4071 lines
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4071 lines
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- #202700 - NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT; SCN1
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- OMIM
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<p>
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<span class="h4">#202700</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/202700"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS202700"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#biochemicalFeatures">Biochemical Features</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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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT" 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=822&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/NBK1533/" 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/6527" 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=202700[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=486" 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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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0080625" 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/202700" 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 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 style="display: table-cell;">Cell Lines</div>
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:202700" 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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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<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> 486<br />
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<strong>DO:</strong> 0080625<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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202700
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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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NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT; SCN1
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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="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
|
<span class="mim-font">
|
|
<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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<tbody>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/19/32?start=-3&limit=10&highlight=32">
|
|
19p13.3
|
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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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Neutropenia, severe congenital 1, autosomal dominant
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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/202700"> 202700 </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 dominant">AD</abbr>
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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="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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ELANE
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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/130130"> 130130 </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>
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<div>
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<div class="btn-group ">
|
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<a href="/clinicalSynopsis/202700" 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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|
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<a href="/phenotypicSeries/PS202700" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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|
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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">
|
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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/202700" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/202700" 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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|
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- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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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>
|
|
<span class="h5 mim-font">
|
|
<strong> HEMATOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Increased absolute neutrophil count (ANC) within 0.0-0.2 x 10(9)/l <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806143&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806143</a>]</span><br /> -
|
|
Anemia, mild <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858586&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858586</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271737000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271737000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D64.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D64.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/285.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">285.9</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001903" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001903</a>]</span><br /> -
|
|
Thrombocytosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/6631009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">6631009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D75.839" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D75.839</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D75.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D75.83</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0836924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0836924</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001894" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001894</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001894" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001894</a>]</span><br /> -
|
|
Increase in blood monocytes (2-3 times normal) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806144&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806144</a>]</span><br /> -
|
|
Eosinophilia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386789004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386789004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.10</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0014457&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014457</a>, <a href="https://bioportal.bioontology.org/search?q=C2240374&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2240374</a>, <a href="https://bioportal.bioontology.org/search?q=C1306759&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1306759</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001880</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001880" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001880</a>]</span><br /> -
|
|
Increased promyelocytes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806145&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806145</a>]</span><br /> -
|
|
Maturation arrest of neutrophil precursors seen on bone marrow biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806146&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806146</a>]</span><br /> -
|
|
Promyelocytes have atypical nuclei and vacuolization of the cytoplasm <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806147</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> IMMUNOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Recurrent severe infections <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806142&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806142</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/451991000124106" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">451991000124106</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002719" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002719</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Onset in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848924</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span><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 neutrophil-expressed elastase gene (ELANE, <a href="/entry/130130#0006">130130.0006</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">
|
|
|
|
|
|
|
|
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|
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|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Neutropenia, severe congenital
|
|
- <a href="/phenotypicSeries/PS202700">PS202700</a>
|
|
- 13 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/1/446?start=-3&limit=10&highlight=446"> 1p34.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617014"> Neutropenia, severe congenital, 7, autosomal recessive </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/617014"> 617014 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/138971"> CSF3R </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/138971"> 138971 </a>
|
|
</span>
|
|
</td>
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<span class="mim-font">
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<a href="/geneMap/1/802?start=-3&limit=10&highlight=802"> 1p22.1 </a>
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<span class="mim-font">
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<a href="/entry/613107"> Neutropenia, severe congenital 2, autosomal dominant </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 dominant">AD</abbr>
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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="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/613107"> 613107 </a>
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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/600871"> GFI1 </a>
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</span>
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<span class="mim-font">
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<a href="/entry/600871"> 600871 </a>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/1059?start=-3&limit=10&highlight=1059"> 1q21.2 </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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<a href="/entry/615285"> Neutropenia, severe congenital, 5, autosomal recessive </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>
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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="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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<a href="/entry/615285"> 615285 </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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<a href="/entry/610035"> VPS45 </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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<a href="/entry/610035"> 610035 </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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<a href="/geneMap/1/1187?start=-3&limit=10&highlight=1187"> 1q21.3 </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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<a href="/entry/610738"> Neutropenia, severe congenital 3, autosomal recessive </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>
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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="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/610738"> 610738 </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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<a href="/entry/605998"> HAX1 </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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<a href="/entry/605998"> 605998 </a>
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</span>
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</td>
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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/3/42?start=-3&limit=10&highlight=42"> 3p25.3 </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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<a href="/entry/616022"> Neutropenia, severe congenital, 6, autosomal recessive </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>
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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="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/616022"> 616022 </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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<a href="/entry/616012"> JAGN1 </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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<a href="/entry/616012"> 616012 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/3/647?start=-3&limit=10&highlight=647"> 3q21.3 </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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<a href="/entry/620674"> ?Neutropenia, severe congenital, 11, autosomal dominant </a>
