bonafe, L., Calcaterra, V., Di Rocco, M., Superti-Furga, A. <strong>Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2.</strong> Clin. Genet. 67: 261-266, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15691365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15691365</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00402.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15691365">Zankl et al. (2005)</a> considered the absence of subcutaneous nodules to be consistent with Winchester syndrome. The authors noted that the endocrine abnormalities had not previously been reported in association with Winchester syndrome and may be fortuitous, especially as there was a family history for thyroid disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15691365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Al-Mayouf, S. M., Majeed, M., Hugosson, C., Bahabri, S. <strong>New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome.</strong> Am. J. Med. Genet. 93: 5-10, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861675</a>] [<a href="https://doi.org/10.1002/1096-8628(20000703)93:1<5::aid-ajmg2>3.0.co;2-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861675">Al-Mayouf et al. (2000)</a> studied 10 patients (6 females and 4 males) from 6 unrelated families in Saudi Arabia with an autosomal recessive disorder characterized by simultaneous presentation of nodulosis, arthropathy, and osteolysis. All 10 patients had nodulosis and distal arthropathy. Eight of them presented with deformed hands and 4 with painful hands. The parents were first cousins in all cases, and 3 families had more than 1 affected child. Osteopenia and undertubulation of bones, distally more than proximally, and upper limbs affected more often than lower limbs, were found in all patients. Osteolysis was seen in carpal and tarsal bones. Other common findings were sclerotic cranial sutures, brachycephaly, and broad medial ends of the clavicles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Al-Aqeel, A., Al Sewairi, W., Edress, B., Gorlin, R. J., Desnick, R. J., Martignetti, J. A. <strong>Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family.</strong> Am. J. Med. Genet. 93: 11-18, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861676</a>] [<a href="https://doi.org/10.1002/1096-8628(20000703)93:1<11::aid-ajmg3>3.0.co;2-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861676">Al-Aqeel et al. (2000)</a> also studied a consanguineous Saudi Arabian family in which 2 affected sibs with facial anomalies and short stature displayed a distal arthropathy of the metacarpal, metatarsal, and interphalangeal joints starting in the first few months of life. The arthropathy eventually progressed to the proximal joints, resulting in crippling ankylosis and severe generalized osteopenia in both sibs. Facial changes included proptosis, a narrow nasal bridge, bulbous nose, and micrognathia. In addition, they had large, painful fibrocollagenous palmar and plantar pads and mild body hirsutism. Affected individuals were of normal intelligence and had normal renal function. Although <a href="#1" class="mim-tip-reference" title="Al-Aqeel, A., Al Sewairi, W., Edress, B., Gorlin, R. J., Desnick, R. J., Martignetti, J. A. <strong>Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family.</strong> Am. J. Med. Genet. 93: 11-18, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861676</a>] [<a href="https://doi.org/10.1002/1096-8628(20000703)93:1<11::aid-ajmg3>3.0.co;2-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861676">Al-Aqeel et al. (2000)</a> suggested that this form of multicentric osteolysis with autosomal recessive inheritance closely resembled the Torg osteolysis syndrome, a unique facial appearance, fibrocollagenous pads, and body hirsutism were not noted in the original description of Torg osteolysis syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861676" 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="#7" class="mim-tip-reference" title="Martignetti, J. A., Al Aqeel, A., Al Sewairi, W., Boumah, C. E., Kambouris, M., Al Mayouf, S., Sheth, K. V., Al Eid, W., Dowling, O., Harris, J., Glucksman, M. J., Bahabri, S., Meyer, B. F., Desnick, R. J. <strong>Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.</strong> Nature Genet. 28: 261-265, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431697</a>] [<a href="https://doi.org/10.1038/90100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431697">Martignetti et al. (2001)</a> mapped the NAO syndrome disease locus to chromosome 16q12-q21 by using members of families studied by <a href="#1" class="mim-tip-reference" title="Al-Aqeel, A., Al Sewairi, W., Edress, B., Gorlin, R. J., Desnick, R. J., Martignetti, J. A. <strong>Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family.</strong> Am. J. Med. Genet. 93: 11-18, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861676</a>] [<a href="https://doi.org/10.1002/1096-8628(20000703)93:1<11::aid-ajmg3>3.0.co;2-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861676">Al-Aqeel et al. (2000)</a> and <a href="#3" class="mim-tip-reference" title="Al-Mayouf, S. M., Majeed, M., Hugosson, C., Bahabri, S. <strong>New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome.</strong> Am. J. Med. Genet. 