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Entry
- #601859 - AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; ALPS
- OMIM
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<span class="h4">#601859</span>
<br />
<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/601859"><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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<li role="presentation" style="margin-left: 1em">
<a href="#otherFeatures">Other Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#nomenclature">Nomenclature</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME" 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>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3468&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.ncbi.nlm.nih.gov/books/NBK1108/" 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://medlineplus.gov/genetics/condition/autoimmune-lymphoproliferative-syndrome" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:6688" 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/601859" 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/OMIA002064/" 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>
</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> 702444009<br />
<strong>ICD10CM:</strong> D89.82<br />
<strong>ICD9CM:</strong> 279.41<br />
<strong>ORPHA:</strong> 3261<br />
<strong>DO:</strong> 6688<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>
601859
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; ALPS
</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">
CANALE-SMITH SYNDROME<br />
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE I, AUTOSOMAL DOMINANT
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA, INCLUDED; ALPS1A, INCLUDED
</span>
</div>
<div>
<span class="h4 mim-font">
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IB, INCLUDED; ALPS1B, INCLUDED<br />
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE I, AUTOSOMAL RECESSIVE, INCLUDED
</span>
</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/1/1427?start=-3&limit=10&highlight=1427">
1q24.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Autoimmune lymphoproliferative syndrome, type IB
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601859"> 601859 </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">
FASLG
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/134638"> 134638 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/377?start=-3&limit=10&highlight=377">
10q23.31
</a>
</span>
</td>
<td>
<span class="mim-font">
{Autoimmune lymphoproliferative syndrome}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601859"> 601859 </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">
FAS
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/134637"> 134637 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/377?start=-3&limit=10&highlight=377">
10q23.31
</a>
</span>
</td>
<td>
<span class="mim-font">
Autoimmune lymphoproliferative syndrome, type IA
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601859"> 601859 </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">
FAS
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/134637"> 134637 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/601859" 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/601859" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/601859" 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> 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> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Urticaria <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64305001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64305001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/126485001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">126485001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/247472004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">247472004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L50</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/L50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L50.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/708" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">708</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/708.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">708.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2186740&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2186740</a>, <a href="https://bioportal.bioontology.org/search?q=C0042109&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042109</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001025" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001025</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001025" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001025</a>]</span><br /> -
Vasculitis rash <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858986&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858986</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">
- Autoimmune hemolytic anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413603009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413603009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/283.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">283.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0002880&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002880</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001890" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001890</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001890" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001890</a>]</span><br /> -
Iron deficiency anemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/87522002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">87522002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D50</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/D50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D50.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">280</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/280.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">280.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162316&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162316</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001891</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001891" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001891</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 /> -
Autoimmune neutropenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/234425008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">234425008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0340971&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0340971</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001904" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001904</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001904" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001904</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 />
</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">
- 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 /> -
Chronic noninfectious lymphadenopathy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858970&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858970</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002730" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002730</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002730" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002730</a>]</span><br /> -
Increased number of peripheral CD3+ T cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858971&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858971</a>]</span><br /> -
Increased number of CD4-/CD8- T cells expressing alpha/beta T-cell receptors <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858973&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858973</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002851" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002851</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002851" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002851</a>]</span><br /> -
Increased proportion of HLA DR+ and CD57+ T cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858974&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858974</a>]</span><br /> -
Reduced delayed hypersensitivity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843386&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843386</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002972" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002972</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002972" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002972</a>]</span><br /> -
Lymph nodes show florid reactive follicular hyperplasia and marked paracortical expansion with immunoblasts and plasma cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858976&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858976</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEOPLASIA </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Increased risk of malignant lymphoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3551387&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3551387</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Increased levels of IgG <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858977</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003237" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003237</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003237" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003237</a>]</span><br /> -
Increased levels of IgA <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239984&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239984</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003261" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003261</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003261" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003261</a>]</span><br /> -
