2636 lines
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Entry
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- #300770 - SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 4; SMDP4
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- OMIM
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<p>
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<span class="h4">#300770</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="/clinicalSynopsis/300770"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
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<a href="/phenotypicSeries/PS265120"> <strong>Phenotypic Series</strong> </a>
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<li role="presentation">
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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="#molecularGenetics">Molecular Genetics</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=SURFACTANT METABOLISM DYSFUNCTION, PULMONARY" 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=20108&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.diseaseinfosearch.org/x/9367" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300770[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=264675" 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 style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:12120" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/300770" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:12120" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 264675<br />
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<strong>DO:</strong> 12120<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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300770
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 4; SMDP4
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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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PULMONARY ALVEOLAR PROTEINOSIS, CONGENITAL, 4<br />
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PAP DUE TO CSF2RA DEFICIENCY<br />
|
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CSF2RA DEFICIENCY
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="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/X/16?start=-3&limit=10&highlight=16">
|
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Xp22.33
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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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Surfactant metabolism dysfunction, pulmonary, 4
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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/300770"> 300770 </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="Pseudoautosomal recessive">PR</abbr>
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<td>
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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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</td>
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<td>
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<span class="mim-font">
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CSF2RA
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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/306250"> 306250 </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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</table>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/300770" 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')">
|
|
<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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|
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<a href="/phenotypicSeries/PS265120" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
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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">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/300770" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/300770" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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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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|
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<div>
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<span class="mim-font">
|
|
|
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- Pseudoautosomal recessive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4746843&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4746843</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> GROWTH </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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<div>
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<span class="h5 mim-font">
|
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<em> Other </em>
|
|
</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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|
|
- Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</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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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Tachypnea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271823003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271823003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R06.82" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R06.82</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/786.06" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">786.06</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0231835&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0231835</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002789" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002789</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002789" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002789</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Airways </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Proteinaceous material and foamy macrophages seen on bronchoalveolar lavage<br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Lung </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Inspiratory crackles <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/75252003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">75252003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0577961&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0577961</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031996" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031996</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0031996" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0031996</a>]</span><br /> -