93: 5-10, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861675</a>] [<a href="https://doi.org/10.1002/1096-8628(20000703)93:1<5::aid-ajmg2>3.0.co;2-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861675">Al-Mayouf et al. (2000)</a> for a genomewide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spanned the gene encoding matrix metalloproteinase-2 (MMP2; <a href="/entry/120360">120360</a>), also known as gelatinase A and collagenase type IV. They found no MMP2 enzymatic activity in serum or fibroblasts of affected family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10861675+10861676+11431697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of NAO syndrome in the families reported by <a href="#1" class="mim-tip-reference" title="Al-Aqeel, A., Al Sewairi, W., Edress, B., Gorlin, R. J., Desnick, R. J., Martignetti, J. A. <strong>Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family.</strong> Am. J. Med. Genet. 93: 11-18, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861676</a>] [<a href="https://doi.org/10.1002/1096-8628(20000703)93:1<11::aid-ajmg3>3.0.co;2-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861676">Al-Aqeel et al. (2000)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861676" 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 the families with NAO syndrome studied by <a href="#1" class="mim-tip-reference" title="Al-Aqeel, A., Al Sewairi, W., Edress, B., Gorlin, R. J., Desnick, R. J., Martignetti, J. A. <strong>Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family.</strong> Am. J. Med. Genet. 93: 11-18, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861676</a>] [<a href="https://doi.org/10.1002/1096-8628(20000703)93:1<11::aid-ajmg3>3.0.co;2-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861676">Al-Aqeel et al. (2000)</a> and <a href="#3" class="mim-tip-reference" title="Al-Mayouf, S. M., Majeed, M., Hugosson, C., Bahabri, S. <strong>New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome.</strong> Am. J. Med. Genet. 93: 5-10, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861675</a>] [<a href="https://doi.org/10.1002/1096-8628(20000703)93:1<5::aid-ajmg2>3.0.co;2-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861675">Al-Mayouf et al. (2000)</a>, <a href="#7" class="mim-tip-reference" title="Martignetti, J. A., Al Aqeel, A., Al Sewairi, W., Boumah, C. E., Kambouris, M., Al Mayouf, S., Sheth, K. V., Al Eid, W., Dowling, O., Harris, J., Glucksman, M. J., Bahabri, S., Meyer, B. F., Desnick, R. J. <strong>Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.</strong> Nature Genet. 28: 261-265, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431697</a>] [<a href="https://doi.org/10.1038/90100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431697">Martignetti et al. (2001)</a> identified different family-specific homoallelic MMP2 mutations (<a href="/entry/120360#0001">120360.0001</a> and <a href="/entry/120360#0002">120360.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10861676+11431697+10861675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an Italian patient diagnosed with Winchester syndrome, <a href="#14" class="mim-tip-reference" title="Zankl, A., Bonafe, L., Calcaterra, V., Di Rocco, M., Superti-Furga, A. <strong>Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2.</strong> Clin. Genet. 67: 261-266, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15691365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15691365</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00402.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15691365">Zankl et al. (2005)</a> identified a homozygous mutation in the MMP2 gene (<a href="/entry/120360#0003">120360.0003</a>), and in 2 sisters of Algerian origin reported by <a href="#6" class="mim-tip-reference" title="Lambert, J. C., Jaffray, J. Y., Michalski, J. C., Ortonne, J. P., Paquis, V., Saunieres, A. M. <strong>Biochemical and ultrastructural study of two familial cases of Winchester syndrome.</strong> J. Genet. Hum. 37: 231-236, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2625626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2625626</a>]" pmid="2625626">Lambert et al. (1989)</a> as having Winchester syndrome, <a href="#9" class="mim-tip-reference" title="Rouzier, C., Vanatka, R., Bannwarth, S., Philip, N., Coussement, A., Paquis-Flucklinger, V., Lambert, J.-C. <strong>A novel homozygous MMP2 mutation in a family with Winchester syndrome.</strong> Clin. Genet. 69: 271-276, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16542393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16542393</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00584.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16542393">Rouzier et al. (2006)</a> identified a homozygous in-frame deletion in the MMP2 gene (<a href="/entry/120360#0004">120360.0004</a>). <a href="#5" class="mim-tip-reference" title="Evans, B. R., Mosig, R. A., Lobl, M., Martignetti, C. R., Camacho, C., Grum-Tokars, V., Glucksman, M. J., Martignetti, J. A. <strong>Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome.</strong> Am. J. Hum. Genet. 91: 572-576, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22922033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22922033</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22922033[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22922033">Evans et al. (2012)</a> found no mutation in the MMP2 gene in one of the original patients with Winchester syndrome (<a href="#13" class="mim-tip-reference" title="Winchester, P., Grossman, H., Lim, W. N., Danes, B. S. <strong>A new acid mucopolysaccharidosis with skeletal deformities simulating rheumatoid arthritis.</strong> Am. J. Roentgen. Radium Ther. Nucl. Med. 106: 121-128, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4238825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4238825</a>] [<a href="https://doi.org/10.2214/ajr.106.1.121" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4238825">Winchester et al., 1969</a>) and instead identified a homozygous mutation in the MMP14 gene (<a href="/entry/600754#0001">600754.0001</a>). <a href="#5" class="mim-tip-reference" title="Evans, B. R., Mosig, R. A., Lobl, M., Martignetti, C. R., Camacho, C., Grum-Tokars, V., Glucksman, M. J., Martignetti, J. A. <strong>Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome.</strong> Am. J. Hum. Genet. 91: 572-576, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22922033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22922033</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22922033[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.07.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22922033">Evans et al. (2012)</a> stated that the patients reported by <a href="#14" class="mim-tip-reference" title="Zankl, A., Bonafe, L., Calcaterra, V., Di Rocco, M., Superti-Furga, A. <strong>Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2.</strong> Clin. Genet. 67: 261-266, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15691365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15691365</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00402.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15691365">Zankl et al. (2005)</a> and <a href="#9" class="mim-tip-reference" title="Rouzier, C., Vanatka, R., Bannwarth, S., Philip, N., Coussement, A., Paquis-Flucklinger, V., Lambert, J.-C. <strong>A novel homozygous MMP2 mutation in a family with Winchester syndrome.</strong> Clin. Genet. 69: 271-276, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16542393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16542393</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00584.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16542393">Rouzier et al. (2006)</a> had MONA, not Winchester syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15691365+16542393+22922033+2625626+4238825" 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 the patient with Torg syndrome reported by <a href="#4" class="mim-tip-reference" title="Eisenstein, D. M., Poznanski, A. K., Pachman, L. M. <strong>Torg osteolysis syndrome.</strong> Am. J. Med. Genet. 80: 207-212, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843039</a>]" pmid="9843039">Eisenstein et al. (1998)</a>, <a href="#15" class="mim-tip-reference" title="Zankl, A., Pachman, L., Poznanski, A., Bonafe, L., Wang, F., Shusterman, Y., Fishman, D. A., Superti-Furga, A. <strong>Torg syndrome is caused by inactivating mutations in MMP2 and is allelic to NAO and Winchester syndrome.</strong> J. Bone Miner. Res. 22: 329-333, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17059372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17059372</a>] [<a href="https://doi.org/10.1359/jbmr.061013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17059372">Zankl et al. (2007)</a> identified compound heterozygosity for mutations in the MMP2 gene (<a href="/entry/120360#0001">120360.0001</a> and <a href="/entry/120360#0005">120360.0005</a>). Gelatin zymography indicated complete loss of MMP activity in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9843039+17059372" 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="#8" class="mim-tip-reference" title="Mosig, R. A., Dowling, O., DiFeo, A., Ramirez, M. C. M., Parker, I. C., Abe, E., Diouri, J., Al Aqeel, A., Wylie, J. D., Oblander, S. A., Madri, J., Bianco, P., Apte, S. S., Zaidi, M., Doty, S. B., Majeska, R. J., Schaffler, M. B., Martignetti, J. A. <strong>Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth.</strong> Hum. Molec. Genet. 16: 1113-1123, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17400654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17400654</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17400654[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddm060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17400654">Mosig et al. (2007)</a> generated Mmp2 -/- mice and observed attenuated features of human multicentric osteolysis with arthritis, including progressive loss of bone mineral density, articular cartilage destruction, and abnormal long bone and craniofacial development. These changes were associated with marked and developmentally restricted decreases in osteoblast and osteoclast numbers in vivo. Mmp2 -/- mice had approximately 50% fewer osteoblasts and osteoclasts than control littermates at 4 days of life, but these differences were nearly resolved by 4 weeks of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17400654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The 2006 revision of the Nosology of Constitutional Disorders of Bone classified Torg and Winchester syndromes as a single entity with NAO syndrome as a variant (<a href="#11" class="mim-tip-reference" title="Superti-Furga, A., Unger, S. <strong>Nosology and classification of genetic skeletal disorders: 2006 revision.</strong> Am. J. Med. Genet. 143A: 1-18, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17120245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17120245</a>] [<a href="https://doi.org/10.1002/ajmg.a.31483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17120245">Superti-Furga and Unger, 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17120245" 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="#Al-Aqeel2005" class="mim-tip-reference" title="Al-Aqeel, A. I. <strong>Al-Aqeel Sewairi syndrome, a new autosomal recessive disorder with multicentric osteolysis, nodulosis and arthropathy: the first genetic defect of matrix metalloproteinase 2 gene.</strong> Saudi Med. J. 26: 24-30, 2005.">Al-Aqeel (2005)</a>
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Al-Aqeel, A., Al Sewairi, W., Edress, B., Gorlin, R. J., Desnick, R. J., Martignetti, J. A.