Increased levels of IgM <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839972&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839972</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003496" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003496</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003496" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003496</a>]</span><br /> -
Direct Coombs positive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74789008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74789008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0520736&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0520736</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004844" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004844</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004844" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004844</a>]</span><br /> -
Platelet antibody positive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858980&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858980</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003454" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003454</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003454" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003454</a>]</span><br /> -
Neutrophil antibody positive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858981&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858981</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003453" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003453</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003453" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003453</a>]</span><br /> -
Phospholipid antibody positive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1858982&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858982</a>]</span><br /> -
Smooth muscle antibody positive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/310290006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">310290006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241185&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241185</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003262" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003262</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003262" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003262</a>]</span><br /> -
Rheumatoid factor positive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165839004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165839004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151379&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151379</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002923" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002923</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002923" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002923</a>]</span><br /> -
Antinuclear antibody positive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165850001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165850001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151480&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151480</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003493" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003493</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003493" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003493</a>]</span><br /> -
Increased interleukin 10 <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866122&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866122</a>]</span><br /> -
Elevated levels of vitamin B12 <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866123&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866123</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Onset in early childhood<br /> -
Recessive inheritance has been reported<br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the Fas antigen gene (FAS, <a href="/entry/134637#0001">134637.0001</a>)<br /> -
Caused by mutation in the Fas ligand gene (FASL, <a href="/entry/134638#0001">134638.0001</a>)<br />
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<p>A number sign (#) is used with this entry because autoimmune lymphoproliferative syndrome (ALPS) type IA is caused by heterozygous mutation in the FAS gene (TNFRSF6, or CD95; <a href="/entry/134637">134637</a>); ALPS type IB is caused by heterozygous mutation in the FAS ligand (FASL) gene (TNFSF6 or CD95L; <a href="/entry/134638">134638</a>). Both germline and somatic mutations in the FAS gene have been identified in patients with ALPS type IA. A subset of patients may have a heterozygous germline mutation combined with a somatic mutation, resulting in a '2-hit' disease mechanism.</p>
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<strong>Description</strong>
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<p>Autoimmune lymphoproliferative syndrome is a heritable disorder of apoptosis, resulting in the accumulation of autoreactive lymphocytes. It manifests in early childhood as nonmalignant lymphadenopathy with hepatosplenomegaly and autoimmune cytopenias (summary by <a href="#3" class="mim-tip-reference" title="Dowdell, K. C., Niemela, J. E., Price, S., Davis, J., Hornung, R. L., Oliveira, J. B., Puck, J. M., Jaffe, E. S., Pittaluga, S., Cohen, J. I., Fleisher, T. A., Rao, V. K. &lt;strong&gt;Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome.&lt;/strong&gt; Blood 115: 5164-5169, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20360470/&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;20360470&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-01-263145&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="20360470">Dowdell et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20360470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a review of the autoimmune lymphoproliferative syndromes, see <a href="#19" class="mim-tip-reference" title="Teachey, D. T., Seif, A. E., Grupp, S. A. &lt;strong&gt;Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS).&lt;/strong&gt; Brit. J. Haemat. 148: 205-216, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19930184/&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;19930184&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19930184[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/10.1111/j.1365-2141.2009.07991.x&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="19930184">Teachey et al. (2009)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19930184" 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 Autoimmune Lymphoproliferative Syndrome</em></strong></p><p>
Type IIA ALPS (ALPS2A; <a href="/entry/603909">603909</a>) is caused by mutation in the caspase-10 gene (CASP10; <a href="/entry/601762">601762</a>). <a href="#13" class="mim-tip-reference" title="Puck, J. M., Straus, S. E. &lt;strong&gt;Somatic mutations--not just for cancer anymore.&lt;/strong&gt; New Eng. J. Med. 351: 1388-1390, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15459299/&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;15459299&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMp048116&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="15459299">Puck and Straus (2004)</a> designated caspase-8 deficiency (<a href="/entry/607271">607271</a>), caused by mutations in the CASP8 gene (<a href="/entry/601763">601763</a>), as type IIB ALPS. ALPS3 (<a href="/entry/615559">615559</a>) is caused by mutation in the PRKCD gene (<a href="/entry/176977">176977</a>). RAS-associated ALPS (RALD, or ALPS4; <a href="/entry/614470">614470</a>) is caused by mutation in the NRAS gene (<a href="/entry/164790">164790</a>). ALPS5 (<a href="/entry/616100">616100</a>) is caused by mutation in the CTLA4 gene (<a href="/entry/123890">123890</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Clinical Features</strong>
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<p><a href="#2" class="mim-tip-reference" title="Canale, V. C., Smith, C. H. &lt;strong&gt;Chronic lymphadenopathy simulating malignant lymphoma.&lt;/strong&gt; J. Pediat. 70: 891-899, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4165068/&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;4165068&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(67)80262-2&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="4165068">Canale and Smith (1967)</a> described a childhood syndrome of lymphadenopathy and splenomegaly associated with autoimmune hemolytic anemia and thrombocytopenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4165068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Sneller, M. C., Straus, S. E., Jaffe, E. S., Jaffe, J. S., Fleisher, T. A., Stetler-Stevenson, M., Strober, W. &lt;strong&gt;A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease.&lt;/strong&gt; J. Clin. Invest. 90: 334-341, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1386609/&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;1386609&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI115867&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="1386609">Sneller et al. (1992)</a> reported 2 unrelated girls with a lymphoproliferative/autoimmune syndrome. The first patient developed cervical lymphadenopathy at age 18 months and anemia associated with splenomegaly at age 24 months. Over the next months, she developed renal insufficiency, and a renal biopsy showed mesangiopathic glomerulonephritis with crescent formation. Serologic studies for infectious etiology, including EBV, CMV, toxoplasmosis, HIV, brucella, and hepatitis were all negative. The second patient was diagnosed with autoimmune hemolytic anemia at age 9 months with a positive direct Coomb's test. At age 4 years, she developed peripheral lymphadenopathy, and CT scan at age 8 years showed hepatomegaly and mediastinal, mesenteric, and retroperitoneal adenopathy. Peripheral blood analysis showed that both patients had increased numbers of B lymphocytes and increased numbers of mature CD3+, CD4-, CD8- T lymphocytes expressing alpha/beta T-cell receptors; these T cells accounted for 40 to 60% of all T cells. Neither lymphocyte population was monoclonal. Lymph node biopsy showed paracortical infiltration of the CD4-, CD8- T cells. <a href="#15" class="mim-tip-reference" title="Sneller, M. C., Straus, S. E., Jaffe, E. S., Jaffe, J. S., Fleisher, T. A., Stetler-Stevenson, M., Strober, W. &lt;strong&gt;A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease.&lt;/strong&gt; J. Clin. Invest. 90: 334-341, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1386609/&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;1386609&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI115867&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="1386609">Sneller et al. (1992)</a> noted that the phenotype in these girls was similar to that of lpr (see <a href="/entry/134637">134637</a>) and gld (see <a href="/entry/134638">134638</a>) mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1386609" 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="#5" class="mim-tip-reference" title="Fisher, G. H., Rosenberg, F. J., Straus, S. E., Dale, J. K., Middelton, L. A., Lin, A. Y., Strober, W., Lenardo, M. J., Puck, J. M. &lt;strong&gt;Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.&lt;/strong&gt; Cell 81: 935-946, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7540117/&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;7540117&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0092-8674(95)90013-6&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="7540117">Fisher et al. (1995)</a> reported 4 unrelated children with ALPS who presented with nonmalignant lymphadenopathy or splenomegaly between 2 months and 5 years of age. All patients had autoimmune hemolytic anemia, thrombocytopenia, and recurrent urticarial rashes consistent with immune vasculitis. Peripheral blood analysis showed hypergammaglobulinemia and expanded populations of CD3+, CD4-, CD8- T lymphocytes in all patients. In vitro studies showed that the expanded T lymphocyte population had impaired TCR-induced apoptosis. <a href="#5" class="mim-tip-reference" title="Fisher, G. H., Rosenberg, F. J., Straus, S. E., Dale, J. K., Middelton, L. A., Lin, A. Y., Strober, W., Lenardo, M. J., Puck, J. M. &lt;strong&gt;Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.&lt;/strong&gt; Cell 81: 935-946, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7540117/&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;7540117&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0092-8674(95)90013-6&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="7540117">Fisher et al. (1995)</a> concluded that the disorder was caused by impaired control of mature lymphocyte homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7540117" 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="Drappa, J., Vaishnaw, A. K., Sullivan, K. E., Chu, J.-L., Elkon, K. B. &lt;strong&gt;Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity.&lt;/strong&gt; New Eng. J. Med. 335: 1643-1649, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8929361/&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;8929361&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199611283352204&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="8929361">Drappa et al. (1996)</a> provided follow-up on 2 patients reported by <a href="#2" class="mim-tip-reference" title="Canale, V. C., Smith, C. H. &lt;strong&gt;Chronic lymphadenopathy simulating malignant lymphoma.&lt;/strong&gt; J. Pediat. 70: 891-899, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4165068/&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;4165068&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(67)80262-2&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="4165068">Canale and Smith (1967)</a>. One patient was a 43-year-old woman who had continued lymphadenopathy and hypergammaglobulinemia throughout her life. She also had several neoplastic lesions, including a breast adenoma, 3 thyroid adenomas, and 2 basal cell carcinomas. Another patient was a 43-year-old man whose lymphadenopathy had gradually diminished during adolescence and was mild during adulthood. He died of hepatocellular carcinoma associated with hepatitis C infection. The patient's son had lymphadenopathy with T-cell hyperplasia and autoimmune hemolytic anemia and thrombocytopenia. Activated T cells from the patients were almost completely resistant to apoptosis induced by ligating the Fas receptor with an anti-Fas antibody. The findings indicated that ALPS is compatible with long-term survival. <a href="#16" class="mim-tip-reference" title="Sneller, M. C., Wang, J., Dale, J. K., Strober, W., Middleton, L. A., Choi, Y., Fleisher, T. A., Lim, M. S., Jaffe, E. S., Puck, J. M., Lenardo, M. J., Straus, S. E. &lt;strong&gt;Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.&lt;/strong&gt; Blood 89: 1341-1348, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9028957/&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;9028957&lt;/a&gt;]" pmid="9028957">Sneller et al. (1997)</a> reported 9 unrelated patients with ALPS characterized by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD3+, CD4-, CD8- T cells. Hemolytic anemia was the most frequent form of autoimmune disease, occurring in 6 patients with or without idiopathic thrombocytopenic purpura. All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the FAS gene were detected in 8 patients, and 7 of 8 kindreds had healthy relatives with FAS mutations. These relatives also showed in vitro abnormalities of FAS-mediated lymphocyte apoptosis, but clinical features of ALPS were not present. In 1 ALPS patient, no FAS or FASL gene mutations were identified, and <a href="#16" class="mim-tip-reference" title="Sneller, M. C., Wang, J., Dale, J. K., Strober, W., Middleton, L. A., Choi, Y., Fleisher, T. A., Lim, M. S., Jaffe, E. S., Puck, J. M., Lenardo, M. J., Straus, S. E. &lt;strong&gt;Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.&lt;/strong&gt; Blood 89: 1341-1348, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9028957/&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;9028957&lt;/a&gt;]" pmid="9028957">Sneller et al. (1997)</a> proposed the designation ALPS type II to refer to the syndrome in the absence of mutations in these genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8929361+9028957+4165068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="van der Burg, M., de Groot, R., Comans-Bitter, W. M., den Hollander, J. C., Hooijkaas, H., Neijens, H. J., Berger, R. M. F., Oranje, A. P., Langerak, A. W., van Dongen, J. J. M. &lt;strong&gt;Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?&lt;/strong&gt; Pediat. Res. 47: 336-343, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10709732/&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;10709732&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-200003000-00009&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="10709732">Van der Burg et al. (2000)</a> reported a girl, born of consanguineous parents, who presented immediately after birth with petechiae, generalized edema, and hepatosplenomegaly. During the first month of life, autoantibodies against red blood cells and platelets were demonstrated. A liver biopsy showed extensive extramedullary hematopoiesis, and she had massive generalized adenopathy of the cervical, mesenteric, and paraaortic lymph nodes. Hypergammaglobulinemia persisted for several years; a cutaneous lupus-like disease appeared at a later stage. The patient had histologically malignant lymph nodes, although monoclonal or oligoclonal rearrangements could not be detected on analysis of the gene encoding the T-cell antigen receptor beta subunit (TCRB; see <a href="/entry/186930">186930</a>). There was no detectable FAS expression on freshly isolated blood leukocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10709732" 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="#18" class="mim-tip-reference" title="Straus, S. E., Lenardo, M., Puck, J. M. &lt;strong&gt;The Canale-Smith syndrome. (Letter)&lt;/strong&gt; New Eng. J. Med. 336: 1457 only, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9148156/&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;9148156&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199705153362016&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="9148156">Straus et al. (1997)</a> stated that their experience with over 20 patients with ALPS from 13 kindreds indicated a wider clinical spectrum than that described by <a href="#2" class="mim-tip-reference" title="Canale, V. C., Smith, C. H. &lt;strong&gt;Chronic lymphadenopathy simulating malignant lymphoma.&lt;/strong&gt; J. Pediat. 70: 891-899, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4165068/&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;4165068&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(67)80262-2&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="4165068">Canale and Smith (1967)</a> or by <a href="#4" class="mim-tip-reference" title="Drappa, J., Vaishnaw, A. K., Sullivan, K. E., Chu, J.-L., Elkon, K. B. &lt;strong&gt;Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity.&lt;/strong&gt; New Eng. J. Med. 335: 1643-1649, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8929361/&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;8929361&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199611283352204&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="8929361">Drappa et al. (1996)</a>, including Guillain-Barre syndrome (<a href="/entry/139393">139393</a>) and panniculitis. In addition, <a href="#18" class="mim-tip-reference" title="Straus, S. E., Lenardo, M., Puck, J. M. &lt;strong&gt;The Canale-Smith syndrome. (Letter)&lt;/strong&gt; New Eng. J. Med. 336: 1457 only, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9148156/&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;9148156&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199705153362016&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="9148156">Straus et al. (1997)</a> noted that B-lymphomas developed in early adulthood in 2 brothers with FAS mutations. Four different patients with ALPS had normal FAS and FASL genes, but impaired apoptosis caused by an abnormality in the FAS pathway, suggesting that abnormalities of other proteins in the FAS-signaling cascade or in parallel apoptotic pathways may also cause ALPS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9148156+8929361+4165068" 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="#17" class="mim-tip-reference" title="Straus, S. E., Jaffe, E. S., Puck, J. M., Dale, J. K., Elkon, K. B., Rosen-Wolff, A., Peters, A. M. J., Sneller, M. C., Hallahan, C. W., Wang, J., Fischer, R. E., Jackson, C. M., Lin, A. Y., Baumler, C., Siegert, E., Marx, A., Vaishnaw, A. K., Grodzicky, T., Fleisher, T. A., Lenardo, M. J. &lt;strong&gt;The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.&lt;/strong&gt; Blood 98: 194-200, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11418480/&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;11418480&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood.v98.1.194&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="11418480">Straus et al. (2001)</a> found that 130 individuals in 39 families segregating ALPS had heterozygous germline FAS mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected. All 10 patients with FAS mutations had defective lymphocyte apoptosis and most had other features of ALPS. The average age of ALPS onset was 5 years, whereas the average age of lymphoma diagnosis was 28 years. The cases in which somatic alterations in FAS were described in lymphomas (e.g., <a href="#6" class="mim-tip-reference" title="Gronbaek, K., Straten, P., Ralfkiaer, E., Ahrenkiel, V., Andersen, M. K., Hansen, N. E., Zeuthen, J., Hou-Jensen, K., Guldberg, P. &lt;strong&gt;Somatic Fas mutations in non-Hodgkin&#x27;s lymphoma: association with extranodal disease and autoimmunity.&lt;/strong&gt; Blood 92: 3018-3024, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9787134/&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;9787134&lt;/a&gt;]" pmid="9787134">Gronbaek et al., 1998</a>) more typically arose later in life. <a href="#17" class="mim-tip-reference" title="Straus, S. E., Jaffe, E. S., Puck, J. M., Dale, J. K., Elkon, K. B., Rosen-Wolff, A., Peters, A. M. J., Sneller, M. C., Hallahan, C. W., Wang, J., Fischer, R. E., Jackson, C. M., Lin, A. Y., Baumler, C., Siegert, E., Marx, A., Vaishnaw, A. K., Grodzicky, T., Fleisher, T. A., Lenardo, M. J. &lt;strong&gt;The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.&lt;/strong&gt; Blood 98: 194-200, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11418480/&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;11418480&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood.v98.1.194&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="11418480">Straus et al. (2001)</a> stated that the mechanism by which FAS defects in ALPS predispose to lymphomas might involve several components. They suggested that the most obvious possibility is that a general expansion of the lymphoid pool provides a larger target cell population for other transforming events. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9787134+11418480" 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="Lim, W.-K., Ursea, R., Rao, K., Buggage, R. R., Suhler, E. B., Dugan, F., Chan, C.-C., Straus, S. E., Nussenblatt, R. B. &lt;strong&gt;Bilateral uveitis in a patient with autoimmune lymphoproliferative syndrome.&lt;/strong&gt; Am. J. Ophthal. 139: 562-563, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15767081/&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;15767081&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajo.2004.09.017&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="15767081">Lim et al. (2005)</a> reported a case of bilateral uveitis in an 8-year old child with ALPS1A. The authors concluded that despite a Th2 immune predominance in ALPS, uveitis, a Th1-mediated disease, might still manifest in these patients. They hypothesized that the pathogenesis of uveitis in ALPS might differ from that of the systemic disease overall. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15767081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<p>ALPS is most often transmitted in an autosomal dominant manner. However, autosomal recessive inheritance of ALPS1A due to homozygous or compound heterozygous mutations in the FAS gene has been described. In addition, <a href="#3" class="mim-tip-reference" title="Dowdell, K. C., Niemela, J. E., Price, S., Davis, J., Hornung, R. L., Oliveira, J. B., Puck, J. M., Jaffe, E. S., Pittaluga, S., Cohen, J. I., Fleisher, T. A., Rao, V. K. &lt;strong&gt;Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome.&lt;/strong&gt; Blood 115: 5164-5169, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20360470/&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;20360470&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-01-263145&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="20360470">Dowdell et al. (2010)</a> noted that one-third of patients may have somatic mutations in the FAS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20360470" 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 girl with severe ALPS1A, born of consanguineous parents, <a href="#21" class="mim-tip-reference" title="van der Burg, M., de Groot, R., Comans-Bitter, W. M., den Hollander, J. C., Hooijkaas, H., Neijens, H. J., Berger, R. M. F., Oranje, A. P., Langerak, A. W., van Dongen, J. J. M. &lt;strong&gt;Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?&lt;/strong&gt; Pediat. Res. 47: 336-343, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10709732/&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;10709732&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-200003000-00009&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="10709732">van der Burg et al. (2000)</a> identified a homozygous 20-bp duplication in the FAS gene (<a href="/entry/134637#0013">134637.0013</a>). The findings indicated that autosomal recessive inheritance. <a href="#21" class="mim-tip-reference" title="van der Burg, M., de Groot, R., Comans-Bitter, W. M., den Hollander, J. C., Hooijkaas, H., Neijens, H. J., Berger, R. M. F., Oranje, A. P., Langerak, A. W., van Dongen, J. J. M. &lt;strong&gt;Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?&lt;/strong&gt; Pediat. Res. 47: 336-343, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10709732/&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;10709732&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-200003000-00009&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="10709732">Van der Burg et al. (2000)</a> noted that <a href="#14" class="mim-tip-reference" title="Rieux-Laucat, F., Le Deist, F., Hivroz, C., Roberts, I. A. G., Debatin, K. M., Fischer, A., de Villartay, J. P. &lt;strong&gt;Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity.&lt;/strong&gt; Science 268: 1347-1349, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7539157/&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;7539157&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.7539157&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="7539157">Rieux-Laucat et al. (1995)</a> and <a href="#1" class="mim-tip-reference" title="Bettinardi, A., Brugnoni, D., Quiros-Roldan, E., Malagoli, A., La Grutta, S., Correra, A., Notarangelo, L. D. &lt;strong&gt;Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis.&lt;/strong&gt; Blood 89: 902-909, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9028321/&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;9028321&lt;/a&gt;]" pmid="9028321">Bettinardi et al. (1997)</a> had reported similar patients with 2 FAS gene mutations (see <a href="/entry/134637#0006">134637.0006</a> and <a href="/entry/134637#0007">134637.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7539157+10709732+9028321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<p><strong><em>ALPS1A Due to Heterozygous Mutations in the FAS Gene</em></strong></p><p>
In 5 unrelated patients with ALPS1A, 1 of whom was reported by <a href="#15" class="mim-tip-reference" title="Sneller, M. C., Straus, S. E., Jaffe, E. S., Jaffe, J. S., Fleisher, T. A., Stetler-Stevenson, M., Strober, W. &lt;strong&gt;A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease.&lt;/strong&gt; J. Clin. Invest. 90: 334-341, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1386609/&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;1386609&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI115867&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="1386609">Sneller et al. (1992)</a>, <a href="#5" class="mim-tip-reference" title="Fisher, G. H., Rosenberg, F. J., Straus, S. E., Dale, J. K., Middelton, L. A., Lin, A. Y., Strober, W., Lenardo, M. J., Puck, J. M. &lt;strong&gt;Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.&lt;/strong&gt; Cell 81: 935-946, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7540117/&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;7540117&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0092-8674(95)90013-6&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="7540117">Fisher et al. (1995)</a> identified heterozygous mutations in the FAS gene (<a href="/entry/134637#0001">134637.0001</a>-<a href="/entry/134637#0005">134637.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7540117+1386609" 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 patients with ALPS1A first reported by <a href="#2" class="mim-tip-reference" title="Canale, V. C., Smith, C. H. &lt;strong&gt;Chronic lymphadenopathy simulating malignant lymphoma.&lt;/strong&gt; J. Pediat. 70: 891-899, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4165068/&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;4165068&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(67)80262-2&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="4165068">Canale and Smith (1967)</a>, <a href="#4" class="mim-tip-reference" title="Drappa, J., Vaishnaw, A. K., Sullivan, K. E., Chu, J.-L., Elkon, K. B. &lt;strong&gt;Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity.&lt;/strong&gt; New Eng. J. Med. 335: 1643-1649, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8929361/&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;8929361&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199611283352204&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="8929361">Drappa et al. (1996)</a> identified heterozygous mutations in the FAS gene (<a href="/entry/134637#0019">134637.0019</a>; <a href="/entry/134637#0020">134637.0020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8929361+4165068" 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>ALPS1A Due to Biallelic Mutations in the FAS Gene</em></strong></p><p>