|
|
Restrictive impairment seen on pulmonary function testing <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1856532&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1856532</a>]</span><br /> -
|
|
Patchy ground glass opacities seen on high-resolution CT<br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
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|
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|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEMATOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hypoxemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1157018000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1157018000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/389087006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">389087006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R09.02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R09.02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/799.02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">799.02</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700292&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700292</a>, <a href="https://bioportal.bioontology.org/search?q=C5548348&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5548348</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012418" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012418</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012418" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012418</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Increased serum surfactant protein D<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the colony-stimulating factor-2 receptor, alpha, low-affinity, granulocyte-macrophage gene (CSF2RA, <a href="/entry/306250#0001">306250.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Surfactant metabolism dysfunction, pulmonary
|
|
- <a href="/phenotypicSeries/PS265120">PS265120</a>
|
|
- 5 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/432?start=-3&limit=10&highlight=432"> 2p11.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/265120"> Surfactant metabolism dysfunction, pulmonary, 1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/265120"> 265120 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/178640"> SFTPB </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/178640"> 178640 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/8/107?start=-3&limit=10&highlight=107"> 8p21.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610913"> Surfactant metabolism dysfunction, pulmonary, 2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610913"> 610913 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/178620"> SFTPC </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/178620"> 178620 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/16/105?start=-3&limit=10&highlight=105"> 16p13.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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<p>A number sign (#) is used with this entry because of evidence that pulmonary surfactant metabolism dysfunction-4 (SMDP4) is caused by mutation in the CSF2RA gene (<a href="/entry/306250">306250</a>) on chromosome Xp22.</p>
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<p>Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. Three forms of PAP have been described: hereditary (usually congenital), secondary, and acquired. Hereditary PAP is associated with mutations in the CSF2RA gene or in genes encoding surfactant proteins. Secondary PAP develops in conditions in which there are reduced numbers or functional impairment of alveolar macrophages and is associated with inhalation of inorganic dust (silica) or toxic fumes, hematologic malignancies, pharmacologic immunosuppression, infections, and impaired CSF2RB (<a href="/entry/138960">138960</a>) expression. Acquired PAP (<a href="/entry/610910">610910</a>), the most common form, usually occurs in adults and is caused by neutralizing autoantibodies to CSF2 (<a href="/entry/138960">138960</a>) (<a href="#1" class="mim-tip-reference" title="Martinez-Moczygemba, M., Doan, M. L., Elidemir, O., Fan, L. L., Cheung, S. W., Lei, J. T., Moore, J. P., Tavana, G., Lewis, L. R., Zhu, Y., Muzny, D. M., Gibbs, R. A., Huston, D. P. <strong>Pulmonary alveolar proteinosis caused by deletion of the GM-CSFR-alpha gene in the X chromosome pseudoautosomal region 1.</strong> J. Exp. Med. 205: 2711-2716, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18955567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18955567</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18955567[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/10.1084/jem.20080759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18955567">Martinez-Moczygemba et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18955567" 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>For a general phenotypic description and a discussion of genetic heterogeneity of congenital pulmonary surfactant metabolism dysfunction, see SMDP1 (<a href="/entry/265120">265120</a>).</p>