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<strong>Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family.</strong>
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Am. J. Med. Genet. 93: 11-18, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861676</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861676" 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/10.1002/1096-8628(20000703)93:1<11::aid-ajmg3>3.0.co;2-3" target="_blank">Full Text</a>]
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Al-Aqeel, A. I.
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<strong>Al-Aqeel Sewairi syndrome, a new autosomal recessive disorder with multicentric osteolysis, nodulosis and arthropathy: the first genetic defect of matrix metalloproteinase 2 gene.</strong>
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Saudi Med. J. 26: 24-30, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15756348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15756348</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15756348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Al-Mayouf, S. M., Majeed, M., Hugosson, C., Bahabri, S.
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Am. J. Med. Genet. 93: 5-10, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861675</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Eisenstein, D. M., Poznanski, A. K., Pachman, L. M.
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<strong>Torg osteolysis syndrome.</strong>
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Am. J. Med. Genet. 80: 207-212, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9843039/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9843039</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843039" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Evans, B. R., Mosig, R. A., Lobl, M., Martignetti, C. R., Camacho, C., Grum-Tokars, V., Glucksman, M. J., Martignetti, J. A.
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<strong>Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome.</strong>
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Am. J. Hum. Genet. 91: 572-576, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22922033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22922033</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22922033[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22922033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<div class="">
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<p class="mim-text-font">
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Lambert, J. C., Jaffray, J. Y., Michalski, J. C., Ortonne, J. P., Paquis, V., Saunieres, A. M.
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<strong>Biochemical and ultrastructural study of two familial cases of Winchester syndrome.</strong>
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J. Genet. Hum. 37: 231-236, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2625626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2625626</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2625626" 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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<a id="7" class="mim-anchor"></a>
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<a id="Martignetti2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Martignetti, J. A., Al Aqeel, A., Al Sewairi, W., Boumah, C. E., Kambouris, M., Al Mayouf, S., Sheth, K. V., Al Eid, W., Dowling, O., Harris, J., Glucksman, M. J., Bahabri, S., Meyer, B. F., Desnick, R. J.
|
|
<strong>Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.</strong>
|
|
Nature Genet. 28: 261-265, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431697</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/90100" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Mosig2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mosig, R. A., Dowling, O., DiFeo, A., Ramirez, M. C. M., Parker, I. C., Abe, E., Diouri, J., Al Aqeel, A., Wylie, J. D., Oblander, S. A., Madri, J., Bianco, P., Apte, S. S., Zaidi, M., Doty, S. B., Majeska, R. J., Schaffler, M. B., Martignetti, J. A.
|
|
<strong>Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth.</strong>
|
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Hum. Molec. Genet. 16: 1113-1123, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17400654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17400654</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17400654[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17400654" 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/10.1093/hmg/ddm060" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Rouzier2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rouzier, C., Vanatka, R., Bannwarth, S., Philip, N., Coussement, A., Paquis-Flucklinger, V., Lambert, J.-C.
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<strong>A novel homozygous MMP2 mutation in a family with Winchester syndrome.</strong>
|
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Clin. Genet. 69: 271-276, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16542393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16542393</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16542393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2006.00584.x" target="_blank">Full Text</a>]
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Sauvegrain1981" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sauvegrain, J., Gaussin, G., Blondet, P., Legendre, H., Challe, J. Y., D'Aboville, M.
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<strong>Osteolyse multicentrique a transmission recessive: quatre cas dans une nouvelle famille.</strong>
|
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Ann. Radiol. 24: 638-642, 1981.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7325547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7325547</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7325547" 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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<a id="11" class="mim-anchor"></a>
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<a id="Superti-Furga2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Superti-Furga, A., Unger, S.
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<strong>Nosology and classification of genetic skeletal disorders: 2006 revision.</strong>
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Am. J. Med. Genet. 143A: 1-18, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17120245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17120245</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17120245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31483" target="_blank">Full Text</a>]
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Torg1969" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Torg, J. S., DiGeorge, A. M., Kirkpatrick, J. A., Jr., Trujillo, M. M.