In a girl with severe ALPS1A, born of consanguineous parents, <a href="#21" class="mim-tip-reference" title="van der Burg, M., de Groot, R., Comans-Bitter, W. M., den Hollander, J. C., Hooijkaas, H., Neijens, H. J., Berger, R. M. F., Oranje, A. P., Langerak, A. W., van Dongen, J. J. M. &lt;strong&gt;Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?&lt;/strong&gt; Pediat. Res. 47: 336-343, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10709732/&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;10709732&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-200003000-00009&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="10709732">van der Burg et al. (2000)</a> identified a homozygous 20-bp duplication in the FAS gene (<a href="/entry/134637#0013">134637.0013</a>). <a href="#21" class="mim-tip-reference" title="van der Burg, M., de Groot, R., Comans-Bitter, W. M., den Hollander, J. C., Hooijkaas, H., Neijens, H. J., Berger, R. M. F., Oranje, A. P., Langerak, A. W., van Dongen, J. J. M. &lt;strong&gt;Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?&lt;/strong&gt; Pediat. Res. 47: 336-343, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10709732/&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;10709732&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1203/00006450-200003000-00009&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="10709732">Van der Burg et al. (2000)</a> noted that <a href="#14" class="mim-tip-reference" title="Rieux-Laucat, F., Le Deist, F., Hivroz, C., Roberts, I. A. G., Debatin, K. M., Fischer, A., de Villartay, J. P. &lt;strong&gt;Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity.&lt;/strong&gt; Science 268: 1347-1349, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7539157/&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;7539157&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.7539157&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="7539157">Rieux-Laucat et al. (1995)</a> and <a href="#1" class="mim-tip-reference" title="Bettinardi, A., Brugnoni, D., Quiros-Roldan, E., Malagoli, A., La Grutta, S., Correra, A., Notarangelo, L. D. &lt;strong&gt;Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis.&lt;/strong&gt; Blood 89: 902-909, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9028321/&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;9028321&lt;/a&gt;]" pmid="9028321">Bettinardi et al. (1997)</a> had reported similar patients with 2 FAS gene mutations (see <a href="/entry/134637#0006">134637.0006</a> and <a href="/entry/134637#0007">134637.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7539157+10709732+9028321" 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>ALPS1A Due to Heterozygous Germline and Additional Somatic Mutations in the FAS Gene</em></strong></p><p>
<a href="#3" class="mim-tip-reference" title="Dowdell, K. C., Niemela, J. E., Price, S., Davis, J., Hornung, R. L., Oliveira, J. B., Puck, J. M., Jaffe, E. S., Pittaluga, S., Cohen, J. I., Fleisher, T. A., Rao, V. K. &lt;strong&gt;Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome.&lt;/strong&gt; Blood 115: 5164-5169, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20360470/&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;20360470&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2010-01-263145&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="20360470">Dowdell et al. (2010)</a> found that 12 (38.7%) of 31 ALPS patients who were negative for germline FAS mutations carried heterozygous somatic FAS mutations in their double-negative T cells. All of the 12 somatic mutations resulted in known or predicted functional loss of normal FAS signaling; 10 mutations led to a premature stop codon. Patients with somatic FAS mutations were clinically similar to those with germline FAS mutations, although they had a slightly lower incidence of splenectomy and lower lymphocyte counts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20360470" 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="#7" class="mim-tip-reference" title="Holzelova, E., Vonarbourg, C., Stolzenberg, M.-C., Arkwright, P. D., Selz, F., Prieur, A.-M., Blanche, S., Bartunkova, J., Vilmer, E., Fischer, A., Le Deist, F., Rieux-Laucat, F. &lt;strong&gt;Autoimmune lymphoproliferative syndrome with somatic Fas mutations.&lt;/strong&gt; New Eng. J. Med. 351: 1409-1418, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15459302/&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;15459302&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa040036&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="15459302">Holzelova et al. (2004)</a> reported 6 children with an unusual form of ALPS, characterized by elevated numbers of double-negative T cells and hypergammaglobulinemia, but normal Fas-mediated apoptosis of T cells in vitro. Double-negative T cells from all 6 patients showed heterozygous mutations in the FAS gene (see, e.g., <a href="/entry/134637#0018">134637.0018</a>). In 2 affected patients, FAS mutations were found in a fraction of CD4+ and CD8+ T cells, monocytes, and CD34+ hematopoietic precursors, but not in hair or mucosal epithelial cells, demonstrating somatic mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Magerus-Chatinet, A., Neven, B., Stolzenberg, M.-C., Daussy, C., Arkwright, P. D., Lanzarotti, N., Schaffner, C., Cluet-Dennetiere, S., Haerynck, F., Michel, G., Bole-Feysot, C., Zarhrate, M.., Radford-Weiss, I., Romana, S. P., Picard, C., Fischer, A., Rieux-Laucat, F. &lt;strong&gt;Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation.&lt;/strong&gt; J. Clin. Invest. 121: 106-112, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21183795/&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;21183795&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21183795[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/10.1172/JCI43752&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="21183795">Magerus-Chatinet et al. (2011)</a> reported 7 unrelated patients with typical features of ALPS associated with heterozygous germline mutations in the FAS gene. Four of the patients had asymptomatic relatives who were heterozygous for the same mutation, suggesting incomplete penetrance. All 7 patients and the carrier relatives had low FAS-mediated T cell apoptosis in vitro compared to controls. However, only the symptomatic patients also had increased double-negative T cells, increased IL10 (<a href="/entry/124092">124092</a>), and increased FAS ligand (FASL; <a href="/entry/134638">134638</a>). Three of the 7 symptomatic patients were subsequently found to carry a heterozygous somatic FAS mutation within double-negative T cells, whereas the remaining 4 symptomatic patients showed somatic loss of the wildtype allele. These somatic events were not found in any of the asymptomatic heterozygous carriers. The additional somatic event in the 7 patients led to a clear and profound TNFRSF6 expression defect in the majority of double-negative T cells in all patients except 1, who carried 2 missense mutations that were predicted to be nonfunctional. The double-mutant lymphocytes could not be killed by FAS ligand. These findings were similar to those observed in patients with biallelic TNFRS6 mutations, and supported the idea of a '2-hit' mechanism in which loss of both alleles in relevant cells causes symptomatic lymphoproliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21183795" 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>ALPS1B Due to Mutations in the FASL Gene</em></strong></p><p>
<a href="#22" class="mim-tip-reference" title="Wu, J., Wilson, J., He, J., Xiang, L., Schur, P. H., Mountz, J. D. &lt;strong&gt;Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease.&lt;/strong&gt; J. Clin. Invest. 98: 1107-1113, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8787672/&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;8787672&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI118892&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="8787672">Wu et al. (1996)</a> reported an African American man with systemic lupus erythematosus (SLE; <a href="/entry/152700">152700</a>) and lymphadenopathy who had a heterozygous mutation in the FASL gene (<a href="/entry/134638#0001">134638.0001</a>). Peripheral blood mononuclear cells from this patient showed decreased FASL activity, decreased activation-induced cell death, and increased T-cell proliferation after activation. Although the patient did not have increased numbers of CD4-, CD8- T cells, <a href="#22" class="mim-tip-reference" title="Wu, J., Wilson, J., He, J., Xiang, L., Schur, P. H., Mountz, J. D. &lt;strong&gt;Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease.&lt;/strong&gt; J. Clin. Invest. 98: 1107-1113, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8787672/&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;8787672&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI118892&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="8787672">Wu et al. (1996)</a> suggested that the lymphadenopathy and autoimmune disease were consistent with an adult type of ALPS. <a href="#9" class="mim-tip-reference" title="Lenardo, M. J. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Bethesda, Md. 1/14/1999."None>Lenardo (1999)</a> noted that although this patient satisfied the rheumatologic criteria for a diagnosis of SLE, the features were more consistent with ALPS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8787672" 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>
