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<title>
Entry
- #614470 - RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER; RALD
- OMIM
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<span class="h4">#614470</span>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/614470"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
<div class="panel-body small mim-panel-body">
<div><a href="https://clinicaltrials.gov/search?cond=(RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER) OR (KRAS OR NRAS)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=20165&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>
<div><a href="https://www.diseaseinfosearch.org/x/7779" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=614470[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>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=268114" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0110117" 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>
<div><a href="http://www.informatics.jax.org/disease/614470" 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>
<div><a href="https://omia.org/OMIA001990/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0110117" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<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.">
&nbsp;
</span>
</span>
</div>
<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">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 723508002<br />
<strong>ORPHA:</strong> 268114<br />
<strong>DO:</strong> 0110117<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
614470
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER; RALD
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IV; ALPS4
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/943?start=-3&limit=10&highlight=943">
1p13.2
</a>
</span>
</td>
<td>
<span class="mim-font">
?RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
</span>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614470"> 614470 </a>
</span>
</td>
<td>
<span class="mim-font">
</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">
NRAS
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/164790"> 164790 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/240?start=-3&limit=10&highlight=240">
12p12.1
</a>
</span>
</td>
<td>
<span class="mim-font">
RAS-associated autoimmune leukoproliferative disorder
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614470"> 614470 </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">
KRAS
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/190070"> 190070 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/614470" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/614470" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/614470" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal 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 />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Recurrent respiratory infections (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806482&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806482</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002205" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002205</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002205" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002205</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Liver </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hepatomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80515008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80515008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019209&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019209</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002240" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002240</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spleen </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Splenomegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16294009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16294009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R16.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R16.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/789.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">789.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0038002&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0038002</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001744" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001744</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Hemolytic anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/61261009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">61261009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D55-D59" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D55-D59</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002878&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002878</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001878" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001878</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001878" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001878</a>]</span><br /> -
Autoimmune thrombocytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128091003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128091003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13172003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13172003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D69.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D69.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/287.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">287.31</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242584&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242584</a>, <a href="https://bioportal.bioontology.org/search?q=C0398650&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0398650</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001973" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001973</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001973" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001973</a>]</span><br /> -
Pancytopenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/127034005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">127034005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D61.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D61.81</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/284.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">284.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0030312&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0030312</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001876" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001876</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001876" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001876</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> IMMUNOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Lymphadenopathy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30746006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30746006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R59.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R59.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R59" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R59</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R59.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R59.1</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/785.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">785.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4282165&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4282165</a>, <a href="https://bioportal.bioontology.org/search?q=C0497156&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0497156</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002716</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002716</a>]</span><br /> -
Recurrent infections (in some patients) <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">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239998&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239998</a> 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> <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 /> -
Autoimmune disorders <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85828009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85828009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M30-M36" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M30-M36</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004364&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004364</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002960" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002960</a>]</span><br /> -
Autoantibodies <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/314067002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">314067002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/30621004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">30621004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004358&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004358</a>, <a href="https://bioportal.bioontology.org/search?q=C1272321&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1272321</a>]</span><br /> -
Hypergammaglobulinemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/127388009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">127388009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020455&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020455</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010702" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010702</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010702" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010702</a>]</span><br /> -
Monocytosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/19636003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">19636003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/418697001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">418697001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085702&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085702</a>, <a href="https://bioportal.bioontology.org/search?q=C0427543&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427543</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012311</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012311</a>]</span><br /> -
B-cell lymphocytosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4013858&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4013858</a>]</span><br /> -
Neutropenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/303011007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">303011007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165517008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165517008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/84828003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">84828003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D70" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D70</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.819" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.819</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D70.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D70.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/288.50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.50</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/288.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0853697&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0853697</a>, <a href="https://bioportal.bioontology.org/search?q=C0027947&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027947</a>, <a href="https://bioportal.bioontology.org/search?q=C0023530&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023530</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001875" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001875</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001882" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001882</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001875" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001875</a>]</span><br /> -
Alpha/beta, CD4-/CD8- T cells are minimally or not increased <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4013859&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4013859</a>]</span><br /> -
Defective lymphocyte apoptosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858969&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858969</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002731" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002731</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002731" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002731</a>]</span><br />
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<strong> NEOPLASIA </strong>
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- Increased risk of hematologic malignancy (1 patient) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4013857&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4013857</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Onset in childhood<br /> -
Caused by somatic mutations<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by somatic mutation in the NRAS proto-oncogene, GTPase, gene (NRAS, <a href="/entry/164790#0003">164790.0003</a>)<br /> -
Caused by somatic mutation in the KRAS proto-oncogene, GTPase, gene (KRAS, <a href="/entry/190070#0005">190070.0005</a>)<br />
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that RAS-associated autoimmune leukoproliferative disorder (RALD) is caused by somatic mutation in the NRAS gene (<a href="/entry/164790">164790</a>) or the KRAS gene (<a href="/entry/190070">190070</a>) on chromosome 12p12. One patient with somatic mutation in the NRAS gene has been reported.</p>