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</span>
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</td>
|
|
<td>
|
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<span class="mim-font">
|
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|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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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="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/620674"> 620674 </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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<a href="/entry/609213"> SEC61A1 </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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<a href="/entry/609213"> 609213 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/11/722?start=-3&limit=10&highlight=722"> 11q13.4 </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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<a href="/entry/619813"> Neutropenia, severe congenital, 9, autosomal dominant </a>
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
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</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/619813"> 619813 </a>
|
|
</span>
|
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</td>
|
|
<td>
|
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<span class="mim-font">
|
|
<a href="/entry/616254"> CLPB </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/616254"> 616254 </a>
|
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</span>
|
|
</td>
|
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</tr>
|
|
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|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/14/166?start=-3&limit=10&highlight=166"> 14q13.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618752"> Neutropenia, severe congenital, 8, autosomal dominant </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/618752"> 618752 </a>
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604857"> SRP54 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604857"> 604857 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/17/628?start=-3&limit=10&highlight=628"> 17q21.31 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612541"> Neutropenia, severe congenital 4, autosomal recessive </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/612541"> 612541 </a>
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611045"> G6PC3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611045"> 611045 </a>
|
|
</span>
|
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</td>
|
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</tr>
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|
<tr>
|
|
<td>
|
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<span class="mim-font">
|
|
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|
<a href="/geneMap/17/628?start=-3&limit=10&highlight=628"> 17q21.31 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612541"> Dursun syndrome </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/612541"> 612541 </a>
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611045"> G6PC3 </a>
|
|
</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/611045"> 611045 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/17/964?start=-3&limit=10&highlight=964"> 17q25.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620534"> ?Neutropenia, severe congenital, 10, autosomal recessive </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
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|
</span>
|
|
</td>
|
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<td>
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<span class="mim-font">
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<a href="/entry/620534"> 620534 </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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<a href="/entry/604858"> SRP68 </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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<a href="/entry/604858"> 604858 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/19/32?start=-3&limit=10&highlight=32"> 19p13.3 </a>
|
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|
</span>
|
|
</td>
|
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<td>
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<span class="mim-font">
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<a href="/entry/202700"> Neutropenia, severe congenital 1, autosomal dominant </a>
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
|
</td>
|
|
<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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</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/202700"> 202700 </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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<a href="/entry/130130"> ELANE </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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<a href="/entry/130130"> 130130 </a>
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</span>
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</td>
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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/253?start=-3&limit=10&highlight=253"> Xp11.23 </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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<a href="/entry/300299"> Neutropenia, severe congenital, X-linked </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="X-linked recessive">XLR</abbr>
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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="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/300299"> 300299 </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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<a href="/entry/300392"> WAS </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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<a href="/entry/300392"> 300392 </a>
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</span>
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</td>
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</table>
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<div class="text-right small">
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because severe congenital neutropenia-1 (SCN1) is caused by heterozygous mutation in the neutrophil elastase gene (ELANE; <a href="/entry/130130">130130</a>) on chromosome 19p13.</p><p>See also cyclic neutropenia (<a href="/entry/162800">162800</a>), which is an allelic disorder.</p>
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<p>Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections (<a href="#27" class="mim-tip-reference" title="Skokowa, J., Germeshausen, M., Zeidler, C., Welte, K. <strong>Severe congenital neutropenia: inheritance and pathophysiology.</strong> Curr. Opin. Hemat. 14: 22-28, 2007. Note: Erratum: Curr. Opin. Hemat. 14: 181 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17133096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17133096</a>] [<a href="https://doi.org/10.1097/00062752-200701000-00006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17133096">Skokowa et al., 2007</a>). About 60% of affected individuals of European and Middle Eastern ancestry have dominant ELANE mutations, resulting in a form of severe congenital neutropenia, which is designated here as SCN1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17133096" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Severe Congenital Neutropenia</em></strong></p><p>
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Severe congenital neutropenia is a genetically heterogeneous disorder showing autosomal dominant, autosomal recessive, and X-linked inheritance. Other autosomal dominant forms are SCN2 (<a href="/entry/613107">613107</a>), caused by mutation in the protooncogene GFI1 (<a href="/entry/600871">600871</a>) on 1p22; SCN8 (<a href="/entry/618752">618752</a>), caused by mutation in the SRP54 gene (<a href="/entry/604857">604857</a>) on 14q13; SCN9 (<a href="/entry/619813">619813</a>), caused by mutation in the CLPB gene (<a href="/entry/616254">616254</a>) on 11q13; and SCN11 (<a href="/entry/620674">620674</a>), caused by mutation in the SEC61A1 gene (<a href="/entry/609213">609213</a>) on chromosome 3q21.</p><p>Autosomal recessive forms include SCN3 (<a href="/entry/610738">610738</a>), caused by mutation in the HAX1 gene (<a href="/entry/605998">605998</a>) on 1q21; SCN4 (<a href="/entry/612541">612541</a>), caused by mutation in the G6PC3 gene (<a href="/entry/611045">611045</a>) on 17q21; SCN5 (<a href="/entry/615285">615285</a>), caused by mutation in the VPS45 gene (<a href="/entry/610035">610035</a>) on 1q21; SCN6 (<a href="/entry/616022">616022</a>), caused by mutation in the JAGN1 gene (<a href="/entry/616012">616012</a>) on 3p25; SCN7 (<a href="/entry/617014">617014</a>), caused by mutation in the CSF3R gene (<a href="/entry/138971">138971</a>) on 1p34; and SCN10 (<a href="/entry/620534">620534</a>), caused by mutation in the SRP68 gene (<a href="/entry/604858">604858</a>) on chromosome 17q25.</p><p>X-linked SCN (SCNX; <a href="/entry/300299">300299</a>) is caused by mutation in the WAS gene (<a href="/entry/300392">300392</a>) on Xp11.</p><p>See also adult chronic idiopathic nonimmune neutropenia (<a href="/entry/607847">607847</a>) and chronic benign familial neutropenia (<a href="/entry/162700">162700</a>).</p><p><strong><em>Susceptibility to Myelodysplastic Syndrome/Acute Myeloid Leukemia</em></strong></p><p>
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SCN patients with acquired mutations in the granulocyte colony-stimulating factor receptor (CSF3R; <a href="/entry/138971">138971</a>) in hematopoietic cells define a group with high risk for progression to myelodysplastic syndrome and/or acute myeloid leukemia. Approximately 80% of SCN patients who develop AML are heterozygous for somatic CSF3R mutations (summary by <a href="#17" class="mim-tip-reference" title="Klimiankou, M., Mellor-Heineke, S., Zeidler, C., Welte, K., Skokowa, J. <strong>Role of CSF3R mutations in the pathomechanism of congenital neutropenia and secondary acute myeloid leukemia.</strong> Ann. N. Y. Acad. Sci. 1370: 119-125, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27270496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27270496</a>] [<a href="https://doi.org/10.1111/nyas.13097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27270496">Klimiankou et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27270496" 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="#11" class="mim-tip-reference" title="Gilman, P. A., Jackson, D. P., Guild, H. G. <strong>Congenital agranulocytosis: prolonged survival and terminal acute leukemia.</strong> Blood 36: 576-585, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4319697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4319697</a>]" pmid="4319697">Gilman et al. (1970)</a> described prolonged survival and death from acute monocytic leukemia at age 14 years and 10 months. About three-fourths of patients die before age 3 years. Fungal and viral infections had not been a problem. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4319697" 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="Freedman, M. H., Bonilla, M. A., Fier, C., Bolyard, A. A., Scarlata, D., Boxer, L. A., Brown, S., Cham, B., Kannourakis, G., Kinsey, S. E., Mori, P. G., Cottle, T., Welte, K., Dale, D. C. <strong>Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy.</strong> Blood 96: 429-436, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10887102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10887102</a>]" pmid="10887102">Freedman et al. (2000)</a> stated that the Severe Chronic Neutropenia International Registry (SCNIR) in Seattle had data on 696 neutropenic patients, including 352 patients with congenital neutropenia, treated with GCSF from 1987 to 2000. The 352 congenital patients were observed for a mean of 6 years (range, 0.1 to 11 years) while being treated. Of these patients, 31 developed myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), for a crude rate of malignant transformation of nearly 9%. None of the 344 patients with idiopathic or cyclic neutropenia developed MDS/AML. Transformation was associated with acquired marrow cytogenetic clonal changes: 18 patients developed a partial or complete loss of chromosome 7, and 9 patients manifested abnormalities of chromosome 21 (usually trisomy 21; <a href="/entry/190685">190685</a>). For each yearly treatment interval, the annual rate of MDS/AML development was less than 2%. <a href="#10" class="mim-tip-reference" title="Freedman, M. H., Bonilla, M. A., Fier, C., Bolyard, A. A., Scarlata, D., Boxer, L. A., Brown, S., Cham, B., Kannourakis, G., Kinsey, S. E., Mori, P. G., Cottle, T., Welte, K., Dale, D. C. <strong>Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy.</strong> Blood 96: 429-436, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10887102/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10887102</a>]" pmid="10887102">Freedman et al. (2000)</a> concluded that although the data did not support a cause-and-effect relationship between development of MDS/AML and GCSF therapy or other patient demographics, they could not exclude a direct contribution of GCSF in the pathogenesis of MDS/AML. Improved survival of congenital neutropenia patients receiving GCSF therapy may allow time for expression of the leukemic predisposition that characterizes the natural history of these disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10887102" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of immunodeficiencies caused by defects in phagocytes, <a href="#20" class="mim-tip-reference" title="Lekstrom-Himes, J. A., Gallin, J. I. <strong>Immunodeficiency diseases caused by defects in phagocytes.</strong> New Eng. J. Med. 343: 1703-1714, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106721</a>] [<a href="https://doi.org/10.1056/NEJM200012073432307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106721">Lekstrom-Himes and Gallin (2000)</a> discussed severe congenital neutropenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11106721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Bonilla, M. A., Gillio, A. P., Ruggeiro, M., Kernan, N. A., Brochstein, J. A., Abboud, M., Fumagalli, L., Vincent, M., Gabrilove, J. L., Welte, K., Souza, L. M., O'Reilly, R. J. <strong>Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis.</strong> New Eng. J. Med. 320: 1574-1580, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2471075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2471075</a>] [<a href="https://doi.org/10.1056/NEJM198906153202402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2471075">Bonilla et al. (1989)</a> administered recombinant human granulocyte colony-stimulating factor (GCSF; <a href="/entry/138970">138970</a>) to 5 patients. All 5 patients showed a response and had sustained neutrophil counts of 1,000 cells per microliter or more for 9 to 13 months while receiving subcutaneous maintenance therapy. Preexisting chronic infections resolved and the number of new infectious episodes decreased. <a href="#5" class="mim-tip-reference" title="Bonilla, M. A., Gillio, A. P., Ruggeiro, M., Kernan, N. A., Brochstein, J. A., Abboud, M., Fumagalli, L., Vincent, M., Gabrilove, J. L., Welte, K., Souza, L. M., O'Reilly, R. J. <strong>Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis.</strong> New Eng. J. Med. 320: 1574-1580, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2471075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2471075</a>] [<a href="https://doi.org/10.1056/NEJM198906153202402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2471075">Bonilla et al. (1989)</a> raised the possibility that the receptors are defective and do not respond to GCSF unless it is administered in pharmacologic doses. This possibility appeared to be confirmed by the findings of <a href="#9" class="mim-tip-reference" title="Dong, F., Hoefsloot, L. H., Schelen, A. M., Broeders, L. C. A. M., Meijer, Y., Veerman, A. J. P., Touw, I. P., Lowenberg, B. <strong>Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia.</strong> Proc. Nat. Acad. Sci. 91: 4480-4484, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7514305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7514305</a>] [<a href="https://doi.org/10.1073/pnas.91.10.4480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7514305">Dong et al. (1994)</a> of somatic mutation in the GCSFR gene (<a href="/entry/138971">138971</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2471075+7514305" 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 SCN, absolute neutrophil counts are usually less than 200 cells per cubic millimeter, with a remainder of the blood counts relatively normal (<a href="#7" class="mim-tip-reference" title="Dale, D. C., Person, R. E., Bolyard, A. A., Aprikyan, A. G., Bos, C., Bonilla, M. A., Boxer, L. A., Kannourakis, G., Zeidler, C., Welte, K., Benson, K. F., Horwitz, M. <strong>Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.</strong> Blood 96: 2317-2322, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001877</a>]" pmid="11001877">Dale et al., 2000</a>). Treatment with GCSF leads to an increase in neutrophil counts to more than 1,000 cells per cubic millimeter in 90% of patients and results in significant improvements in survival and quality of life (<a href="#6" class="mim-tip-reference" title="Dale, D. C., Bonilla, M. A., Davis, M. W., Nakanishi, A. M., Hammond, W. P., Kurtzberg, J., Wang, W., Jakubowski, A., Winton, E., Lalezari, P., Robinson, W., Glaspy, J. A., Emerson, S., Gabrilove, J., Vincent, M., Boxer, L. A. <strong>A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia.</strong> Blood 81: 2496-2502, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8490166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8490166</a>]" pmid="8490166">Dale et al., 1993</a>; <a href="#4" class="mim-tip-reference" title="Bonilla, M. A., Dale, D., Zeidler, C., Last, L., Reiter, A., Ruggeiro, M., Davis, M., Koci, B., Hammond, W., Gillio, A., Welte, K. <strong>Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias.</strong> Brit. J. Haemat. 88: 723-730, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7529539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7529539</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1994.tb05110.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7529539">Bonilla et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11001877+7529539+8490166" 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="#32" class="mim-tip-reference" title="Yakisan, E., Schirg, E., Zeidler, C., Bishop, N. J., Reiter, A., Hirt, A., Riehm, H., Welte, K. <strong>High incidence of significant bone loss in patients with severe congenital neutropenia (Kostmann's syndrome).</strong> J. Pediat. 131: 592-597, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9386665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9386665</a>] [<a href="https://doi.org/10.1016/s0022-3476(97)70068-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9386665">Yakisan et al. (1997)</a> noted that although r-metHuGCSF treatment of children with severe congenital neutropenia has substantially improved the patients' quality of life and life expectancy, bone pain and unusual fractures have been reported in treated patients. The authors reviewed roentgenograms in 29 of 30 patients to evaluate bone loss before and during treatment and assessed bone mineral status in 17 of the 30 patients. Their data indicated a high incidence of bone mineral loss in children with severe congenital neutropenia. The investigators concluded that it is more likely that the bone loss was caused by the pathophysiologic features of the underlying disease; however, they could not rule out the possibility that r-metHuGCSF accelerates bone mineral loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9386665" 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>Myeloid precursor cells from patients with severe congenital neutropenia (SCN) require pharmacologic dosages of recombinant human granulocyte colony-stimulating factor (GCSF) to differentiate normal neutrophils. Because JAK2 (<a href="/entry/147796">147796</a>), a nonreceptor tyrosine kinase, is involved in the signaling pathway of GCSF, <a href="#23" class="mim-tip-reference" title="Rauprich, P., Kasper, B., Tidow, N., Welte, K. <strong>The protein tyrosine kinase JAK2 is activated in neutrophils from patients with severe congenital neutropenia.</strong> Blood 86: 4500-4505, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541539</a>]" pmid="8541539">Rauprich et al. (1995)</a> studied the expression and activity of JAK2 in neutrophils from SCN patients during therapy. The immunoprecipitated JAK2 protein showed increased tyrosine phosphorylation in neutrophils from SCN patients as compared with that in neutrophils from healthy controls. <a href="#23" class="mim-tip-reference" title="Rauprich, P., Kasper, B., Tidow, N., Welte, K. <strong>The protein tyrosine kinase JAK2 is activated in neutrophils from patients with severe congenital neutropenia.</strong> Blood 86: 4500-4505, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541539</a>]" pmid="8541539">Rauprich et al. (1995)</a> pointed out that only a few patients, who subsequently develop acute myeloid leukemia, have a point mutation in the cytoplasmic region of the GCSF receptor, resulting in a truncation from the C terminus of the receptor and an inability of the receptor to transduce the signal on GCSF stimulation. Thus they suspected that various defects are responsible for SCN. That pharmacologic doses of GCSF are required to overcome the neutropenia suggested a defect of other specific molecules in the GCSF signal transduction pathway. The primary defect does not appear to be in JAK2; it may be that the phosphotyrosines on the receptor create binding sites for STAT proteins (signal transducers and activators of transcription; see <a href="/entry/600555">600555</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8541539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Skokowa, J., Cario, G., Uenalan, M., Schambach, A., Germeshausen, M., Battmer, K., Zeidler, C., Lehmann, U., Eder, M., Baum, C., Grosschedl, R., Stanulla, M., Scherr, M., Welte, K. <strong>LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia.</strong> Nature Med. 12: 1191-1197, 2006. Note: Erratum: Nature Med. 12: 1329 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17063141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17063141</a>] [<a href="https://doi.org/10.1038/nm1474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17063141">Skokowa et al. (2006)</a> found significantly decreased or absent LEF1 (<a href="/entry/153245">153245</a>) expression in arrested promyelocytes from patients with congenital neutropenia. LEF1 decrease resulted in defective expression of downstream target genes, including CCND1 (<a href="/entry/168461">168461</a>), MYC (<a href="/entry/190080">190080</a>), and BIRC5 (<a href="/entry/603352">603352</a>). Promyelocytes from healthy individuals showed highest LEF1 expression. Reconstitution of LEF1 in early hematopoietic progenitors from 2 individuals with congenital neutropenia resulted in the differentiation of these progenitors into mature granulocytes. LEF1 directly bound to and regulated the transcription factor CEBPA (<a href="/entry/116897">116897</a>). The findings indicated that LEF1 plays a role in granulopoiesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17063141" 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 SCN1 in the patients reported by <a href="#7" class="mim-tip-reference" title="Dale, D. C., Person, R. E., Bolyard, A. A., Aprikyan, A. G., Bos, C., Bonilla, M. A., Boxer, L. A., Kannourakis, G., Zeidler, C., Welte, K., Benson, K. F., Horwitz, M. <strong>Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.</strong> Blood 96: 2317-2322, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001877</a>]" pmid="11001877">Dale et al. (2000)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001877" 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>After demonstrating mutations in the ELA2 gene (ELANE; <a href="/entry/130130">130130</a>) in patients with cyclic neutropenia (<a href="/entry/162800">162800</a>), <a href="#7" class="mim-tip-reference" title="Dale, D. C., Person, R. E., Bolyard, A. A., Aprikyan, A. G., Bos, C., Bonilla, M. A., Boxer, L. A., Kannourakis, G., Zeidler, C., Welte, K., Benson, K. F., Horwitz, M. <strong>Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.</strong> Blood 96: 2317-2322, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001877</a>]" pmid="11001877">Dale et al. (2000)</a> hypothesized that congenital neutropenia is also due to mutation in this gene. They performed mutation analysis by sequencing PCR-amplified genomic DNA for each of the 5 exons of the ELA2 gene and 20 bases of the flanking regions. In 22 of 25 patients with congenital neutropenia, 18 different heterozygous mutations were found. All 4 patients with cyclic neutropenia, but none of the 3 patients with Shwachman-Diamond syndrome (<a href="/entry/260400">260400</a>), had mutations of ELA2. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. In the congenital neutropenia patients, 5 different mutations were found in families with 2 or more affected members. Three instances of father-daughter pairs, 1 mother-son pair, and 1 mother with 2 affected sons by different fathers suggested autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001877" 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="#16" class="mim-tip-reference" title="Ishikawa, N., Okada, S., Miki, M., Shirao, K., Kihara, H., Tsumura, M., Nakamura, K., Kawaguchi, H., Ohtsubo, M., Yasunaga, S., Matsubara, K., Sako, M., Hara, J., Shiohara, M., Kojima, S., Sato, T., Takihara, Y., Kobayashi, M. <strong>Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene.</strong> J. Med. Genet. 45: 802-807, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18611981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18611981</a>] [<a href="https://doi.org/10.1136/jmg.2008.058297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18611981">Ishikawa et al. (2008)</a> identified heterozygous mutations in the ELA2 gene in 11 (61%) of 18 Japanese patients with severe congenital neutropenia. Five (28%) patients had SCN3 (<a href="/entry/610738">610738</a>) due to mutation in the HAX1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18611981" 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>Among 109 probands with SCN, <a href="#28" class="mim-tip-reference" title="Smith, B. N., Ancliff, P. J., Pizzey, A., Khwaja, A., Linch, D. C., Gale, R. E. <strong>Homozygous HAX1 mutations in severe congenital neutropenia patients with sporadic disease: a novel mutation in two unrelated British kindreds.</strong> Brit. J. Haemat. 144: 762-770, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19036076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19036076</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2008.07493.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19036076">Smith et al. (2008)</a> found that 33 (30%) had 24 different ELA2 mutations, 2 (2%) had WAS (<a href="/entry/300392">300392</a>) mutations, and 4 (4%) had HAX1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19036076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Progression to Myelodysplastic Syndrome and Acute Myeloid Leukemia</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Dong, F., Hoefsloot, L. H., Schelen, A. M., Broeders, L. C. A. M., Meijer, Y., Veerman, A. J. P., Touw, I. P., Lowenberg, B. <strong>Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia.</strong> Proc. Nat. Acad. Sci. 91: 4480-4484, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7514305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7514305</a>] [<a href="https://doi.org/10.1073/pnas.91.10.4480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7514305">Dong et al. (1994)</a> used RT-PCR to amplify cDNA for granulocyte colony-stimulating factor receptor (CSF3R; <a href="/entry/138971">138971</a>) in patients with severe congenital neutropenia, referred to as Kostmann syndrome, and screened for mutations by single-strand conformation polymorphism (SSCP) analysis. In 1 patient, they identified a somatic point mutation that resulted in the cytoplasmic truncation of the GCSF receptor protein. The mutation was present predominantly in the granulocytic lineage. Further functional characterization demonstrated that the truncated receptor was unable to transduce a maturation signal. <a href="#9" class="mim-tip-reference" title="Dong, F., Hoefsloot, L. H., Schelen, A. M., Broeders, L. C. A. M., Meijer, Y., Veerman, A. J. P., Touw, I. P., Lowenberg, B. <strong>Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia.</strong> Proc. Nat. Acad. Sci. 91: 4480-4484, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7514305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7514305</a>] [<a href="https://doi.org/10.1073/pnas.91.10.4480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7514305">Dong et al. (1994)</a> suggested that the mutant receptor chain may act in a dominant-negative manner to block granulocyte maturation. <a href="#9" class="mim-tip-reference" title="Dong, F., Hoefsloot, L. H., Schelen, A. M., Broeders, L. C. A. M., Meijer, Y., Veerman, A. J. P., Touw, I. P., Lowenberg, B. <strong>Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia.</strong> Proc. Nat. Acad. Sci. 91: 4480-4484, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7514305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7514305</a>] [<a href="https://doi.org/10.1073/pnas.91.10.4480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7514305">Dong et al. (1994)</a> commented that congenital neutropenia may be a heterogeneous group of disorders with different basic etiologies. They also commented that cases of this disorder that terminated in acute leukemia had been reported (<a href="#11" class="mim-tip-reference" title="Gilman, P. A., Jackson, D. P., Guild, H. G. <strong>Congenital agranulocytosis: prolonged survival and terminal acute leukemia.</strong> Blood 36: 576-585, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4319697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4319697</a>]" pmid="4319697">Gilman et al., 1970</a>; <a href="#21" class="mim-tip-reference" title="Lui, V., Ragab, A. H., Findley, H., Frauen, B. <strong>Infantile genetic agranulocytosis and acute lymphocytic leukemia in two sibs.</strong> J. Pediat. 92: 1028, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/275472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">275472</a>] [<a href="https://doi.org/10.1016/s0022-3476(78)80399-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="275472">Lui et al., 1978</a>; <a href="#24" class="mim-tip-reference" title="Rosen, R. B., Kang, S.-J. <strong>Congenital agranulocytosis terminating in acute myelomonocytic leukemia.</strong> J. Pediat. 94: 406-408, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/284110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">284110</a>] [<a href="https://doi.org/10.1016/s0022-3476(79)80581-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="284110">Rosen and Kang, 1979</a>) and that some patients with the disorder developed leukemia or myelodysplastic syndrome following treatment with GCSF. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4319697+7514305+275472+284110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Dong, F., Brynes, R. K., Tidow, N., Welte, K., Lowenberg, B., Touw, I. P. <strong>Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia.</strong> New Eng. J. Med. 333: 487-493, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7542747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7542747</a>] [<a href="https://doi.org/10.1056/NEJM199508243330804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7542747">Dong et al. (1995)</a> described mutations in the GCSFR gene in hematopoietic cells from 2 patients with acute myeloid leukemia and histories of severe congenital neutropenia. Like the mutation in the patient reported by <a href="#9" class="mim-tip-reference" title="Dong, F., Hoefsloot, L. H., Schelen, A. M., Broeders, L. C. A. M., Meijer, Y., Veerman, A. J. P., Touw, I. P., Lowenberg, B. <strong>Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia.</strong> Proc. Nat. Acad. Sci. 91: 4480-4484, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7514305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7514305</a>] [<a href="https://doi.org/10.1073/pnas.91.10.4480" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7514305">Dong et al. (1994)</a>, the mutations truncated the C-terminal cytoplasmic region of the GCSF receptor. The mutation in one of the patients was already present in the neutropenic phase that preceded the development of acute myeloid leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7542747+7514305" 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>SCN patients are at increased risk of developing acute myelogenous leukemia (AML) or myelodysplasia (MDS). In the series of <a href="#30" class="mim-tip-reference" title="Welte, K., Dale, D. <strong>Pathophysiology and treatment of severe chronic neutropenia.</strong> Ann. Hemat. 72: 158-165, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8624368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8624368</a>] [<a href="https://doi.org/10.1007/s002770050156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8624368">Welte and Dale (1996)</a>, 10% of the patients with SCN followed for 5 or more years developed AML or MDS. Patients with GCSFR mutations appeared to be at the greatest risk; <a href="#31" class="mim-tip-reference" title="Welte, K., Touw, I. P. <strong>G-CSF receptor mutations in patients with severe chronic neutropenia: a step in leukemogenesis? (Abstract)</strong> Blood 90: 1921A only, 1997."None>Welte and Touw (1997)</a> found that 8 of 16 patients with SCN and GCSFR mutations developed AML or MDS. Conversely, no patients with SCN and without a mutation of the CSF3R gene had been reported who developed AML or MDS. This striking association led to speculation that CSF3R mutations may contribute to leukemogenesis in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8624368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Tidow, N., Pilz, C., Teichmann, B., Muller-Brechlin, A., Germeshausen, M., Kasper, B., Rauprich, P., Sykora, K.-W., Welte, K. <strong>Clinical relevance of point mutations in the cytoplasmic domain of the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia.</strong> Blood 89: 2369-2375, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9116280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9116280</a>]" pmid="9116280">Tidow et al. (1997)</a> concluded that GCSFR mutations are acquired abnormalities detected in the process of evolution to acute myelocytic leukemia (AML). <a href="#7" class="mim-tip-reference" title="Dale, D. C., Person, R. E., Bolyard, A. A., Aprikyan, A. G., Bos, C., Bonilla, M. A., Boxer, L. A., Kannourakis, G., Zeidler, C., Welte, K., Benson, K. F., Horwitz, M. <strong>Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.</strong> Blood 96: 2317-2322, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001877</a>]" pmid="11001877">Dale et al. (2000)</a> stated that prevalence data suggested that a minority of patients manifest this mutation, and it seemed much more likely that mutations of the ELA2 gene lead to compromised myeloid differentiation and create the risk for development of AML. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11001877+9116280" 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>Among 82 patients with SCN, <a href="#25" class="mim-tip-reference" title="Rosenberg, P. S., Alter, B. P., Link, D. C., Stein, S., Rodger, E., Bolyard, A. A., Aprikyan, A. A., Bonilla, M. A., Dror, Y., Kannourakis, G., Newburger, P. E., Boxer, L. A., Dale, D. C. <strong>Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia.</strong> Brit. J. Haemat. 140: 210-213, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18028488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18028488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18028488[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2007.06897.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18028488">Rosenberg et al. (2007)</a> found no difference in the risk of MDS/AML in patients with mutant ELA2 (63%) compared to those with wildtype ELA2 (37%). The cumulative incidences at 15 years were 36% and 25%, respectively. Two of 4 patients with the G185R mutation (<a href="/entry/130130#0011">130130.0011</a>) developed MDS/AML by 15 years follow-up, whereas none of 7 patients with the P110L (<a href="/entry/130130#0006">130130.0006</a>) mutation or 5 patients with the S97L (<a href="/entry/130130#0008">130130.0008</a>) mutation had developed MDS/AML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18028488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between autosomal dominant severe congenital neutropenia and variation in the TCIRG1 gene, see <a href="/entry/604592#0008">604592.0008</a>.</p>