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<p><a href="#1" class="mim-tip-reference" title="Martinez-Moczygemba, M., Doan, M. L., Elidemir, O., Fan, L. L., Cheung, S. W., Lei, J. T., Moore, J. P., Tavana, G., Lewis, L. R., Zhu, Y., Muzny, D. M., Gibbs, R. A., Huston, D. P. <strong>Pulmonary alveolar proteinosis caused by deletion of the GM-CSFR-alpha gene in the X chromosome pseudoautosomal region 1.</strong> J. Exp. Med. 205: 2711-2716, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18955567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18955567</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18955567[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/10.1084/jem.20080759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18955567">Martinez-Moczygemba et al. (2008)</a> reported a 4-year-old female with symptoms associated with Turner syndrome and respiratory insufficiency who had been diagnosed with PAP at age 3 years. She had exhibited respiratory failure caused by respiratory syncytial virus pneumonia in the first month of life, with a diagnosis of reactive airways disease. The patient presented with respiratory distress and hypoxemia, with a 'crazy paving' pattern on chest imaging. Open lung biopsy revealed alveolar proteinaceous material without alveolar epithelial hyperplasia or chronic interstitial changes, and bronchoalveolar lavage revealed proteinaceous material and foamy macrophages. ELISA showed no anti-CSF2 antibodies and elevated baseline CSF2 serum levels. Exogenous CSF2 administration, which may be efficacious in some patients with acquired PAP, resulted in no clinical improvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18955567" 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="Suzuki, T., Sakagami, T., Rubin, B. K., Nogee, L. M., Wood, R. E., Zimmerman, S. L., Smolarek, T., Dishop, M. K., Wert, S. E., Whitsett, J. A., Grabowski, G., Carey, B. C., Stevens, C., van der Loo, J. C. M., Trapnell, B. C. <strong>Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA.</strong> J. Exp. Med. 205: 2703-2710, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18955570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18955570</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18955570[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/10.1084/jem.20080990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18955570">Suzuki et al. (2008)</a> reported 2 sisters with PAP. The index patient presented at age 6 years with a 2-year history of progressive tachypnea and failure to thrive. Both parents were well developed and healthy with no history of lung disease. Examination of the patient revealed moderate tachypnea, mild tachycardia, and inspiratory crackles. Pulmonary function testing showed severe restrictive impairment. Oxygen saturation was 88% while breathing room air and decreased while talking or walking a short distance. PAP diagnosis was suspected based on chest radiography and confirmed by histopathologic examination of lung tissue. CSF2 autoantibodies were absent. Serum SPD (SFTPD; <a href="/entry/178635">178635</a>) was increased in the patient compared with her parents and controls. The patient's 8-year-old sister, who was thought to be healthy, also had increased serum SPD. Subsequent clinical evaluation revealed that the sister had poor growth, a diffusion capacity for carbon dioxide of 57% that predicted, and mild patchy ground glass opacities throughout both lungs, consistent with a diagnosis of PAP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18955570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using flow cytometry, <a href="#1" class="mim-tip-reference" title="Martinez-Moczygemba, M., Doan, M. L., Elidemir, O., Fan, L. L., Cheung, S. W., Lei, J. T., Moore, J. P., Tavana, G., Lewis, L. R., Zhu, Y., Muzny, D. M., Gibbs, R. A., Huston, D. P. <strong>Pulmonary alveolar proteinosis caused by deletion of the GM-CSFR-alpha gene in the X chromosome pseudoautosomal region 1.</strong> J. Exp. Med. 205: 2711-2716, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18955567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18955567</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18955567[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/10.1084/jem.20080759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18955567">Martinez-Moczygemba et al. (2008)</a> found that CSF2RA was absent on monocytes from the patient they reported with PAP. The patient's mother expressed CSF2RA on all monocytes, whereas the patient's father and sister expressed CSF2RA only on a subpopulation of monocytes. Stimulation of granulocytes with CSF2 induced upregulation of CD11B (ITGAM; <a href="/entry/120980">120980</a>) in the mother, but not the patient. Karyotypic analysis showed that the patient had 1 X chromosome of apparently normal length and 1 X chromosome with a truncated Xp arm that did not hybridize with a PAR1 probe. RT-PCR analysis detected expression of CSF2RA and IL3RA (<a href="/entry/308385">308385</a>), which are located in PAR1, in leukocytes from the patient's family members, but not in those from the patient. PCR analysis of the 11 coding exons of the CSF2RA gene detected a deletion of exons 5 through 13 (<a href="/entry/306250#0001">306250.0001</a>), providing a genetic basis for the absence of CSF2RA mRNA and protein. The authors noted that the deletion affecting CSF2RA likely extends to IL3RA, but that impaired IL3 (<a href="/entry/147740">147740</a>) responses do not result in PAP in mice and have not been associated with PAP in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18955567" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using flow cytometry, <a href="#3" class="mim-tip-reference" title="Suzuki, T., Sakagami, T., Rubin, B. K., Nogee, L. M., Wood, R. E., Zimmerman, S. L., Smolarek, T., Dishop, M. K., Wert, S. E., Whitsett, J. A., Grabowski, G., Carey, B. C., Stevens, C., van der Loo, J. C. M., Trapnell, B. C. <strong>Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA.</strong> J. Exp. Med. 205: 2703-2710, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18955570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18955570</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18955570[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/10.1084/jem.20080990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18955570">Suzuki et al. (2008)</a> found that both CSF2RA and CSF2RB were present on leukocytes from the 2 sisters they reported with PAP, as well as all family members tested. However, Western blot analysis showed that the affected sisters expressed only a truncated form of CSF2RA, whereas their father was heterozygous for the normal and truncated forms, and their mother expressed only normal CSF2RA. CSF2 binding and CSF2-dependent signaling were severely reduced, but not abolished, in the sisters, and their CD11B stimulation test was abnormal. <a href="#3" class="mim-tip-reference" title="Suzuki, T., Sakagami, T., Rubin, B. K., Nogee, L. M., Wood, R. E., Zimmerman, S. L., Smolarek, T., Dishop, M. K., Wert, S. E., Whitsett, J. A., Grabowski, G., Carey, B. C., Stevens, C., van der Loo, J. C. M., Trapnell, B. C. <strong>Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA.</strong> J. Exp. Med. 205: 2703-2710, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18955570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18955570</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18955570[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/10.1084/jem.20080990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18955570">Suzuki et al. (2008)</a> identified a mutation in the CSF2RA gene in the affected sisters that resulted in a gly174-to-arg (G174R; <a href="/entry/306250#0002">306250.0002</a>) substitution that altered 1 of 11 predicted N-glycosylation sites. The father was heterozygous for the G174R mutation, but the mother had only wildtype CSF2RA, suggesting a deletion of 1 maternal CSF2RA allele. PCR analysis showed that CSF2RA copy number was reduced in the sisters and their mother, but not in the father. FISH analysis demonstrated a 1.6-Mb deletion of PAR1, including the CSF2RA gene, in 1 X chromosome of the sisters and mother. Transfection of CSF2RA with the G174R mutation into 293 cells faithfully reproduced the CSF2 signaling defect at physiologic CSF2 concentrations. At high CSF2 concentrations, similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow disease progression in the 2 sisters. <a href="#3" class="mim-tip-reference" title="Suzuki, T., Sakagami, T., Rubin, B. K., Nogee, L. M., Wood, R. E., Zimmerman, S. L., Smolarek, T., Dishop, M. K., Wert, S. E., Whitsett, J. A., Grabowski, G., Carey, B. C., Stevens, C., van der Loo, J. C. M., Trapnell, B. C. <strong>Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA.</strong> J. Exp. Med. 205: 2703-2710, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18955570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18955570</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18955570[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/10.1084/jem.20080990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18955570">Suzuki et al. (2008)</a> concluded that PAP may be caused by compound heterozygous abnormalities affecting the CSF2RA gene, and that CSF2 signaling is critical for surfactant homeostasis in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18955570" 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="#1" class="mim-tip-reference" title="Martinez-Moczygemba, M., Doan, M. L., Elidemir, O., Fan, L. L., Cheung, S. W., Lei, J. T., Moore, J. P., Tavana, G., Lewis, L. R., Zhu, Y., Muzny, D. M., Gibbs, R. A., Huston, D. P. <strong>Pulmonary alveolar proteinosis caused by deletion of the GM-CSFR-alpha gene in the X chromosome pseudoautosomal region 1.</strong> J. Exp. Med. 205: 2711-2716, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18955567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18955567</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18955567[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/10.1084/jem.20080759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18955567">Martinez-Moczygemba et al. (2008)</a> noted that diagnosing PAP due to CSF2RA deficiency has important therapeutic implications, since bone marrow transplantation from a healthy donor should result in CSF2RA expression on leukocytes and thereby cure the impaired surfactant homeostasis that underlies PAP. The patient they reported with PAP due to CSF2RA deficiency underwent bone marrow transplantation, but she died of an infectious respiratory complication 4 weeks after transplantation, before the establishment of immune competency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18955567" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using Csf2rb (<a href="/entry/138981">138981</a>)-null mice, which develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (HPAP) in children with CSF2RA or CSF2RB mutations, <a href="#2" class="mim-tip-reference" title="Suzuki, T., Arumugam, P., Sakagami, T., Lachmann, N., Chalk, C., Sallese, A., Abe, S., Trapnell, C., Carey, B., Moritz, T., Malik, P., Lutzko, C., Wood, R. E., Trapnell, B. C. <strong>Pulmonary macrophage transplantation therapy.</strong> Nature 514: 450-454, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25274301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25274301</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25274301[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/10.1038/nature13807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25274301">Suzuki et al. (2014)</a> showed that pulmonary macrophage transplantation (PMT) of either wildtype or Csf2rb gene-corrected macrophages without myeloablation was safe and well tolerated. One administration corrected lung disease and secondary systemic manifestations, normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least 1 year, as did therapeutic effects. <a href="#2" class="mim-tip-reference" title="Suzuki, T., Arumugam, P., Sakagami, T., Lachmann, N., Chalk, C., Sallese, A., Abe, S., Trapnell, C., Carey, B., Moritz, T., Malik, P., Lutzko, C., Wood, R. E., Trapnell, B. C. <strong>Pulmonary macrophage transplantation therapy.</strong> Nature 514: 450-454, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25274301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25274301</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25274301[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/10.1038/nature13807" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25274301">Suzuki et al. (2014)</a> concluded that their findings identified mechanisms regulating alveolar macrophage population size in health and disease, indicated that GMCSF (<a href="/entry/138960">138960</a>) is required for phenotypic determination of alveolar macrophages, and supported translation of PMT as the first specific therapy for children with hereditary pulmonary alveolar proteinosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25274301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Martinez-Moczygemba2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Martinez-Moczygemba, M., Doan, M. L., Elidemir, O., Fan, L. L., Cheung, S. W., Lei, J. T., Moore, J. P., Tavana, G., Lewis, L. R., Zhu, Y., Muzny, D. M., Gibbs, R. A., Huston, D. P.