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<p>RAS-associated leukoproliferative disorder (RALD) is characterized by lymphadenopathy, splenomegaly, and variable autoimmune phenomena, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and neutropenia. Laboratory studies show an expansion of lymphocytes due to defective apoptosis, as well as significant autoantibodies. Some patients have recurrent infections, and there may be an increased risk of hematologic malignancy (summary by <a href="#3" class="mim-tip-reference" title="Oliveira, J. B. &lt;strong&gt;The expanding spectrum of the autoimmune lymphoproliferative syndromes.&lt;/strong&gt; Curr. Opin. Pediat. 25: 722-729, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24240292/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24240292&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/MOP.0000000000000032&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24240292">Oliveira, 2013</a> and <a href="#1" class="mim-tip-reference" title="Niemela, J. E., Lu, L., Fleisher, T. A., Davis, J., Caminha, I., Natter, M., Beer, L. A., Dowdell, K. C., Pittaluga, S., Raffeld, M., Rao, V. K., Oliveira, J. B. &lt;strong&gt;Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.&lt;/strong&gt; Blood 117: 2883-2886, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21079152/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21079152&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21079152[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-07-295501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21079152">Niemela et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24240292+21079152" 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>The disorder shows significant overlap with autoimmune lymphoproliferative syndrome (ALPS; <a href="/entry/601859">601859</a>) and was originally designated ALPS IV.</p>
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<p><a href="#2" class="mim-tip-reference" title="Oliveira, J. B., Bidere, N., Niemela, J. E., Zheng, L., Sakai, K., Nix, C. P., Danner, R. L., Barb, J., Munson, P. J., Puck, J. M., Dale, J., Straus, S. E., Fleisher, T. A., Lenardo, M. J. &lt;strong&gt;NRAS mutation causes a human autoimmune lymphoproliferative syndrome.&lt;/strong&gt; Proc. Nat. Acad. Sci. 104: 8953-8958, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17517660/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17517660&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17517660[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0702975104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17517660">Oliveira et al. (2007)</a> reported a 49-year-old patient with autoimmune lymphoproliferative syndrome who had a lifelong overexpansion of lymphocytes and a history of childhood leukemia and early adulthood lymphoma, both successfully treated. There were no developmental defects. Laboratory studies showed increased serum CD4-/CD8- (double-negative) alpha/beta T cells and lymph node follicular hyperplasia. There was no evidence of CD95 (<a href="/entry/134637">134637</a>)-mediated apoptosis, but the patient's lymphocytes resisted death by IL2 (<a href="/entry/147680">147680</a>) withdrawal, indicating a specific defect in lymphocyte apoptosis. Further studies of the patient's lymphocytes showed a decrease of the proapoptotic protein BIM (BCL2L11; <a href="/entry/603827">603827</a>), which is critical for cytokine withdrawal-induced mitochondrial apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17517660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Niemela, J. E., Lu, L., Fleisher, T. A., Davis, J., Caminha, I., Natter, M., Beer, L. A., Dowdell, K. C., Pittaluga, S., Raffeld, M., Rao, V. K., Oliveira, J. B. &lt;strong&gt;Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.&lt;/strong&gt; Blood 117: 2883-2886, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21079152/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21079152&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21079152[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-07-295501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21079152">Niemela et al. (2010)</a> reported 2 unrelated Caucasian girls with RALD presenting in childhood. One had lymphadenopathy, splenomegaly, and recurrent upper respiratory infections. She developed several autoimmune conditions, including hemolytic anemia and thrombocytopenia. Laboratory studies showed hypergammaglobulinemia, B-cell lymphocytosis, monocytosis, and autoantibodies. Alpha/beta CD4-/CD8- T cells were not increased. She continued to have recurrent inflammatory episodes affecting the respiratory tract, but without documentation of an infectious agent. She died at age 13 years after a fever and cardiac arrest. The second patient presented at age 5 years with acute viral infections and was found to have splenomegaly, neutropenia, monocytosis, thrombocytopenia, and a facial rash. Throughout childhood, she had recurrent vasculitis of the lower limbs and developed pancytopenia and lymphadenopathy. Laboratory studies showed autoantibodies and hypergammaglobulinemia. Her psychomotor development was normal. Patient T cells showed resistance to apoptosis after IL2 withdrawal, and BIM levels were reduced. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21079152" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Takagi, M., Shinoda, K., Piao, J., Mitsuiki, N., Takagi, M., Matsuda, K., Muramatsu, H., Doisaki, S., Nagasawa, M., Morio, T., Kasahara, Y., Koike, K., Kojima, S., Takao, A., Mizutani, S. &lt;strong&gt;Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation.&lt;/strong&gt; Blood 117: 2887-2890, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21063026/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21063026&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-08-301515&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21063026">Takagi et al. (2011)</a> reported 2 unrelated children who presented with RALD at ages 9 and 5 months, respectively. Both had significant lymphadenopathy and hepatosplenomegaly, hemolytic anemia, autoimmune thrombocytopenia, hypergammaglobulinemia, and autoantibodies. Neither had a significant increase of CD4-/CD8- alpha/beta T cells, but T cells from both patients showed apoptotic resistance to IL2 withdrawal. Western blot analysis showed decreased expression of BIM in activated T cells and B cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21063026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Molecular Genetics</strong>