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<p>To test the hypothesis that CSF3R mutations may contribute to leukemogenesis in SCN patients, <a href="#22" class="mim-tip-reference" title="McLemore, M. L., Poursine-Laurent, J., Link, D. C. <strong>Increased granulocyte colony-stimulating factor responsiveness but normal resting granulopoiesis in mice carrying a targeted granulocyte colony-stimulating factor receptor mutation derived from a patient with severe congenital neutropenia.</strong> J. Clin. Invest. 102: 483-492, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9691084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9691084</a>] [<a href="https://doi.org/10.1172/JCI3216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9691084">McLemore et al. (1998)</a> generated mice carrying a targeted, 'knock-in' mutation of their Csf3r gene that reproduced the mutation found in a patient with SCN and AML. A point mutation (C to T at nucleotide 2403) was introduced into exon 17 of the Csf3r gene, using homologous recombination in embryonic stem cells. The mutation generated a premature stop codon that led to truncation of the C-terminal 96 amino acids and reproduced the mutation found in a patient with SCN by <a href="#8" class="mim-tip-reference" title="Dong, F., Brynes, R. K., Tidow, N., Welte, K., Lowenberg, B., Touw, I. P. <strong>Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia.</strong> New Eng. J. Med. 333: 487-493, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7542747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7542747</a>] [<a href="https://doi.org/10.1056/NEJM199508243330804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7542747">Dong et al. (1995)</a>. The mutant allele was expressed in a myeloid-specific fashion at levels comparable to the wildtype allele. Mice heterozygous or homozygous for this mutation had normal levels of circulating neutrophils and no evidence for a block in myeloid maturation, indicating that resting granulopoiesis was normal. However, in response to GCSF treatment, these mice demonstrated a significantly greater increase in the level of circulating neutrophils. This effect appeared to be due to increased neutrophil production as the absolute number of GCSF-responsive progenitors in the bone marrow and their proliferation in response to GCSF was increased. Furthermore, the in vitro survival and GCSF-dependent suppression of apoptosis of mutant neutrophils were normal. Despite this evidence for a hyperproliferative response to GCSF, no cases of AML were detected. These data demonstrated that the GCSFR mutation found in patients with SCN is not sufficient to induce either an SCN phenotype or AML in mice. <a href="#22" class="mim-tip-reference" title="McLemore, M. L., Poursine-Laurent, J., Link, D. C. <strong>Increased granulocyte colony-stimulating factor responsiveness but normal resting granulopoiesis in mice carrying a targeted granulocyte colony-stimulating factor receptor mutation derived from a patient with severe congenital neutropenia.</strong> J. Clin. Invest. 102: 483-492, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9691084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9691084</a>] [<a href="https://doi.org/10.1172/JCI3216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9691084">McLemore et al. (1998)</a> suggested that the results represent strong evidence that these mutations are not responsible for the impaired granulopoiesis present in patients with SCN. In fact, the results of the study suggested that expression of the mutant GCSFR on myeloid progenitors may render them hyperresponsive to GCSF. Whether this altered GCSF-responsiveness contributes to the development of AML and/or MDS in patients with SCN will require further study. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9691084+7542747" 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>At about the same time as the report by <a href="#22" class="mim-tip-reference" title="McLemore, M. L., Poursine-Laurent, J., Link, D. C. <strong>Increased granulocyte colony-stimulating factor responsiveness but normal resting granulopoiesis in mice carrying a targeted granulocyte colony-stimulating factor receptor mutation derived from a patient with severe congenital neutropenia.</strong> J. Clin. Invest. 102: 483-492, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9691084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9691084</a>] [<a href="https://doi.org/10.1172/JCI3216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9691084">McLemore et al. (1998)</a>, <a href="#14" class="mim-tip-reference" title="Hermans, M. H. A., Ward, A. C., Antonissen, C., Karis, A., Lowenberg, B., Touw, I. P. <strong>Perturbed granulopoiesis in mice with a targeted mutation in the granulocyte colony-stimulating factor receptor gene associated with severe chronic neutropenia.</strong> Blood 92: 32-39, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9639496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9639496</a>]" pmid="9639496">Hermans et al. (1998)</a> reported that mice either heterozygous or homozygous for a mutation in the Csf3r gene had no normal resting granulopoiesis and had reduced numbers of neutrophils in their blood, indicating a block in maturation due to the truncation of the GCSF receptor. <a href="#15" class="mim-tip-reference" title="Hermans, M. <strong>Personal Communication.</strong> Rotterdam, The Netherlands 11/25/1998."None>Hermans (1998)</a> suggested that the increased expression of truncated GCSF receptor in the model of <a href="#22" class="mim-tip-reference" title="McLemore, M. L., Poursine-Laurent, J., Link, D. C. <strong>Increased granulocyte colony-stimulating factor responsiveness but normal resting granulopoiesis in mice carrying a targeted granulocyte colony-stimulating factor receptor mutation derived from a patient with severe congenital neutropenia.</strong> J. Clin. Invest. 102: 483-492, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9691084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9691084</a>] [<a href="https://doi.org/10.1172/JCI3216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9691084">McLemore et al. (1998)</a> may have compensated for the mutation and explained the absence of neutropenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9691084+9639496" 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="#13" class="mim-tip-reference" title="Hedenberg, F. <strong>Infantile agranulocytosis of probably congenital origin.</strong> Acta Paediat. 48: 77-84, 1959.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13626582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13626582</a>]" pmid="13626582">Hedenberg (1959)</a> found that addition of sulfur-containing amino acids to tissue cultures led to maturation of white cells. <a href="#19" class="mim-tip-reference" title="L'Esperance, P. L., Brunning, R., Good, R. A. <strong>Congenital neutropenia: in vitro growth of colonies mimicking the disease.</strong> Proc. Nat. Acad. Sci. 70: 669-672, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4514979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4514979</a>] [<a href="https://doi.org/10.1073/pnas.70.3.669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4514979">L'Esperance et al. (1973)</a> showed that the disease could be reproduced in tissue culture. <a href="#2" class="mim-tip-reference" title="Barak, Y., Paran, M., Levin, S., Sachs, L. <strong>In vitro induction of myeloid proliferation and maturation in infantile genetic agranulocytosis.</strong> Blood 38: 74-80, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4326838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4326838</a>]" pmid="4326838">Barak et al. (1971)</a> also cultured marrow cells from a patient with this disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4514979+13626582+4326838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="L'Esperance, P. L., Brunning, R., Deinard, A. S., Park, B. H., Biggar, W. D., Good, R. A. <strong>Congenital neutropenia: impaired maturation with diminished stem-cell input.In: Bergsma, D. : Immunodeficiency in Man and Animals.</strong> New York: National Foundation-March of Dimes (pub.) 1975. Pp. 59-65."None>L'Esperance et al. (1975)</a> proposed heterogeneity of this disorder because in soft agar cultures of bone marrow one patient showed 'loose' colonies developing only to promyelocytes, whereas a second produced normal neutrophil colonies. Maturation arrest occurs at the promyelocyte stage.</p><p><a href="#12" class="mim-tip-reference" title="Hansen, J. A., Dupont, B., L'Esperance, P. L., Good, R. A. <strong>Congenital neutropenia: abnormal neutrophil differentiation associated with HLA.</strong> Immunogenetics 4: 327-332, 1977."None>Hansen et al. (1977)</a> found association with HLA-B12 (see <a href="/entry/142830">142830</a>) and postulated linkage disequilibrium. A gene controlling neutrophil differentiation was presumably closely linked to the HLA complex. <a href="#12" class="mim-tip-reference" title="Hansen, J. A., Dupont, B., L'Esperance, P. L., Good, R. A. <strong>Congenital neutropenia: abnormal neutrophil differentiation associated with HLA.</strong> Immunogenetics 4: 327-332, 1977."None>Hansen et al. (1977)</a> suggested that the relationship may reflect a basic function of the histocompatibility system, namely, coding for cell-surface determinants fundamental to cell-cell recognition and to control of cellular differentiation.</p>
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<a href="#Andrews1960" class="mim-tip-reference" title="Andrews, J. P., McClellan, J. T., Scott, C. H. <strong>Lethal congenital neutropenia with eosinophilia occurring in two siblings.</strong> Am. J. Med. 29: 358-362, 1960.">Andrews et al. (1960)</a>; <a href="#Bjure1962" class="mim-tip-reference" title="Bjure, J., Nilsson, L. R., Plum, C. M. <strong>Familial neutropenia possibly caused by deficiency of a plasma factor.</strong> Acta Paediat. 51: 497-508, 1962.">Bjure et al. (1962)</a>
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Andrews, J. P., McClellan, J. T., Scott, C. H.
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<strong>Lethal congenital neutropenia with eosinophilia occurring in two siblings.</strong>
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Am. J. Med. 29: 358-362, 1960.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13683481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13683481</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13683481" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0002-9343(60)90031-0" target="_blank">Full Text</a>]
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Barak, Y., Paran, M., Levin, S., Sachs, L.
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<strong>In vitro induction of myeloid proliferation and maturation in infantile genetic agranulocytosis.</strong>
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Blood 38: 74-80, 1971.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4326838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4326838</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4326838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Acta Paediat. 51: 497-508, 1962.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13971340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13971340</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13971340" 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.1651-2227.1962.tb06574.x" target="_blank">Full Text</a>]
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Bonilla, M. A., Dale, D., Zeidler, C., Last, L., Reiter, A., Ruggeiro, M., Davis, M., Koci, B., Hammond, W., Gillio, A., Welte, K.
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<strong>Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias.</strong>
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Brit. J. Haemat. 88: 723-730, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7529539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7529539</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7529539" 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.1365-2141.1994.tb05110.x" target="_blank">Full Text</a>]
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Bonilla, M. A., Gillio, A. P., Ruggeiro, M., Kernan, N. A., Brochstein, J. A., Abboud, M., Fumagalli, L., Vincent, M., Gabrilove, J. L., Welte, K., Souza, L. M., O'Reilly, R. J.
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<strong>Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis.</strong>
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New Eng. J. Med. 320: 1574-1580, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2471075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2471075</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2471075" 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/10.1056/NEJM198906153202402" target="_blank">Full Text</a>]
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Rosenberg, P. S., Alter, B. P., Link, D. C., Stein, S., Rodger, E., Bolyard, A. A., Aprikyan, A. A., Bonilla, M. A., Dror, Y., Kannourakis, G., Newburger, P. E., Boxer, L. A., Dale, D. C.
|
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<strong>Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia.</strong>
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Brit. J. Haemat. 140: 210-213, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18028488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18028488</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18028488[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=18028488" 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.1365-2141.2007.06897.x" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Skokowa2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Skokowa, J., Cario, G., Uenalan, M., Schambach, A., Germeshausen, M., Battmer, K., Zeidler, C., Lehmann, U., Eder, M., Baum, C., Grosschedl, R., Stanulla, M., Scherr, M., Welte, K.
|
|
<strong>LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia.</strong>
|
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Nature Med. 12: 1191-1197, 2006. Note: Erratum: Nature Med. 12: 1329 only, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17063141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17063141</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17063141" 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/nm1474" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Skokowa2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Skokowa, J., Germeshausen, M., Zeidler, C., Welte, K.