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<strong>Hereditary multicentric osteolysis with recessive transmission: a new syndrome.</strong>
|
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J. Pediat. 75: 243-252, 1969.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5795345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5795345</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5795345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(69)80395-1" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Winchester1969" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Winchester, P., Grossman, H., Lim, W. N., Danes, B. S.
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<strong>A new acid mucopolysaccharidosis with skeletal deformities simulating rheumatoid arthritis.</strong>
|
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Am. J. Roentgen. Radium Ther. Nucl. Med. 106: 121-128, 1969.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4238825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4238825</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4238825" 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/10.2214/ajr.106.1.121" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Zankl2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zankl, A., Bonafe, L., Calcaterra, V., Di Rocco, M., Superti-Furga, A.
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<strong>Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2.</strong>
|
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Clin. Genet. 67: 261-266, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15691365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15691365</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15691365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2004.00402.x" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Zankl2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zankl, A., Pachman, L., Poznanski, A., Bonafe, L., Wang, F., Shusterman, Y., Fishman, D. A., Superti-Furga, A.
|
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<strong>Torg syndrome is caused by inactivating mutations in MMP2 and is allelic to NAO and Winchester syndrome.</strong>
|
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J. Bone Miner. Res. 22: 329-333, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17059372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17059372</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17059372" 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/10.1359/jbmr.061013" target="_blank">Full Text</a>]
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</p>
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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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<a id="contributors" class="mim-anchor"></a>
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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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Ada Hamosh - updated : 9/25/2013
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 1/20/2011<br>Kelly A. Przylepa - updated : 1/27/2009<br>Victor A. McKusick - updated : 12/29/1998
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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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 : 6/4/1986
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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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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<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 : 01/08/2024
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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 : 06/04/2022<br>carol : 04/24/2020<br>mcolton : 03/04/2015<br>carol : 9/25/2013<br>wwang : 2/2/2011<br>terry : 1/20/2011<br>carol : 2/20/2009<br>carol : 2/12/2009<br>carol : 2/12/2009<br>carol : 1/27/2009<br>mgross : 3/17/1999<br>carol : 1/4/1999<br>terry : 12/29/1998<br>mimadm : 3/11/1994<br>carol : 9/4/1992<br>supermim : 3/17/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>carol : 6/13/1988
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</span>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 259600
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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MULTICENTRIC OSTEOLYSIS, NODULOSIS, AND ARTHROPATHY; MONA
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</h3>
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<div>
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<br />
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<div >
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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TORG SYNDROME<br />
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NODULOSIS-ARTHROPATHY-OSTEOLYSIS SYNDROME<br />
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NAO SYNDROME<br />
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AL-AQEEL SEWAIRI SYNDROME<br />
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OSTEOLYSIS, HEREDITARY MULTICENTRIC<br />
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TORG-WINCHESTER SYNDROME, FORMERLY
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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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 716868003;
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<strong>ORPHA:</strong> 371428;
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</span>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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16q12.2
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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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Multicentric osteolysis, nodulosis, and arthropathy
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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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259600
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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 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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MMP2
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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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120360