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<strong>Pulmonary alveolar proteinosis caused by deletion of the GM-CSFR-alpha gene in the X chromosome pseudoautosomal region 1.</strong>
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J. Exp. Med. 205: 2711-2716, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18955567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18955567</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18955567[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=18955567" 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/10.1084/jem.20080759" target="_blank">Full Text</a>]
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<a id="Suzuki2014" class="mim-anchor"></a>
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<p class="mim-text-font">
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Suzuki, T., Arumugam, P., Sakagami, T., Lachmann, N., Chalk, C., Sallese, A., Abe, S., Trapnell, C., Carey, B., Moritz, T., Malik, P., Lutzko, C., Wood, R. E., Trapnell, B. C.
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<strong>Pulmonary macrophage transplantation therapy.</strong>
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Nature 514: 450-454, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25274301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25274301</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25274301[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=25274301" 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/nature13807" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Suzuki2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Suzuki, T., Sakagami, T., Rubin, B. K., Nogee, L. M., Wood, R. E., Zimmerman, S. L., Smolarek, T., Dishop, M. K., Wert, S. E., Whitsett, J. A., Grabowski, G., Carey, B. C., Stevens, C., van der Loo, J. C. M., Trapnell, B. C.
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<strong>Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA.</strong>
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J. Exp. Med. 205: 2703-2710, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18955570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18955570</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18955570[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=18955570" 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/10.1084/jem.20080990" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </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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Ada Hamosh - updated : 12/30/2014
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Paul J. Converse - updated : 3/31/2009
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Creation Date:
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Matthew B. Gross : 3/30/2009
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carol : 07/21/2017
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<span class="mim-text-font">
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alopez : 01/05/2015<br>alopez : 12/30/2014<br>ckniffin : 12/1/2011<br>terry : 4/28/2011<br>ckniffin : 4/27/2009<br>mgross : 3/31/2009<br>mgross : 3/31/2009<br>mgross : 3/31/2009
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<span class="mim-font">
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<strong>#</strong> 300770
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<h3>
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SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 4; SMDP4
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<br />
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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PULMONARY ALVEOLAR PROTEINOSIS, CONGENITAL, 4<br />
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PAP DUE TO CSF2RA DEFICIENCY<br />
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CSF2RA DEFICIENCY
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<strong>ORPHA:</strong> 264675;
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<strong>DO:</strong> 12120;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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<th>
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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Xp22.33
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<td>
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<span class="mim-font">
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Surfactant metabolism dysfunction, pulmonary, 4
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<span class="mim-font">
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300770
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<td>
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<span class="mim-font">
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Pseudoautosomal recessive
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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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</td>