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<strong>Severe congenital neutropenia: inheritance and pathophysiology.</strong>
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Curr. Opin. Hemat. 14: 22-28, 2007. Note: Erratum: Curr. Opin. Hemat. 14: 181 only, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17133096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17133096</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17133096" 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/10.1097/00062752-200701000-00006" target="_blank">Full Text</a>]
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<a id="28" class="mim-anchor"></a>
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<a id="Smith2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Smith, B. N., Ancliff, P. J., Pizzey, A., Khwaja, A., Linch, D. C., Gale, R. E.
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<strong>Homozygous HAX1 mutations in severe congenital neutropenia patients with sporadic disease: a novel mutation in two unrelated British kindreds.</strong>
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Brit. J. Haemat. 144: 762-770, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19036076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19036076</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19036076" 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.1365-2141.2008.07493.x" target="_blank">Full Text</a>]
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</p>
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<a id="29" class="mim-anchor"></a>
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<a id="Tidow1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tidow, N., Pilz, C., Teichmann, B., Muller-Brechlin, A., Germeshausen, M., Kasper, B., Rauprich, P., Sykora, K.-W., Welte, K.
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<strong>Clinical relevance of point mutations in the cytoplasmic domain of the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia.</strong>
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Blood 89: 2369-2375, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9116280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9116280</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9116280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="30" class="mim-anchor"></a>
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<a id="Welte1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Welte, K., Dale, D.
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<strong>Pathophysiology and treatment of severe chronic neutropenia.</strong>
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Ann. Hemat. 72: 158-165, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8624368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8624368</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8624368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s002770050156" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Welte1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Welte, K., Touw, I. P.
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<strong>G-CSF receptor mutations in patients with severe chronic neutropenia: a step in leukemogenesis? (Abstract)</strong>
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Blood 90: 1921A only, 1997.
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</p>
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<li>
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<a id="32" class="mim-anchor"></a>
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<a id="Yakisan1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yakisan, E., Schirg, E., Zeidler, C., Bishop, N. J., Reiter, A., Hirt, A., Riehm, H., Welte, K.
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<strong>High incidence of significant bone loss in patients with severe congenital neutropenia (Kostmann's syndrome).</strong>
|
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J. Pediat. 131: 592-597, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9386665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9386665</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9386665" 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(97)70068-4" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<br />
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</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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Cassandra L. Kniffin - updated : 01/29/2020
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 6/30/2016<br>Cassandra L. Kniffin - updated : 6/18/2009<br>Cassandra L. Kniffin - updated : 2/11/2009<br>Cassandra L. Kniffin - updated : 5/21/2008<br>Anne M. Stumpf - reorganized : 2/1/2007<br>Victor A. McKusick - updated : 1/30/2007<br>Cassandra L. Kniffin - updated : 10/17/2006<br>Victor A. McKusick - updated : 9/17/2004<br>Victor A. McKusick - updated : 6/3/2003<br>Victor A. McKusick - updated : 1/9/2001<br>Victor A. McKusick - updated : 1/4/2001<br>Ada Hamosh - updated : 11/6/2000<br>Victor A. McKusick - updated : 9/28/2000<br>Victor A. McKusick - updated : 12/4/1998<br>Victor A. McKusick - updated : 10/1/1998<br>Moyra Smith - updated : 12/18/1997
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/2/1986
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div 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 : 04/03/2024
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/12/2024<br>ckniffin : 01/10/2024<br>alopez : 10/04/2023<br>ckniffin : 10/04/2023<br>alopez : 08/02/2023<br>carol : 04/11/2022<br>ckniffin : 03/28/2022<br>alopez : 01/31/2020<br>ckniffin : 01/29/2020<br>carol : 07/18/2018<br>carol : 07/06/2016<br>carol : 7/5/2016<br>carol : 7/5/2016<br>ckniffin : 6/30/2016<br>carol : 9/23/2014<br>mcolton : 9/23/2014<br>ckniffin : 9/22/2014<br>carol : 8/7/2014<br>carol : 7/14/2014<br>ckniffin : 7/10/2014<br>ckniffin : 7/16/2013<br>terry : 3/14/2013<br>wwang : 6/8/2011<br>ckniffin : 6/7/2011<br>wwang : 6/7/2011<br>mgross : 10/29/2009<br>wwang : 7/22/2009<br>ckniffin : 6/18/2009<br>wwang : 4/6/2009<br>ckniffin : 2/11/2009<br>wwang : 1/26/2009<br>ckniffin : 1/21/2009<br>wwang : 5/27/2008<br>ckniffin : 5/21/2008<br>wwang : 2/27/2007<br>wwang : 2/26/2007<br>alopez : 2/1/2007<br>alopez : 2/1/2007<br>terry : 1/30/2007<br>wwang : 12/11/2006<br>wwang : 10/25/2006<br>ckniffin : 10/17/2006<br>ckniffin : 10/17/2006<br>alopez : 9/17/2004<br>terry : 9/17/2004<br>terry : 6/2/2004<br>alopez : 7/28/2003<br>alopez : 6/3/2003<br>terry : 6/3/2003<br>carol : 3/20/2002<br>mcapotos : 12/17/2001<br>terry : 12/13/2001<br>mcapotos : 1/22/2001<br>mcapotos : 1/22/2001<br>mcapotos : 1/12/2001<br>terry : 1/9/2001<br>terry : 1/4/2001<br>carol : 11/6/2000<br>carol : 11/6/2000<br>mcapotos : 10/17/2000<br>mcapotos : 10/16/2000<br>terry : 9/28/2000<br>carol : 12/8/1998<br>terry : 12/4/1998<br>terry : 11/18/1998<br>carol : 10/6/1998<br>terry : 10/1/1998<br>dkim : 9/11/1998<br>mark : 1/30/1998<br>mark : 1/30/1998<br>alopez : 6/10/1997<br>terry : 5/10/1997<br>mark : 3/11/1996<br>terry : 3/4/1996<br>mark : 2/13/1996<br>mimadm : 11/12/1995<br>mark : 10/9/1995<br>carol : 1/24/1995<br>davew : 8/15/1994<br>jason : 6/13/1994<br>warfield : 3/7/1994
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<h3>
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<span class="mim-font">
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<strong>#</strong> 202700
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<h3>
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<span class="mim-font">
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NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT; SCN1
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</h3>
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<span class="mim-text-font">
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<strong>ORPHA:</strong> 486;
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<strong>DO:</strong> 0080625;
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</span>
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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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<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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<tbody>
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<span class="mim-font">
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19p13.3
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</td>
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<td>
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<span class="mim-font">
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Neutropenia, severe congenital 1, autosomal dominant
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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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202700
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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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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ELANE
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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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130130
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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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<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 severe congenital neutropenia-1 (SCN1) is caused by heterozygous mutation in the neutrophil elastase gene (ELANE; 130130) on chromosome 19p13.</p><p>See also cyclic neutropenia (162800), which is an allelic disorder.</p>
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<div>
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<br />
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</div>
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<strong>Description</strong>
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<p>Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections (Skokowa et al., 2007). About 60% of affected individuals of European and Middle Eastern ancestry have dominant ELANE mutations, resulting in a form of severe congenital neutropenia, which is designated here as SCN1. </p><p><strong><em>Genetic Heterogeneity of Severe Congenital Neutropenia</em></strong></p><p>
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Severe congenital neutropenia is a genetically heterogeneous disorder showing autosomal dominant, autosomal recessive, and X-linked inheritance. Other autosomal dominant forms are SCN2 (613107), caused by mutation in the protooncogene GFI1 (600871) on 1p22; SCN8 (618752), caused by mutation in the SRP54 gene (604857) on 14q13; SCN9 (619813), caused by mutation in the CLPB gene (616254) on 11q13; and SCN11 (620674), caused by mutation in the SEC61A1 gene (609213) on chromosome 3q21.</p><p>Autosomal recessive forms include SCN3 (610738), caused by mutation in the HAX1 gene (605998) on 1q21; SCN4 (612541), caused by mutation in the G6PC3 gene (611045) on 17q21; SCN5 (615285), caused by mutation in the VPS45 gene (610035) on 1q21; SCN6 (616022), caused by mutation in the JAGN1 gene (616012) on 3p25; SCN7 (617014), caused by mutation in the CSF3R gene (138971) on 1p34; and SCN10 (620534), caused by mutation in the SRP68 gene (604858) on chromosome 17q25.</p><p>X-linked SCN (SCNX; 300299) is caused by mutation in the WAS gene (300392) on Xp11.</p><p>See also adult chronic idiopathic nonimmune neutropenia (607847) and chronic benign familial neutropenia (162700).</p><p><strong><em>Susceptibility to Myelodysplastic Syndrome/Acute Myeloid Leukemia</em></strong></p><p>