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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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<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 multicentric osteolysis, nodulosis, and arthropathy (MONA) is caused by homozygous or compound heterozygous mutation in the MMP2 gene (120360) on chromosome 16q12.</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>Description</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>Zankl et al. (2007) defined what they considered to be a continuous clinical spectrum involving Torg syndrome, Winchester syndrome (277950), and NAO syndrome. Torg syndrome is characterized by the presence of multiple, painless, subcutaneous nodules and mild to moderate osteoporosis and osteolysis that is usually limited to the hands and feet. Radiographically, the osteolysis is accompanied by a characteristic widening of the metacarpal and metatarsal bones. Winchester syndrome presents with severe osteolysis in the hands and feet and generalized osteoporosis and bone thinning, similar to NAO, but subcutaneous nodules are characteristically absent. Various additional features including coarse face, corneal opacities, gum hypertrophy, and EKG changes have been reported. NAO syndrome, which has only been described in patients from Saudi Arabia, is generally more severe, with multiple prominent and painful subcutaneous nodules, massive osteolysis in the hands and feet, and generalized osteoporosis. Coarse face and body hirsutism are additional features. </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>Among the offspring of double second cousins, Torg et al. (1969) described a novel skeletal disorder. In addition to collapse and resorption of the carpal and tarsal bones, there was osteoporosis, cortical thinning, and increased caliber of the tubular and long bones. Clinically, the disorder was characterized by fusiform enlargement of the digits and flexion contractures of the knees, hip, and elbows. The radiologic features mentioned distinguish the disorder from the autosomal dominant form of hereditary osteolysis (166300). </p><p>Sauvegrain et al. (1981) described what appeared to be the same disorder in 4 members of a family. Eisenstein et al. (1998) described a single case of a 9-year-old girl who initially presented at age 4 years with evidence of arthritis in her hands, feet, and large joints. Although she had a partial response to antiinflammatory medications and had some laboratory results consistent with inflammatory disease, radiographs showed carpal and tarsal osteolysis associated with interphalangeal joint erosions. There was also widening of the shafts of the metacarpals and metatarsals with thinning of the cortices. Based on both the clinical progression of her illness and the radiologic characteristics, the diagnosis of Torg osteolysis was proposed by Eisenstein et al. (1998). </p><p>Lambert et al. (1989) reported 2 affected French sisters, born of consanguineous parents originating from Algeria. Rouzier et al. (2006) provided a detailed clinical history and follow-up of the sisters. At age 3 years, the older sister developed painful contracture of the left fifth finger with a progressive extension to other fingers. Later, she presented with flexion contracture of the wrists, elbows, and shoulders. Lower limbs were also affected in a distal-to-proximal manner, and she was wheelchair-bound by age 10 years. Other features included a shortened trunk, coarse facial features, and thickened skin with hypertrichosis on the anterior sides of the legs and ankles. The younger sister had earlier onset at age 6 months and a more severe course. Reexamination of the sisters at ages 35 and 24 years, respectively, showed short stature, increased weight, flexion contractures of the large joints, kyphosis, and very small hands and feet. The skin was thin, and hypertrichosis in the older sister had disappeared. There were no cataracts and intellectual development was normal. Radiographic examination showed obvious progression of osteopenia with generalized cortical thinning, progressive osteolysis of the carpal and tarsal bones, resorptive deformities of the phalanges, and destruction of the interphalangeal and metacarpophalangeal joints. Other radiographic features included slender metatarsal diaphyses, ankylosed knee joints, incurved diaphyses of the femur and fibula, misshapen pelvis, marked excavation of the acetabulum, erosions of the articular surfaces of the hip joint, and biconcave aspect of the vertebral bodies and scoliosis. </p><p>Zankl et al. (2005) reported an affected child born of consanguineous parents from southern Italy. After a healthy first year of life, the child's height and weight fell below the third percentile. During the second year of life, she developed degenerative changes in the fingers which extended rapidly to other joints, confining her to a wheelchair at age 3 years. During childhood, she developed type I diabetes mellitus (see 222100) and hypothyroidism. Despite her disabilities, she showed normal mental development and attended a regular school. Clinical examination at age 21 years showed a woman of very short stature, low weight (16 kg), and marked brachydactyly of the hands and feet. She had mild coarse facial features, generalized hypertrichosis, and a serpiginous, erythematous skin lesion on the neck. Subcutaneous nodules were not present. Radiologic evaluation showed severe generalized osteoporosis and osteolytic changes, particularly in the hands and feet. Zankl et al. (2005) considered the absence of subcutaneous nodules to be consistent with Winchester syndrome. The authors noted that the endocrine abnormalities had not previously been reported in association with Winchester syndrome and may be fortuitous, especially as there was a family history for thyroid disease. </p><p>Al-Mayouf et al. (2000) studied 10 patients (6 females and 4 males) from 6 unrelated families in Saudi Arabia with an autosomal recessive disorder characterized by simultaneous presentation of nodulosis, arthropathy, and osteolysis. All 10 patients had nodulosis and distal arthropathy. Eight of them presented with deformed hands and 4 with painful hands. The parents were first cousins in all cases, and 3 families had more than 1 affected child. Osteopenia and undertubulation of bones, distally more than proximally, and upper limbs affected more often than lower limbs, were found in all patients. Osteolysis was seen in carpal and tarsal bones. Other common findings were sclerotic cranial sutures, brachycephaly, and broad medial ends of the clavicles. </p><p>Al-Aqeel et al. (2000) also studied a consanguineous Saudi Arabian family in which 2 affected sibs with facial anomalies and short stature displayed a distal arthropathy of the metacarpal, metatarsal, and interphalangeal joints starting in the first few months of life. The arthropathy eventually progressed to the proximal joints, resulting