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<td>
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<span class="mim-font">
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CSF2RA
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</td>
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<td>
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<span class="mim-font">
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306250
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that pulmonary surfactant metabolism dysfunction-4 (SMDP4) is caused by mutation in the CSF2RA gene (306250) on chromosome Xp22.</p>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. Three forms of PAP have been described: hereditary (usually congenital), secondary, and acquired. Hereditary PAP is associated with mutations in the CSF2RA gene or in genes encoding surfactant proteins. Secondary PAP develops in conditions in which there are reduced numbers or functional impairment of alveolar macrophages and is associated with inhalation of inorganic dust (silica) or toxic fumes, hematologic malignancies, pharmacologic immunosuppression, infections, and impaired CSF2RB (138960) expression. Acquired PAP (610910), the most common form, usually occurs in adults and is caused by neutralizing autoantibodies to CSF2 (138960) (Martinez-Moczygemba et al., 2008). </p><p>For a general phenotypic description and a discussion of genetic heterogeneity of congenital pulmonary surfactant metabolism dysfunction, see SMDP1 (265120).</p>
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<p>Martinez-Moczygemba et al. (2008) reported a 4-year-old female with symptoms associated with Turner syndrome and respiratory insufficiency who had been diagnosed with PAP at age 3 years. She had exhibited respiratory failure caused by respiratory syncytial virus pneumonia in the first month of life, with a diagnosis of reactive airways disease. The patient presented with respiratory distress and hypoxemia, with a 'crazy paving' pattern on chest imaging. Open lung biopsy revealed alveolar proteinaceous material without alveolar epithelial hyperplasia or chronic interstitial changes, and bronchoalveolar lavage revealed proteinaceous material and foamy macrophages. ELISA showed no anti-CSF2 antibodies and elevated baseline CSF2 serum levels. Exogenous CSF2 administration, which may be efficacious in some patients with acquired PAP, resulted in no clinical improvement. </p><p>Suzuki et al. (2008) reported 2 sisters with PAP. The index patient presented at age 6 years with a 2-year history of progressive tachypnea and failure to thrive. Both parents were well developed and healthy with no history of lung disease. Examination of the patient revealed moderate tachypnea, mild tachycardia, and inspiratory crackles. Pulmonary function testing showed severe restrictive impairment. Oxygen saturation was 88% while breathing room air and decreased while talking or walking a short distance. PAP diagnosis was suspected based on chest radiography and confirmed by histopathologic examination of lung tissue. CSF2 autoantibodies were absent. Serum SPD (SFTPD; 178635) was increased in the patient compared with her parents and controls. The patient's 8-year-old sister, who was thought to be healthy, also had increased serum SPD. Subsequent clinical evaluation revealed that the sister had poor growth, a diffusion capacity for carbon dioxide of 57% that predicted, and mild patchy ground glass opacities throughout both lungs, consistent with a diagnosis of PAP. </p>
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<p>Using flow cytometry, Martinez-Moczygemba et al. (2008) found that CSF2RA was absent on monocytes from the patient they reported with PAP. The patient's mother expressed CSF2RA on all monocytes, whereas the patient's father and sister expressed CSF2RA only on a subpopulation of monocytes. Stimulation of granulocytes with CSF2 induced upregulation of CD11B (ITGAM; 120980) in the mother, but not the patient. Karyotypic analysis showed that the patient had 1 X chromosome of apparently normal length and 1 X chromosome with a truncated Xp arm that did not hybridize with a PAR1 probe. RT-PCR analysis detected expression of CSF2RA and IL3RA (308385), which are located in PAR1, in leukocytes from the patient's family members, but not in those from the patient. PCR analysis of the 11 coding exons of the CSF2RA gene detected a deletion of exons 5 through 13 (306250.0001), providing a genetic basis for the absence of CSF2RA mRNA and protein. The authors noted that the deletion affecting CSF2RA likely extends to IL3RA, but that impaired IL3 (147740) responses do not result in PAP in mice and have not been associated with PAP in humans. </p><p>Using flow cytometry, Suzuki et al. (2008) found that both CSF2RA and CSF2RB were present on leukocytes from the 2 sisters they reported with PAP, as well as all family members tested. However, Western blot analysis showed that the affected