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<p>In a patient with ALPS type IV, <a href="#2" class="mim-tip-reference" title="Oliveira, J. B., Bidere, N., Niemela, J. E., Zheng, L., Sakai, K., Nix, C. P., Danner, R. L., Barb, J., Munson, P. J., Puck, J. M., Dale, J., Straus, S. E., Fleisher, T. A., Lenardo, M. J. &lt;strong&gt;NRAS mutation causes a human autoimmune lymphoproliferative syndrome.&lt;/strong&gt; Proc. Nat. Acad. Sci. 104: 8953-8958, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17517660/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17517660&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17517660[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0702975104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17517660">Oliveira et al. (2007)</a> identified a heterozygous mutation in the NRAS gene (G13D; <a href="/entry/164790#0003">164790.0003</a>). The mutation was found in the patient's lymphoblasts, peripheral blood mononuclear cells, monocytes, EBV-transformed B cells, and buccal epithelial cells. It was not present in the patient's unaffected relatives, suggesting de novo occurrence. In vitro functional expression studies showed that the G13D mutation caused increased activation of NRAS and augmented downstream signaling, resulting in downregulation of the proapoptotic factor BIM. <a href="#1" class="mim-tip-reference" title="Niemela, J. E., Lu, L., Fleisher, T. A., Davis, J., Caminha, I., Natter, M., Beer, L. A., Dowdell, K. C., Pittaluga, S., Raffeld, M., Rao, V. K., Oliveira, J. B. &lt;strong&gt;Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.&lt;/strong&gt; Blood 117: 2883-2886, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21079152/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21079152&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21079152[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-07-295501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21079152">Niemela et al. (2010)</a> stated that the NRAS mutation found by <a href="#2" class="mim-tip-reference" title="Oliveira, J. B., Bidere, N., Niemela, J. E., Zheng, L., Sakai, K., Nix, C. P., Danner, R. L., Barb, J., Munson, P. J., Puck, J. M., Dale, J., Straus, S. E., Fleisher, T. A., Lenardo, M. J. &lt;strong&gt;NRAS mutation causes a human autoimmune lymphoproliferative syndrome.&lt;/strong&gt; Proc. Nat. Acad. Sci. 104: 8953-8958, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17517660/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17517660&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17517660[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0702975104&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17517660">Oliveira et al. (2007)</a> was a somatic mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17517660+21079152" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated girls with RALD, <a href="#1" class="mim-tip-reference" title="Niemela, J. E., Lu, L., Fleisher, T. A., Davis, J., Caminha, I., Natter, M., Beer, L. A., Dowdell, K. C., Pittaluga, S., Raffeld, M., Rao, V. K., Oliveira, J. B. &lt;strong&gt;Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.&lt;/strong&gt; Blood 117: 2883-2886, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21079152/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21079152&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21079152[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-07-295501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21079152">Niemela et al. (2010)</a> identified 2 different somatic heterozygous gain-of-function mutations in the KRAS gene (G12D, <a href="/entry/190070#0005">190070.0005</a> and G13C, <a href="/entry/190070#0023">190070.0023</a>). In vitro studies indicated that the activating KRAS mutations impaired cytokine withdrawal-induced T-cell apoptosis through suppression of the proapoptotic protein BIM, and facilitated lymphocyte proliferation through downregulation of CDKN1B (<a href="/entry/600778">600778</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21079152" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated children with RALD, <a href="#4" class="mim-tip-reference" title="Takagi, M., Shinoda, K., Piao, J., Mitsuiki, N., Takagi, M., Matsuda, K., Muramatsu, H., Doisaki, S., Nagasawa, M., Morio, T., Kasahara, Y., Koike, K., Kojima, S., Takao, A., Mizutani, S. &lt;strong&gt;Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation.&lt;/strong&gt; Blood 117: 2887-2890, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21063026/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21063026&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-08-301515&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21063026">Takagi et al. (2011)</a> identified a somatic heterozygous mutation in the KRAS gene (G13D; <a href="/entry/190070#0003">190070.0003</a>). The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21063026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Niemela2010" class="mim-anchor"></a>
<div class="">
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Niemela, J. E., Lu, L., Fleisher, T. A., Davis, J., Caminha, I., Natter, M., Beer, L. A., Dowdell, K. C., Pittaluga, S., Raffeld, M., Rao, V. K., Oliveira, J. B.
<strong>Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.</strong>
Blood 117: 2883-2886, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21079152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21079152</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21079152[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=21079152" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1182/blood-2010-07-295501" target="_blank">Full Text</a>]
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<a id="Oliveira2007" class="mim-anchor"></a>
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Oliveira, J. B., Bidere, N., Niemela, J. E., Zheng, L., Sakai, K., Nix, C. P., Danner, R. L., Barb, J., Munson, P. J., Puck, J. M., Dale, J., Straus, S. E., Fleisher, T. A., Lenardo, M. J.
<strong>NRAS mutation causes a human autoimmune lymphoproliferative syndrome.</strong>
Proc. Nat. Acad. Sci. 104: 8953-8958, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17517660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17517660</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17517660[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=17517660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.0702975104" target="_blank">Full Text</a>]
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<a id="Oliveira2013" class="mim-anchor"></a>
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Oliveira, J. B.
<strong>The expanding spectrum of the autoimmune lymphoproliferative syndromes.</strong>
Curr. Opin. Pediat. 25: 722-729, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24240292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24240292</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24240292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/MOP.0000000000000032" target="_blank">Full Text</a>]
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<a id="Takagi2011" class="mim-anchor"></a>
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Takagi, M., Shinoda, K., Piao, J., Mitsuiki, N., Takagi, M., Matsuda, K., Muramatsu, H., Doisaki, S., Nagasawa, M., Morio, T., Kasahara, Y., Koike, K., Kojima, S., Takao, A., Mizutani, S.