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SCN patients with acquired mutations in the granulocyte colony-stimulating factor receptor (CSF3R; 138971) in hematopoietic cells define a group with high risk for progression to myelodysplastic syndrome and/or acute myeloid leukemia. Approximately 80% of SCN patients who develop AML are heterozygous for somatic CSF3R mutations (summary by Klimiankou et al., 2016). </p>
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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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<p>Gilman et al. (1970) described prolonged survival and death from acute monocytic leukemia at age 14 years and 10 months. About three-fourths of patients die before age 3 years. Fungal and viral infections had not been a problem. </p><p>Freedman et al. (2000) stated that the Severe Chronic Neutropenia International Registry (SCNIR) in Seattle had data on 696 neutropenic patients, including 352 patients with congenital neutropenia, treated with GCSF from 1987 to 2000. The 352 congenital patients were observed for a mean of 6 years (range, 0.1 to 11 years) while being treated. Of these patients, 31 developed myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), for a crude rate of malignant transformation of nearly 9%. None of the 344 patients with idiopathic or cyclic neutropenia developed MDS/AML. Transformation was associated with acquired marrow cytogenetic clonal changes: 18 patients developed a partial or complete loss of chromosome 7, and 9 patients manifested abnormalities of chromosome 21 (usually trisomy 21; 190685). For each yearly treatment interval, the annual rate of MDS/AML development was less than 2%. Freedman et al. (2000) concluded that although the data did not support a cause-and-effect relationship between development of MDS/AML and GCSF therapy or other patient demographics, they could not exclude a direct contribution of GCSF in the pathogenesis of MDS/AML. Improved survival of congenital neutropenia patients receiving GCSF therapy may allow time for expression of the leukemic predisposition that characterizes the natural history of these disorders. </p><p>In a review of immunodeficiencies caused by defects in phagocytes, Lekstrom-Himes and Gallin (2000) discussed severe congenital neutropenia. </p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Management</strong>
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<p>Bonilla et al. (1989) administered recombinant human granulocyte colony-stimulating factor (GCSF; 138970) to 5 patients. All 5 patients showed a response and had sustained neutrophil counts of 1,000 cells per microliter or more for 9 to 13 months while receiving subcutaneous maintenance therapy. Preexisting chronic infections resolved and the number of new infectious episodes decreased. Bonilla et al. (1989) raised the possibility that the receptors are defective and do not respond to GCSF unless it is administered in pharmacologic doses. This possibility appeared to be confirmed by the findings of Dong et al. (1994) of somatic mutation in the GCSFR gene (138971). </p><p>In SCN, absolute neutrophil counts are usually less than 200 cells per cubic millimeter, with a remainder of the blood counts relatively normal (Dale et al., 2000). Treatment with GCSF leads to an increase in neutrophil counts to more than 1,000 cells per cubic millimeter in 90% of patients and results in significant improvements in survival and quality of life (Dale et al., 1993; Bonilla et al., 1994). </p><p>Yakisan et al. (1997) noted that although r-metHuGCSF treatment of children with severe congenital neutropenia has substantially improved the patients' quality of life and life expectancy, bone pain and unusual fractures have been reported in treated patients. The authors reviewed roentgenograms in 29 of 30 patients to evaluate bone loss before and during treatment and assessed bone mineral status in 17 of the 30 patients. Their data indicated a high incidence of bone mineral loss in children with severe congenital neutropenia. The investigators concluded that it is more likely that the bone loss was caused by the pathophysiologic features of the underlying disease; however, they could not rule out the possibility that r-metHuGCSF accelerates bone mineral loss. </p>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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<span class="mim-text-font">
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<p>Myeloid precursor cells from patients with severe congenital neutropenia (SCN) require pharmacologic dosages of recombinant human granulocyte colony-stimulating factor (GCSF) to differentiate normal neutrophils. Because JAK2 (147796), a nonreceptor tyrosine kinase, is involved in the signaling pathway of GCSF, Rauprich et al. (1995) studied the expression and activity of JAK2 in neutrophils from SCN patients during therapy. The immunoprecipitated JAK2 protein showed increased tyrosine phosphorylation in neutrophils from SCN patients as compared with that in neutrophils from healthy controls. Rauprich et al. (1995) pointed out that only a few patients, who subsequently develop acute myeloid leukemia, have a point mutation in the cytoplasmic region of the GCSF receptor, resulting in a truncation from the C terminus of the receptor and an inability of the receptor to transduce the signal on GCSF stimulation. Thus they suspected that various defects are responsible for SCN. That pharmacologic doses of GCSF are required to overcome the neutropenia suggested a defect of other specific molecules in the GCSF signal transduction pathway. The primary defect does not appear to be in JAK2; it may be that the phosphotyrosines on the receptor create binding sites for STAT proteins (signal transducers and activators of transcription; see 600555). </p><p>Skokowa et al. (2006) found significantly decreased or absent LEF1 (153245) expression in arrested promyelocytes from patients with congenital neutropenia. LEF1 decrease resulted in defective expression of downstream target genes, including CCND1 (168461), MYC (190080), and BIRC5 (603352). Promyelocytes from healthy individuals showed highest LEF1 expression. Reconstitution of LEF1 in early hematopoietic progenitors from 2 individuals with congenital neutropenia resulted in the differentiation of these progenitors into mature granulocytes. LEF1 directly bound to and regulated the transcription factor CEBPA (116897). The findings indicated that LEF1 plays a role in granulopoiesis. </p>
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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 class="mim-text-font">
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<p>The transmission pattern of SCN1 in the patients reported by Dale et al. (2000) was consistent with autosomal dominant inheritance. </p>
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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 class="mim-text-font">
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<p>After demonstrating mutations in the ELA2 gene (ELANE; 130130) in patients with cyclic neutropenia (162800), Dale et al. (2000) hypothesized that congenital neutropenia is also due to mutation in this gene. They performed mutation analysis by sequencing PCR-amplified genomic DNA for each of the 5 exons of the ELA2 gene and 20 bases of the flanking regions. In 22 of 25 patients with congenital neutropenia, 18 different heterozygous mutations were found. All 4 patients with cyclic neutropenia, but none of the 3 patients with Shwachman-Diamond syndrome (260400), had mutations of ELA2. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. In the congenital neutropenia patients, 5 different mutations were found in families with 2 or more affected members. Three instances of father-daughter pairs, 1 mother-son pair, and 1 mother with 2 affected sons by different fathers suggested autosomal dominant inheritance. </p><p>Ishikawa et al. (2008) identified heterozygous mutations in the ELA2 gene in 11 (61%) of 18 Japanese patients with severe congenital neutropenia. Five (28%) patients had SCN3 (610738) due to mutation in the HAX1 gene. </p><p>Among 109 probands with SCN, Smith et al. (2008) found that 33 (30%) had 24 different ELA2 mutations, 2 (2%) had WAS (300392) mutations, and 4 (4%) had HAX1 mutations. </p><p><strong><em>Progression to Myelodysplastic Syndrome and Acute Myeloid Leukemia</em></strong></p><p>
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Dong et al. (1994) used RT-PCR to amplify cDNA for granulocyte colony-stimulating factor receptor (CSF3R; 138971) in patients with severe congenital neutropenia, referred to as Kostmann syndrome, and screened for mutations by single-strand conformation polymorphism (SSCP) analysis. In 1 patient, they identified a somatic point mutation that resulted in the cytoplasmic truncation of the GCSF receptor protein. The mutation was present predominantly in the granulocytic lineage. Further functional characterization demonstrated that the truncated receptor was unable to transduce a maturation signal. Dong et al. (1994) suggested that the mutant receptor chain may act in a dominant-negative manner to block granulocyte maturation. Dong et al. (1994) commented that congenital neutropenia may be a heterogeneous group of disorders with different basic etiologies. They also commented that cases of this disorder that terminated in acute leukemia had been reported (Gilman et al., 1970; Lui et al., 1978; Rosen and Kang, 1979) and that some patients with the disorder developed leukemia or myelodysplastic syndrome following treatment with GCSF. </p><p>Dong et al. (1995) described mutations in the GCSFR gene in hematopoietic cells from 2 patients with acute myeloid leukemia and histories of severe congenital neutropenia. Like the mutation in the patient reported by Dong et al. (1994), the mutations truncated the C-terminal cytoplasmic region of the GCSF receptor. The mutation in one of the patients was already present in the neutropenic phase that preceded the development of acute myeloid leukemia. </p><p>SCN patients are at increased risk of developing acute myelogenous leukemia (AML) or myelodysplasia (MDS). In the series of Welte and Dale (1996), 10% of the patients with SCN followed for 5 or more years developed AML or MDS. Patients with GCSFR mutations appeared to be at the greatest risk; Welte and Touw (1997) found that 8 of 16 patients with SCN and GCSFR mutations developed AML or MDS. Conversely, no patients with SCN and without a mutation of the CSF3R gene had been reported who developed AML or MDS. This striking association led to speculation that CSF3R mutations may contribute to leukemogenesis in these patients. </p><p>Tidow et al. (1997) concluded that GCSFR mutations are acquired abnormalities detected in the process of evolution to acute myelocytic leukemia (AML). Dale et al. (2000) stated that prevalence data suggested that a minority of patients manifest this mutation, and it seemed much more likely that mutations of the ELA2 gene lead to compromised myeloid differentiation and create the risk for development of AML. </p><p>Among 82 patients with SCN, Rosenberg et al. (2007) found no difference in the risk of MDS/AML in patients with mutant ELA2 (63%) compared to those with wildtype ELA2 (37%). The cumulative incidences at 15 years were 36% and 25%, respectively. Two of 4 patients with the G185R mutation (130130.0011) developed MDS/AML by 15 years follow-up, whereas none of 7 patients with the P110L (130130.0006) mutation or 5 patients with the S97L (130130.0008) mutation had developed MDS/AML. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between autosomal dominant severe congenital neutropenia and variation in the TCIRG1 gene, see 604592.0008.</p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>To test the hypothesis that CSF3R mutations may contribute to leukemogenesis in SCN patients, McLemore et al. (1998) generated mice carrying a targeted, 'knock-in' mutation of their Csf3r gene that reproduced the mutation found in a patient with SCN and AML. A point mutation (C to T at nucleotide 2403) was introduced into exon 17 of the Csf3r gene, using homologous recombination in embryonic stem cells. The mutation generated a premature stop codon that led to truncation of the C-terminal 96 amino acids and reproduced the mutation found in a patient with SCN by Dong et al. (1995). The mutant allele was expressed in a myeloid-specific fashion at levels comparable to the wildtype allele. Mice heterozygous or homozygous for this mutation had normal levels of circulating neutrophils and no evidence for a block in myeloid maturation, indicating that resting granulopoiesis was normal. However, in response to GCSF treatment, these mice demonstrated a significantly greater increase in the level of circulating neutrophils. This effect appeared to be due to increased neutrophil production as the absolute number of GCSF-responsive progenitors in the bone marrow and their proliferation in response to GCSF was increased. Furthermore, the in vitro survival and GCSF-dependent suppression of apoptosis of mutant neutrophils were normal. Despite this evidence for a hyperproliferative response to GCSF, no cases of AML were detected. These data demonstrated that the GCSFR mutation found in patients with SCN is not sufficient to induce either an SCN phenotype or AML in mice. McLemore et al. (1998) suggested that the results represent strong evidence that these mutations are not responsible for the impaired granulopoiesis present in patients with SCN. In fact, the results of the study suggested that expression of the mutant GCSFR on myeloid progenitors may render them hyperresponsive to GCSF. Whether this altered GCSF-responsiveness contributes to the development of AML and/or MDS in patients with SCN will require further study. </p><p>At about the same time as the report by McLemore et al. (1998), Hermans et al. (1998) reported that mice either heterozygous or homozygous for a mutation in the Csf3r gene had no normal resting granulopoiesis and had reduced numbers of neutrophils in their blood, indicating a block in maturation due to the truncation of the GCSF receptor. Hermans (1998) suggested that the increased expression of truncated GCSF receptor in the model of McLemore et al. (1998) may have compensated for the mutation and explained the absence of neutropenia. </p>
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</span>
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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>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>Hedenberg (1959) found that addition of sulfur-containing amino acids to tissue cultures led to maturation of white cells. L'Esperance et al. (1973) showed that the disease could be reproduced in tissue culture. Barak et al. (1971) also cultured marrow cells from a patient with this disease. </p><p>L'Esperance et al. (1975) proposed heterogeneity of this disorder because in soft agar cultures of bone marrow one patient showed 'loose' colonies developing only to promyelocytes, whereas a second produced normal neutrophil colonies. Maturation arrest occurs at the promyelocyte stage.</p><p>Hansen et al. (1977) found association with HLA-B12 (see 142830) and postulated linkage disequilibrium. A gene controlling neutrophil differentiation was presumably closely linked to the HLA complex. Hansen et al. (1977) suggested that the relationship may reflect a basic function of the histocompatibility system, namely, coding for cell-surface determinants fundamental to cell-cell recognition and to control of cellular differentiation.</p>
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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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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Andrews et al. (1960); Bjure et al. (1962)
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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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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Andrews, J. P., McClellan, J. T., Scott, C. H.
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<strong>Lethal congenital neutropenia with eosinophilia occurring in two siblings.</strong>
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Am. J. Med. 29: 358-362, 1960.
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[PubMed: 13683481]
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[Full Text: https://doi.org/10.1016/0002-9343(60)90031-0]
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</p>
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<li>
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<p class="mim-text-font">
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Barak, Y., Paran, M., Levin, S., Sachs, L.
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<strong>In vitro induction of myeloid proliferation and maturation in infantile genetic agranulocytosis.</strong>
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Blood 38: 74-80, 1971.
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[PubMed: 4326838]
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<p class="mim-text-font">
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Bjure, J., Nilsson, L. R., Plum, C. M.
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<strong>Familial neutropenia possibly caused by deficiency of a plasma factor.</strong>
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Acta Paediat. 51: 497-508, 1962.
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[PubMed: 13971340]
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[Full Text: https://doi.org/10.1111/j.1651-2227.1962.tb06574.x]
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<p class="mim-text-font">
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Bonilla, M. A., Dale, D., Zeidler, C., Last, L., Reiter, A., Ruggeiro, M., Davis, M., Koci, B., Hammond, W., Gillio, A., Welte, K.
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<strong>Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias.</strong>
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Brit. J. Haemat. 88: 723-730, 1994.
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[PubMed: 7529539]
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[Full Text: https://doi.org/10.1111/j.1365-2141.1994.tb05110.x]
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Bonilla, M. A., Gillio, A. P., Ruggeiro, M., Kernan, N. A., Brochstein, J. A., Abboud, M., Fumagalli, L., Vincent, M., Gabrilove, J. L., Welte, K., Souza, L. M., O'Reilly, R. J.
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<strong>Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis.</strong>
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New Eng. J. Med. 320: 1574-1580, 1989.
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[PubMed: 2471075]
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[Full Text: https://doi.org/10.1056/NEJM198906153202402]
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Dale, D. C., Bonilla, M. A., Davis, M. W., Nakanishi, A. M., Hammond, W. P., Kurtzberg, J., Wang, W., Jakubowski, A., Winton, E., Lalezari, P., Robinson, W., Glaspy, J. A., Emerson, S., Gabrilove, J., Vincent, M., Boxer, L. A.
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<strong>A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia.</strong>
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Blood 81: 2496-2502, 1993.
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[PubMed: 8490166]
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<p class="mim-text-font">
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Dale, D. C., Person, R. E., Bolyard, A. A., Aprikyan, A. G., Bos, C., Bonilla, M. A., Boxer, L. A., Kannourakis, G., Zeidler, C., Welte, K., Benson, K. F., Horwitz, M.
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<strong>Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.</strong>
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Blood 96: 2317-2322, 2000.
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[PubMed: 11001877]
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<li>
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<p class="mim-text-font">
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Dong, F., Brynes, R. K., Tidow, N., Welte, K., Lowenberg, B., Touw, I. P.
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<strong>Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia.</strong>
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New Eng. J. Med. 333: 487-493, 1995.
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[PubMed: 7542747]
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[Full Text: https://doi.org/10.1056/NEJM199508243330804]
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</li>
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<li>
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<p class="mim-text-font">
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Dong, F., Hoefsloot, L. H., Schelen, A. M., Broeders, L. C. A. M., Meijer, Y., Veerman, A. J. P., Touw, I. P., Lowenberg, B.
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<strong>Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia.</strong>
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Proc. Nat. Acad. Sci. 91: 4480-4484, 1994.
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[PubMed: 7514305]
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[Full Text: https://doi.org/10.1073/pnas.91.10.4480]
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</li>
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<li>
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<p class="mim-text-font">
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Freedman, M. H., Bonilla, M. A., Fier, C., Bolyard, A. A., Scarlata, D., Boxer, L. A., Brown, S., Cham, B., Kannourakis, G., Kinsey, S. E., Mori, P. G., Cottle, T., Welte, K., Dale, D. C.
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<strong>Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy.</strong>
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Cassandra L. Kniffin - updated : 01/29/2020<br>Cassandra L. Kniffin - updated : 6/30/2016<br>Cassandra L. Kniffin - updated : 6/18/2009<br>Cassandra L. Kniffin - updated : 2/11/2009<br>Cassandra L. Kniffin - updated : 5/21/2008<br>Anne M. Stumpf - reorganized : 2/1/2007<br>Victor A. McKusick - updated : 1/30/2007<br>Cassandra L. Kniffin - updated : 10/17/2006<br>Victor A. McKusick - updated : 9/17/2004<br>Victor A. McKusick - updated : 6/3/2003<br>Victor A. McKusick - updated : 1/9/2001<br>Victor A. McKusick - updated : 1/4/2001<br>Ada Hamosh - updated : 11/6/2000<br>Victor A. McKusick - updated : 9/28/2000<br>Victor A. McKusick - updated : 12/4/1998<br>Victor A. McKusick - updated : 10/1/1998<br>Moyra Smith - updated : 12/18/1997
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