sisters expressed only a truncated form of CSF2RA, whereas their father was heterozygous for the normal and truncated forms, and their mother expressed only normal CSF2RA. CSF2 binding and CSF2-dependent signaling were severely reduced, but not abolished, in the sisters, and their CD11B stimulation test was abnormal. Suzuki et al. (2008) identified a mutation in the CSF2RA gene in the affected sisters that resulted in a gly174-to-arg (G174R; 306250.0002) substitution that altered 1 of 11 predicted N-glycosylation sites. The father was heterozygous for the G174R mutation, but the mother had only wildtype CSF2RA, suggesting a deletion of 1 maternal CSF2RA allele. PCR analysis showed that CSF2RA copy number was reduced in the sisters and their mother, but not in the father. FISH analysis demonstrated a 1.6-Mb deletion of PAR1, including the CSF2RA gene, in 1 X chromosome of the sisters and mother. Transfection of CSF2RA with the G174R mutation into 293 cells faithfully reproduced the CSF2 signaling defect at physiologic CSF2 concentrations. At high CSF2 concentrations, similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow disease progression in the 2 sisters. Suzuki et al. (2008) concluded that PAP may be caused by compound heterozygous abnormalities affecting the CSF2RA gene, and that CSF2 signaling is critical for surfactant homeostasis in humans. </p>
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<p>Martinez-Moczygemba et al. (2008) noted that diagnosing PAP due to CSF2RA deficiency has important therapeutic implications, since bone marrow transplantation from a healthy donor should result in CSF2RA expression on leukocytes and thereby cure the impaired surfactant homeostasis that underlies PAP. The patient they reported with PAP due to CSF2RA deficiency underwent bone marrow transplantation, but she died of an infectious respiratory complication 4 weeks after transplantation, before the establishment of immune competency. </p>
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<p>Using Csf2rb (138981)-null mice, which develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (HPAP) in children with CSF2RA or CSF2RB mutations, Suzuki et al. (2014) showed that pulmonary macrophage transplantation (PMT) of either wildtype or Csf2rb gene-corrected macrophages without myeloablation was safe and well tolerated. One administration corrected lung disease and secondary systemic manifestations, normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least 1 year, as did therapeutic effects. Suzuki et al. (2014) concluded that their findings identified mechanisms regulating alveolar macrophage population size in health and disease, indicated that GMCSF (138960) is required for phenotypic determination of alveolar macrophages, and supported translation of PMT as the first specific therapy for children with hereditary pulmonary alveolar proteinosis. </p>
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Martinez-Moczygemba, M., Doan, M. L., Elidemir, O., Fan, L. L., Cheung, S. W., Lei, J. T., Moore, J. P., Tavana, G., Lewis, L. R., Zhu, Y., Muzny, D. M., Gibbs, R. A., Huston, D. P.
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<strong>Pulmonary alveolar proteinosis caused by deletion of the GM-CSFR-alpha gene in the X chromosome pseudoautosomal region 1.</strong>
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J. Exp. Med. 205: 2711-2716, 2008.
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[PubMed: 18955567]
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[Full Text: https://doi.org/10.1084/jem.20080759]
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Suzuki, T., Arumugam, P., Sakagami, T., Lachmann, N., Chalk, C., Sallese, A., Abe, S., Trapnell, C., Carey, B., Moritz, T., Malik, P., Lutzko, C., Wood, R. E., Trapnell, B. C.
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<strong>Pulmonary macrophage transplantation therapy.</strong>
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Nature 514: 450-454, 2014.
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[PubMed: 25274301]
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[Full Text: https://doi.org/10.1038/nature13807]
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Suzuki, T., Sakagami, T., Rubin, B. K., Nogee, L. M., Wood, R. E., Zimmerman, S. L., Smolarek, T., Dishop, M. K., Wert, S. E., Whitsett, J. A., Grabowski, G., Carey, B. C., Stevens, C., van der Loo, J. C. M., Trapnell, B. C.
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<strong>Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA.</strong>
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J. Exp. Med. 205: 2703-2710, 2008.
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[PubMed: 18955570]
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[Full Text: https://doi.org/10.1084/jem.20080990]
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Ada Hamosh - updated : 12/30/2014<br>Paul J. Converse - updated : 3/31/2009
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