<strong>Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation.</strong>
Blood 117: 2887-2890, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21063026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21063026</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21063026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1182/blood-2010-08-301515" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 11/12/2014
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Carol A. Bocchini : 2/6/2012
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carol : 11/25/2024
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carol : 11/18/2014<br>mcolton : 11/13/2014<br>mcolton : 11/13/2014<br>ckniffin : 11/12/2014<br>carol : 2/6/2012
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<strong>#</strong> 614470
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RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER; RALD
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AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IV; ALPS4
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<span class="mim-text-font">
<strong>SNOMEDCT:</strong> 723508002; &nbsp;
<strong>ORPHA:</strong> 268114; &nbsp;
<strong>DO:</strong> 0110117; &nbsp;
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<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
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<th>
Location
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<th>
Phenotype
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<th>
Phenotype <br /> MIM number
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<th>
Inheritance
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<th>
Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<td>
<span class="mim-font">
1p13.2
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<span class="mim-font">
?RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic
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<span class="mim-font">
614470
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<td>
<span class="mim-font">
</span>
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<td>
<span class="mim-font">
3
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<td>
<span class="mim-font">
NRAS
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<td>
<span class="mim-font">
164790
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<td>
<span class="mim-font">
12p12.1
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<td>
<span class="mim-font">
RAS-associated autoimmune leukoproliferative disorder
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<td>
<span class="mim-font">
614470
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<td>
<span class="mim-font">
Autosomal dominant
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<td>
<span class="mim-font">
3
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<span class="mim-font">
KRAS
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<td>
<span class="mim-font">
190070
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<span class="mim-font">
<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that RAS-associated autoimmune leukoproliferative disorder (RALD) is caused by somatic mutation in the NRAS gene (164790) or the KRAS gene (190070) on chromosome 12p12. One patient with somatic mutation in the NRAS gene has been reported.</p>
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<strong>Description</strong>
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<p>RAS-associated leukoproliferative disorder (RALD) is characterized by lymphadenopathy, splenomegaly, and variable autoimmune phenomena, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and neutropenia. Laboratory studies show an expansion of lymphocytes due to defective apoptosis, as well as significant autoantibodies. Some patients have recurrent infections, and there may be an increased risk of hematologic malignancy (summary by Oliveira, 2013 and Niemela et al., 2010). </p><p>The disorder shows significant overlap with autoimmune lymphoproliferative syndrome (ALPS; 601859) and was originally designated ALPS IV.</p>
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<strong>Clinical Features</strong>
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<p>Oliveira et al. (2007) reported a 49-year-old patient with autoimmune lymphoproliferative syndrome who had a lifelong overexpansion of lymphocytes and a history of childhood leukemia and early adulthood lymphoma, both successfully treated. There were no developmental defects. Laboratory studies showed increased serum CD4-/CD8- (double-negative) alpha/beta T cells and lymph node follicular hyperplasia. There was no evidence of CD95 (134637)-mediated apoptosis, but the patient's lymphocytes resisted death by IL2 (147680) withdrawal, indicating a specific defect in lymphocyte apoptosis. Further studies of the patient's lymphocytes showed a decrease of the proapoptotic protein BIM (BCL2L11; 603827), which is critical for cytokine withdrawal-induced mitochondrial apoptosis. </p><p>Niemela et al. (2010) reported 2 unrelated Caucasian girls with RALD presenting in childhood. One had lymphadenopathy, splenomegaly, and recurrent upper respiratory infections. She developed several autoimmune conditions, including