in crippling ankylosis and severe generalized osteopenia in both sibs. Facial changes included proptosis, a narrow nasal bridge, bulbous nose, and micrognathia. In addition, they had large, painful fibrocollagenous palmar and plantar pads and mild body hirsutism. Affected individuals were of normal intelligence and had normal renal function. Although Al-Aqeel et al. (2000) suggested that this form of multicentric osteolysis with autosomal recessive inheritance closely resembled the Torg osteolysis syndrome, a unique facial appearance, fibrocollagenous pads, and body hirsutism were not noted in the original description of Torg osteolysis syndrome. </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>Mapping</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>Martignetti et al. (2001) mapped the NAO syndrome disease locus to chromosome 16q12-q21 by using members of families studied by Al-Aqeel et al. (2000) and Al-Mayouf et al. (2000) for a genomewide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spanned the gene encoding matrix metalloproteinase-2 (MMP2; 120360), also known as gelatinase A and collagenase type IV. They found no MMP2 enzymatic activity in serum or fibroblasts of affected family members. </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>Inheritance</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>The transmission pattern of NAO syndrome in the families reported by Al-Aqeel et al. (2000) was consistent with autosomal recessive inheritance. </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 the families with NAO syndrome studied by Al-Aqeel et al. (2000) and Al-Mayouf et al. (2000), Martignetti et al. (2001) identified different family-specific homoallelic MMP2 mutations (120360.0001 and 120360.0002). </p><p>In an Italian patient diagnosed with Winchester syndrome, Zankl et al. (2005) identified a homozygous mutation in the MMP2 gene (120360.0003), and in 2 sisters of Algerian origin reported by Lambert et al. (1989) as having Winchester syndrome, Rouzier et al. (2006) identified a homozygous in-frame deletion in the MMP2 gene (120360.0004). Evans et al. (2012) found no mutation in the MMP2 gene in one of the original patients with Winchester syndrome (Winchester et al., 1969) and instead identified a homozygous mutation in the MMP14 gene (600754.0001). Evans et al. (2012) stated that the patients reported by Zankl et al. (2005) and Rouzier et al. (2006) had MONA, not Winchester syndrome. </p><p>In the patient with Torg syndrome reported by Eisenstein et al. (1998), Zankl et al. (2007) identified compound heterozygosity for mutations in the MMP2 gene (120360.0001 and 120360.0005). Gelatin zymography indicated complete loss of MMP activity in this patient. </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>Animal Model</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>Mosig et al. (2007) generated Mmp2 -/- mice and observed attenuated features of human multicentric osteolysis with arthritis, including progressive loss of bone mineral density, articular cartilage destruction, and abnormal long bone and craniofacial development. These changes were associated with marked and developmentally restricted decreases in osteoblast and osteoclast numbers in vivo. Mmp2 -/- mice had approximately 50% fewer osteoblasts and osteoclasts than control littermates at 4 days of life, but these differences were nearly resolved by 4 weeks of age. </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>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The 2006 revision of the Nosology of Constitutional Disorders of Bone classified Torg and Winchester syndromes as a single entity with NAO syndrome as a variant (Superti-Furga and Unger, 2007). </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">
|
|
<strong>See Also:</strong>
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</span>
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</h4>
|
|
<span class="mim-text-font">
|
|
Al-Aqeel (2005)
|
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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">
|
|
<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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Al-Aqeel, A., Al Sewairi, W., Edress, B., Gorlin, R. J., Desnick, R. J., Martignetti, J. A.
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<strong>Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family.</strong>
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Am. J. Med. Genet. 93: 11-18, 2000.
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[PubMed: 10861676]
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[Full Text: https://doi.org/10.1002/1096-8628(20000703)93:1<11::aid-ajmg3>3.0.co;2-3]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Al-Aqeel, A. I.
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<strong>Al-Aqeel Sewairi syndrome, a new autosomal recessive disorder with multicentric osteolysis, nodulosis and arthropathy: the first genetic defect of matrix metalloproteinase 2 gene.</strong>
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Saudi Med. J. 26: 24-30, 2005.
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[PubMed: 15756348]
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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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Al-Mayouf, S. M., Majeed, M., Hugosson, C., Bahabri, S.
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<strong>New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome.</strong>
|
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Am. J. Med. Genet. 93: 5-10, 2000.
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[PubMed: 10861675]
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[Full Text: https://doi.org/10.1002/1096-8628(20000703)93:1<5::aid-ajmg2>3.0.co;2-y]
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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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Eisenstein, D. M., Poznanski, A. K., Pachman, L. M.
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<strong>Torg osteolysis syndrome.</strong>
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Am. J. Med. Genet. 80: 207-212, 1998.
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[PubMed: 9843039]
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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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Evans, B. R., Mosig, R. A., Lobl, M., Martignetti, C. R., Camacho, C., Grum-Tokars, V., Glucksman, M. J., Martignetti, J. A.
|
|
<strong>Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome.</strong>
|
|
Am. J. Hum. Genet. 91: 572-576, 2012.