For discussion of a possible association between ALPS and variation in the RELA gene, see <a href="/entry/164014#0002">164014.0002</a>.</p>
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<p><a href="#20" class="mim-tip-reference" title="Vaishnaw, A. K., Sullivan, K. E., Elkon, K. B. &lt;strong&gt;Reply to S. E. Straus. (Letter)&lt;/strong&gt; New Eng. J. Med. 336: 1457-1458, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9148156/&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;9148156&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199705153362016&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="9148156">Vaishnaw et al. (1997)</a> urged the use of the eponym 'Canale-Smith syndrome.' They argued that the term 'lymphoproliferative syndrome' connotes malignancy, but that lymphadenopathy associated with FAS mutations results primarily from the accumulation of lymphocytes due to the failure of FAS-mediated apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9148156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Krammer, P. H. &lt;strong&gt;CD95&#x27;s deadly mission in the immune system.&lt;/strong&gt; Nature 407: 789-795, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11048730/&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;11048730&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/35037728&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="11048730">Krammer (2000)</a> and <a href="#12" class="mim-tip-reference" title="Nagata, S. &lt;strong&gt;Human autoimmune lymphoproliferative syndrome, a defect in the apoptosis-inducing Fas receptor: a lesson from the mouse model.&lt;/strong&gt; J. Hum. Genet. 43: 2-8, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9609991/&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;9609991&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s100380050029&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="9609991">Nagata (1998)</a> pointed out that the recessive lymphoproliferation (lpr) phenotype and the generalized lymphoproliferative disease (gld) phenotype are mouse models of aberrant T-cell accumulation. In lpr mice, a splicing defect in the Fas gene results in greatly decreased expression of Fas. In mice with the lpr/cg (complementing gld) allele, a point mutation in the intracellular death domain of Fas abolishes the transmission of the apoptotic signal. In gld mice, a point mutation in the C terminus of Fasl impairs its ability to interact successfully with its receptor. These mutations lead to a failure of apoptosis and complex immune disorders in lpr and gld mutant mice that are analogous to the human disorders ALPS1A and ALPS1B. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9609991+11048730" 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="Bettinardi1997" class="mim-anchor"></a>
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<p class="mim-text-font">
Bettinardi, A., Brugnoni, D., Quiros-Roldan, E., Malagoli, A., La Grutta, S., Correra, A., Notarangelo, L. D.
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<a id="Canale1967" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Canale, V. C., Smith, C. H.
<strong>Chronic lymphadenopathy simulating malignant lymphoma.</strong>
J. Pediat. 70: 891-899, 1967.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4165068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4165068</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4165068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(67)80262-2" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
<a id="Dowdell2010" class="mim-anchor"></a>
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<p class="mim-text-font">
Dowdell, K. C., Niemela, J. E., Price, S., Davis, J., Hornung, R. L., Oliveira, J. B., Puck, J. M., Jaffe, E. S., Pittaluga, S., Cohen, J. I., Fleisher, T. A., Rao, V. K.
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[<a href="https://doi.org/10.1182/blood-2010-01-263145" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
<a id="Drappa1996" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Drappa, J., Vaishnaw, A. K., Sullivan, K. E., Chu, J.-L., Elkon, K. B.
<strong>Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity.</strong>
New Eng. J. Med. 335: 1643-1649, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929361</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8929361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199611283352204" target="_blank">Full Text</a>]
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<a id="Fisher1995" class="mim-anchor"></a>
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Fisher, G. H., Rosenberg, F. J., Straus, S. E., Dale, J. K., Middelton, L. A., Lin, A. Y., Strober, W., Lenardo, M. J., Puck, J. M.
<strong>Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.</strong>
Cell 81: 935-946, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7540117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7540117</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7540117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0092-8674(95)90013-6" target="_blank">Full Text</a>]
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<a id="Gronbaek1998" class="mim-anchor"></a>
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Gronbaek, K., Straten, P., Ralfkiaer, E., Ahrenkiel, V., Andersen, M. K., Hansen, N. E., Zeuthen, J., Hou-Jensen, K., Guldberg, P.
<strong>Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity.</strong>
Blood 92: 3018-3024, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9787134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9787134</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9787134" 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="Holzelova2004" class="mim-anchor"></a>
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Holzelova, E., Vonarbourg, C., Stolzenberg, M.-C., Arkwright, P. D., Selz, F., Prieur, A.-M., Blanche, S., Bartunkova, J., Vilmer, E., Fischer, A., Le Deist, F., Rieux-Laucat, F.
<strong>Autoimmune lymphoproliferative syndrome with somatic Fas mutations.</strong>
New Eng. J. Med. 351: 1409-1418, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459302</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa040036" target="_blank">Full Text</a>]
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<a id="Krammer2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Krammer, P. H.
<strong>CD95's deadly mission in the immune system.</strong>
Nature 407: 789-795, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11048730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11048730</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11048730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/35037728" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
<a id="Lenardo1999" class="mim-anchor"></a>
<div class="">
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Lenardo, M. J.
<strong>Personal Communication.</strong>
Bethesda, Md. 1/14/1999.
</p>
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<a id="Lim2005" class="mim-anchor"></a>
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Lim, W.-K., Ursea, R., Rao, K., Buggage, R. R., Suhler, E. B., Dugan, F., Chan, C.-C., Straus, S. E., Nussenblatt, R. B.
<strong>Bilateral uveitis in a patient with autoimmune lymphoproliferative syndrome.</strong>
Am. J. Ophthal. 139: 562-563, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15767081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15767081</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15767081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ajo.2004.09.017" target="_blank">Full Text</a>]
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<a id="Magerus-Chatinet2011" class="mim-anchor"></a>
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Magerus-Chatinet, A., Neven, B., Stolzenberg, M.-C., Daussy, C., Arkwright, P. D., Lanzarotti, N., Schaffner, C., Cluet-Dennetiere, S., Haerynck, F., Michel, G., Bole-Feysot, C., Zarhrate, M.., Radford-Weiss, I., Romana, S. P., Picard, C., Fischer, A., Rieux-Laucat, F.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21183795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21183795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21183795[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=21183795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI43752" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
<a id="Nagata1998" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Nagata, S.
<strong>Human autoimmune lymphoproliferative syndrome, a defect in the apoptosis-inducing Fas receptor: a lesson from the mouse model.</strong>
J. Hum. Genet. 43: 2-8, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9609991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9609991</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9609991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s100380050029" target="_blank">Full Text</a>]
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<a id="Puck2004" class="mim-anchor"></a>
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Puck, J. M., Straus, S. E.
<strong>Somatic mutations--not just for cancer anymore.</strong>
New Eng. J. Med. 351: 1388-1390, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15459299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15459299</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15459299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMp048116" target="_blank">Full Text</a>]
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<a id="Rieux-Laucat1995" class="mim-anchor"></a>
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<p class="mim-text-font">
Rieux-Laucat, F., Le Deist, F., Hivroz, C., Roberts, I. A. G., Debatin, K. M., Fischer, A., de Villartay, J. P.