hemolytic anemia and thrombocytopenia. Laboratory studies showed hypergammaglobulinemia, B-cell lymphocytosis, monocytosis, and autoantibodies. Alpha/beta CD4-/CD8- T cells were not increased. She continued to have recurrent inflammatory episodes affecting the respiratory tract, but without documentation of an infectious agent. She died at age 13 years after a fever and cardiac arrest. The second patient presented at age 5 years with acute viral infections and was found to have splenomegaly, neutropenia, monocytosis, thrombocytopenia, and a facial rash. Throughout childhood, she had recurrent vasculitis of the lower limbs and developed pancytopenia and lymphadenopathy. Laboratory studies showed autoantibodies and hypergammaglobulinemia. Her psychomotor development was normal. Patient T cells showed resistance to apoptosis after IL2 withdrawal, and BIM levels were reduced. </p><p>Takagi et al. (2011) reported 2 unrelated children who presented with RALD at ages 9 and 5 months, respectively. Both had significant lymphadenopathy and hepatosplenomegaly, hemolytic anemia, autoimmune thrombocytopenia, hypergammaglobulinemia, and autoantibodies. Neither had a significant increase of CD4-/CD8- alpha/beta T cells, but T cells from both patients showed apoptotic resistance to IL2 withdrawal. Western blot analysis showed decreased expression of BIM in activated T cells and B cells. </p>
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<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
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<p>In a patient with ALPS type IV, Oliveira et al. (2007) identified a heterozygous mutation in the NRAS gene (G13D; 164790.0003). The mutation was found in the patient's lymphoblasts, peripheral blood mononuclear cells, monocytes, EBV-transformed B cells, and buccal epithelial cells. It was not present in the patient's unaffected relatives, suggesting de novo occurrence. In vitro functional expression studies showed that the G13D mutation caused increased activation of NRAS and augmented downstream signaling, resulting in downregulation of the proapoptotic factor BIM. Niemela et al. (2010) stated that the NRAS mutation found by Oliveira et al. (2007) was a somatic mutation. </p><p>In 2 unrelated girls with RALD, Niemela et al. (2010) identified 2 different somatic heterozygous gain-of-function mutations in the KRAS gene (G12D, 190070.0005 and G13C, 190070.0023). In vitro studies indicated that the activating KRAS mutations impaired cytokine withdrawal-induced T-cell apoptosis through suppression of the proapoptotic protein BIM, and facilitated lymphocyte proliferation through downregulation of CDKN1B (600778). </p><p>In 2 unrelated children with RALD, Takagi et al. (2011) identified a somatic heterozygous mutation in the KRAS gene (G13D; 190070.0003). The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes. </p>
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<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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<p />
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<ol>
<li>
<p class="mim-text-font">
Niemela, J. E., Lu, L., Fleisher, T. A., Davis, J., Caminha, I., Natter, M., Beer, L. A., Dowdell, K. C., Pittaluga, S., Raffeld, M., Rao, V. K., Oliveira, J. B.
<strong>Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis.</strong>
Blood 117: 2883-2886, 2010.
[PubMed: 21079152]
[Full Text: https://doi.org/10.1182/blood-2010-07-295501]
</p>
</li>
<li>
<p class="mim-text-font">
Oliveira, J. B., Bidere, N., Niemela, J. E., Zheng, L., Sakai, K., Nix, C. P., Danner, R. L., Barb, J., Munson, P. J., Puck, J. M., Dale, J., Straus, S. E., Fleisher, T. A., Lenardo, M. J.
<strong>NRAS mutation causes a human autoimmune lymphoproliferative syndrome.</strong>
Proc. Nat. Acad. Sci. 104: 8953-8958, 2007.
[PubMed: 17517660]
[Full Text: https://doi.org/10.1073/pnas.0702975104]
</p>
</li>
<li>
<p class="mim-text-font">
Oliveira, J. B.
<strong>The expanding spectrum of the autoimmune lymphoproliferative syndromes.</strong>
Curr. Opin. Pediat. 25: 722-729, 2013.
[PubMed: 24240292]
[Full Text: https://doi.org/10.1097/MOP.0000000000000032]
</p>
</li>
<li>
<p class="mim-text-font">
Takagi, M., Shinoda, K., Piao, J., Mitsuiki, N., Takagi, M., Matsuda, K., Muramatsu, H., Doisaki, S., Nagasawa, M., Morio, T., Kasahara, Y., Koike, K., Kojima, S., Takao, A., Mizutani, S.
<strong>Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation.</strong>
Blood 117: 2887-2890, 2011.
[PubMed: 21063026]
[Full Text: https://doi.org/10.1182/blood-2010-08-301515]
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</ol>
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Contributors:
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<span class="mim-text-font">
Cassandra L. Kniffin - updated : 11/12/2014
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Creation Date:
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<span class="mim-text-font">
Carol A. Bocchini : 2/6/2012
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Edit History:
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carol : 11/25/2024<br>carol : 11/18/2014<br>mcolton : 11/13/2014<br>mcolton : 11/13/2014<br>ckniffin : 11/12/2014<br>carol : 2/6/2012
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