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[PubMed: 22922033]
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[Full Text: https://doi.org/10.1016/j.ajhg.2012.07.022]
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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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Lambert, J. C., Jaffray, J. Y., Michalski, J. C., Ortonne, J. P., Paquis, V., Saunieres, A. M.
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<strong>Biochemical and ultrastructural study of two familial cases of Winchester syndrome.</strong>
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J. Genet. Hum. 37: 231-236, 1989.
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[PubMed: 2625626]
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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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Martignetti, J. A., Al Aqeel, A., Al Sewairi, W., Boumah, C. E., Kambouris, M., Al Mayouf, S., Sheth, K. V., Al Eid, W., Dowling, O., Harris, J., Glucksman, M. J., Bahabri, S., Meyer, B. F., Desnick, R. J.
|
|
<strong>Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.</strong>
|
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Nature Genet. 28: 261-265, 2001.
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[PubMed: 11431697]
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[Full Text: https://doi.org/10.1038/90100]
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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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Mosig, R. A., Dowling, O., DiFeo, A., Ramirez, M. C. M., Parker, I. C., Abe, E., Diouri, J., Al Aqeel, A., Wylie, J. D., Oblander, S. A., Madri, J., Bianco, P., Apte, S. S., Zaidi, M., Doty, S. B., Majeska, R. J., Schaffler, M. B., Martignetti, J. A.
|
|
<strong>Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth.</strong>
|
|
Hum. Molec. Genet. 16: 1113-1123, 2007.
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[PubMed: 17400654]
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[Full Text: https://doi.org/10.1093/hmg/ddm060]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Rouzier, C., Vanatka, R., Bannwarth, S., Philip, N., Coussement, A., Paquis-Flucklinger, V., Lambert, J.-C.
|
|
<strong>A novel homozygous MMP2 mutation in a family with Winchester syndrome.</strong>
|
|
Clin. Genet. 69: 271-276, 2006.
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|
[PubMed: 16542393]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2006.00584.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">
|
|
Sauvegrain, J., Gaussin, G., Blondet, P., Legendre, H., Challe, J. Y., D'Aboville, M.
|
|
<strong>Osteolyse multicentrique a transmission recessive: quatre cas dans une nouvelle famille.</strong>
|
|
Ann. Radiol. 24: 638-642, 1981.
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[PubMed: 7325547]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Superti-Furga, A., Unger, S.
|
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<strong>Nosology and classification of genetic skeletal disorders: 2006 revision.</strong>
|
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Am. J. Med. Genet. 143A: 1-18, 2007.
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[PubMed: 17120245]
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[Full Text: https://doi.org/10.1002/ajmg.a.31483]
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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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Torg, J. S., DiGeorge, A. M., Kirkpatrick, J. A., Jr., Trujillo, M. M.
|
|
<strong>Hereditary multicentric osteolysis with recessive transmission: a new syndrome.</strong>
|
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J. Pediat. 75: 243-252, 1969.
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[PubMed: 5795345]
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[Full Text: https://doi.org/10.1016/s0022-3476(69)80395-1]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Winchester, P., Grossman, H., Lim, W. N., Danes, B. S.
|
|
<strong>A new acid mucopolysaccharidosis with skeletal deformities simulating rheumatoid arthritis.</strong>
|
|
Am. J. Roentgen. Radium Ther. Nucl. Med. 106: 121-128, 1969.
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[PubMed: 4238825]
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[Full Text: https://doi.org/10.2214/ajr.106.1.121]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Zankl, A., Bonafe, L., Calcaterra, V., Di Rocco, M., Superti-Furga, A.
|
|
<strong>Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2.</strong>
|
|
Clin. Genet. 67: 261-266, 2005.
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|
[PubMed: 15691365]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2004.00402.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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Zankl, A., Pachman, L., Poznanski, A., Bonafe, L., Wang, F., Shusterman, Y., Fishman, D. A., Superti-Furga, A.
|
|
<strong>Torg syndrome is caused by inactivating mutations in MMP2 and is allelic to NAO and Winchester syndrome.</strong>
|
|
J. Bone Miner. Res. 22: 329-333, 2007.
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[PubMed: 17059372]
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[Full Text: https://doi.org/10.1359/jbmr.061013]
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Ada Hamosh - updated : 9/25/2013<br>Marla J. F. O'Neill - updated : 1/20/2011<br>Kelly A. Przylepa - updated : 1/27/2009<br>Victor A. McKusick - updated : 12/29/1998
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Victor A. McKusick : 6/4/1986
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