<strong>Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity.</strong>
Science 268: 1347-1349, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7539157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7539157</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7539157" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.7539157" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="15" class="mim-anchor"></a>
<a id="Sneller1992" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Sneller, M. C., Straus, S. E., Jaffe, E. S., Jaffe, J. S., Fleisher, T. A., Stetler-Stevenson, M., Strober, W.
<strong>A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease.</strong>
J. Clin. Invest. 90: 334-341, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1386609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1386609</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1386609" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI115867" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="16" class="mim-anchor"></a>
<a id="Sneller1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Sneller, M. C., Wang, J., Dale, J. K., Strober, W., Middleton, L. A., Choi, Y., Fleisher, T. A., Lim, M. S., Jaffe, E. S., Puck, J. M., Lenardo, M. J., Straus, S. E.
<strong>Clinical, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis.</strong>
Blood 89: 1341-1348, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9028957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9028957</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9028957" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
</div>
</li>
<li>
<a id="17" class="mim-anchor"></a>
<a id="Straus2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Straus, S. E., Jaffe, E. S., Puck, J. M., Dale, J. K., Elkon, K. B., Rosen-Wolff, A., Peters, A. M. J., Sneller, M. C., Hallahan, C. W., Wang, J., Fischer, R. E., Jackson, C. M., Lin, A. Y., Baumler, C., Siegert, E., Marx, A., Vaishnaw, A. K., Grodzicky, T., Fleisher, T. A., Lenardo, M. J.
<strong>The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.</strong>
Blood 98: 194-200, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11418480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11418480</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11418480" 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.v98.1.194" target="_blank">Full Text</a>]
</p>
</div>
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<a id="18" class="mim-anchor"></a>
<a id="Straus1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Straus, S. E., Lenardo, M., Puck, J. M.
<strong>The Canale-Smith syndrome. (Letter)</strong>
New Eng. J. Med. 336: 1457 only, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9148156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9148156</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9148156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199705153362016" target="_blank">Full Text</a>]
</p>
</div>
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<a id="19" class="mim-anchor"></a>
<a id="Teachey2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Teachey, D. T., Seif, A. E., Grupp, S. A.
<strong>Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS).</strong>
Brit. J. Haemat. 148: 205-216, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19930184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19930184</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19930184[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=19930184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1365-2141.2009.07991.x" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="20" class="mim-anchor"></a>
<a id="Vaishnaw1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vaishnaw, A. K., Sullivan, K. E., Elkon, K. B.
<strong>Reply to S. E. Straus. (Letter)</strong>
New Eng. J. Med. 336: 1457-1458, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9148156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9148156</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9148156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199705153362016" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="21" class="mim-anchor"></a>
<a id="van der Burg2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
van der Burg, M., de Groot, R., Comans-Bitter, W. M., den Hollander, J. C., Hooijkaas, H., Neijens, H. J., Berger, R. M. F., Oranje, A. P., Langerak, A. W., van Dongen, J. J. M.
<strong>Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?</strong>
Pediat. Res. 47: 336-343, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10709732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10709732</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10709732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1203/00006450-200003000-00009" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="22" class="mim-anchor"></a>
<a id="Wu1996" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wu, J., Wilson, J., He, J., Xiang, L., Schur, P. H., Mountz, J. D.
<strong>Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease.</strong>
J. Clin. Invest. 98: 1107-1113, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8787672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8787672</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8787672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI118892" target="_blank">Full Text</a>]
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Cassandra L. Kniffin - updated : 3/1/2016
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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">
<span class="mim-text-font">
Cassandra L. Kniffin - updated : 5/10/2011<br>Jane Kelly - updated : 7/1/2005<br>Cassandra L. Kniffin - reorganized : 11/17/2004<br>Victor A. McKusick - updated : 9/20/2001<br>Paul J. Converse - updated : 10/11/2000<br>Victor A. McKusick - updated : 5/3/1999<br>Victor A. McKusick - updated : 3/16/1999<br>Victor A. McKusick - updated : 6/16/1997
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<span class="mim-text-font">
Victor A. McKusick : 6/11/1997
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<a id="editHistory" class="mim-anchor"></a>
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carol : 01/24/2019
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ckniffin : 01/18/2019<br>carol : 09/20/2016<br>alopez : 03/01/2016<br>ckniffin : 3/1/2016<br>carol : 12/1/2014<br>ckniffin : 12/1/2014<br>carol : 11/18/2014<br>mcolton : 11/13/2014<br>ckniffin : 11/13/2014<br>mgross : 10/7/2013<br>carol : 2/6/2012<br>carol : 2/6/2012<br>wwang : 5/23/2011<br>ckniffin : 5/10/2011<br>wwang : 1/30/2008<br>ckniffin : 12/20/2007<br>carol : 1/20/2006<br>alopez : 7/1/2005<br>carol : 11/17/2004<br>ckniffin : 11/3/2004<br>mcapotos : 12/20/2001<br>mcapotos : 9/27/2001<br>mcapotos : 9/21/2001<br>terry : 9/20/2001<br>alopez : 10/11/2000<br>carol : 10/27/1999<br>mgross : 6/21/1999<br>mgross : 6/16/1999<br>terry : 5/20/1999<br>mgross : 5/10/1999<br>mgross : 5/10/1999<br>mgross : 5/10/1999<br>terry : 5/3/1999<br>carol : 3/17/1999<br>terry : 3/16/1999<br>dkim : 7/24/1998<br>terry : 11/7/1997<br>alopez : 6/17/1997<br>alopez : 6/16/1997<br>mark : 6/11/1997<br>mark : 6/11/1997
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<h3>
<span class="mim-font">
<strong>#</strong> 601859
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<h3>
<span class="mim-font">
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; ALPS
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<span class="mim-font">
<em>Alternative titles; symbols</em>
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<h4>
<span class="mim-font">
CANALE-SMITH SYNDROME<br />
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE I, AUTOSOMAL DOMINANT
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<span class="mim-font">
Other entities represented in this entry:
</span>
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<span class="h3 mim-font">
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA, INCLUDED; ALPS1A, INCLUDED
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<span class="h4 mim-font">
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IB, INCLUDED; ALPS1B, INCLUDED<br />
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE I, AUTOSOMAL RECESSIVE, INCLUDED
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<strong>SNOMEDCT:</strong> 702444009; &nbsp;
<strong>ICD10CM:</strong> D89.82; &nbsp;
<strong>ICD9CM:</strong> 279.41; &nbsp;
<strong>ORPHA:</strong> 3261; &nbsp;
<strong>DO:</strong> 6688; &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
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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</thead>
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<td>
<span class="mim-font">
1q24.3
</span>
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<td>
<span class="mim-font">
Autoimmune lymphoproliferative syndrome, type IB
</span>
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<td>
<span class="mim-font">
601859
</span>
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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">
FASLG
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<span class="mim-font">
134638
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<span class="mim-font">
10q23.31
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</td>
<td>
<span class="mim-font">
{Autoimmune lymphoproliferative syndrome}
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<span class="mim-font">
601859
</span>
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<td>
<span class="mim-font">
Autosomal dominant
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<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
FAS
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<td>
<span class="mim-font">
134637
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<td>
<span class="mim-font">
10q23.31
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<td>
<span class="mim-font">
Autoimmune lymphoproliferative syndrome, type IA
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<td>
<span class="mim-font">
601859
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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">
FAS
</span>
</td>
<td>
<span class="mim-font">
134637
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</tbody>
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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 autoimmune lymphoproliferative syndrome (ALPS) type IA is caused by heterozygous mutation in the FAS gene (TNFRSF6, or CD95; 134637); ALPS type IB is caused by heterozygous mutation in the FAS ligand (FASL) gene (TNFSF6 or CD95L; 134638). Both germline and somatic mutations in the FAS gene have been identified in patients with ALPS type IA. A subset of patients may have a heterozygous germline mutation combined with a somatic mutation, resulting in a '2-hit' disease mechanism.</p>
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<strong>Description</strong>
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<p>Autoimmune lymphoproliferative syndrome is a heritable disorder of apoptosis, resulting in the accumulation of autoreactive lymphocytes. It manifests in early childhood as nonmalignant lymphadenopathy with hepatosplenomegaly and autoimmune cytopenias (summary by Dowdell et al., 2010). </p><p>For a review of the autoimmune lymphoproliferative syndromes, see Teachey et al. (2009). </p><p><strong><em>Genetic Heterogeneity of Autoimmune Lymphoproliferative Syndrome</em></strong></p><p>
Type IIA ALPS (ALPS2A; 603909) is caused by mutation in the caspase-10 gene (CASP10; 601762). Puck and Straus (2004) designated caspase-8 deficiency (607271), caused by mutations in the CASP8 gene (601763), as type IIB ALPS. ALPS3 (615559) is caused by mutation in the PRKCD gene (176977). RAS-associated ALPS (RALD, or ALPS4; 614470) is caused by mutation in the NRAS gene (164790). ALPS5 (616100) is caused by mutation in the CTLA4 gene (123890). </p>
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<span class="mim-font">
<strong>Clinical Features</strong>
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<p>Canale and Smith (1967) described a childhood syndrome of lymphadenopathy and splenomegaly associated with autoimmune hemolytic anemia and thrombocytopenia. </p><p>Sneller et al. (1992) reported 2 unrelated girls with a lymphoproliferative/autoimmune syndrome. The first patient developed cervical lymphadenopathy at age 18 months and anemia associated with splenomegaly at age 24 months. Over the next months, she developed renal insufficiency, and a renal biopsy showed mesangiopathic glomerulonephritis with crescent formation. Serologic studies for infectious etiology, including EBV, CMV, toxoplasmosis, HIV, brucella, and hepatitis were all negative. The second patient was diagnosed with autoimmune hemolytic anemia at age 9 months with a positive direct Coomb's test. At age 4 years, she developed peripheral lymphadenopathy, and CT scan at age 8 years showed hepatomegaly and mediastinal, mesenteric, and retroperitoneal adenopathy. Peripheral blood analysis showed that both patients had increased numbers of B lymphocytes and increased numbers of mature CD3+, CD4-, CD8- T lymphocytes expressing alpha/beta T-cell receptors; these T cells accounted for 40 to 60% of all T cells. Neither lymphocyte population was monoclonal. Lymph node biopsy showed paracortical infiltration of the CD4-, CD8- T cells. Sneller et al. (1992) noted that the phenotype in these girls was similar to that of lpr (see 134637) and gld (see 134638) mice. </p><p>Fisher et al. (1995) reported 4 unrelated children with ALPS who presented with nonmalignant lymphadenopathy or splenomegaly between 2 months and 5 years of age. All patients had autoimmune hemolytic anemia, thrombocytopenia, and recurrent urticarial rashes consistent with immune vasculitis. Peripheral blood analysis showed hypergammaglobulinemia and expanded populations of CD3+, CD4-, CD8- T lymphocytes in all patients. In vitro studies showed that the expanded T lymphocyte population had impaired TCR-induced apoptosis. Fisher et al. (1995) concluded that the disorder was caused by impaired control of mature lymphocyte homeostasis. </p><p>Drappa et al. (1996) provided follow-up on 2 patients reported by Canale and Smith (1967). One patient was a 43-year-old woman who had continued lymphadenopathy and hypergammaglobulinemia throughout her life. She also had several neoplastic lesions, including a breast adenoma, 3 thyroid adenomas, and 2 basal cell carcinomas. Another patient was a 43-year-old man whose lymphadenopathy had gradually diminished during adolescence and was mild during adulthood. He died of hepatocellular carcinoma associated with hepatitis C infection. The patient's son had lymphadenopathy with T-cell hyperplasia and autoimmune hemolytic anemia and thrombocytopenia. Activated T cells from the patients were almost completely resistant to apoptosis induced by ligating the Fas receptor with an anti-Fas antibody. The findings indicated that ALPS is compatible with long-term survival. Sneller et al. (1997) reported 9 unrelated patients with ALPS characterized by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD3+, CD4-, CD8- T cells. Hemolytic anemia was the most frequent form of autoimmune disease, occurring in 6 patients with or without idiopathic thrombocytopenic purpura. All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the FAS gene were detected in 8 patients, and 7 of 8 kindreds had healthy relatives with FAS mutations. These relatives also showed in vitro abnormalities of FAS-mediated lymphocyte apoptosis, but clinical features of ALPS were not present. In 1 ALPS patient, no FAS or FASL gene mutations were identified, and Sneller et al. (1997) proposed the designation ALPS type II to refer to the syndrome in the absence of mutations in these genes. </p><p>Van der Burg et al. (2000) reported a girl, born of consanguineous parents, who presented immediately after birth with petechiae, generalized edema, and hepatosplenomegaly. During the first month of life, autoantibodies against red blood cells and platelets were demonstrated. A liver biopsy showed extensive extramedullary hematopoiesis, and she had massive generalized adenopathy of the cervical, mesenteric, and paraaortic lymph nodes. Hypergammaglobulinemia persisted for several years; a cutaneous lupus-like disease appeared at a later stage. The patient had histologically malignant lymph nodes, although monoclonal or oligoclonal rearrangements could not be detected on analysis of the gene encoding the T-cell antigen receptor beta subunit (TCRB; see 186930). There was no detectable FAS expression on freshly isolated blood leukocytes. </p>
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<h4>
<span class="mim-font">
<strong>Other Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Straus et al. (1997) stated that their experience with over 20 patients with ALPS from 13 kindreds indicated a wider clinical spectrum than that described by Canale and Smith (1967) or by Drappa et al. (1996), including Guillain-Barre syndrome (139393) and panniculitis. In addition, Straus et al. (1997) noted that B-lymphomas developed in early adulthood in 2 brothers with FAS mutations. Four different patients with ALPS had normal FAS and FASL genes, but impaired apoptosis caused by an abnormality in the FAS pathway, suggesting that abnormalities of other proteins in the FAS-signaling cascade or in parallel apoptotic pathways may also cause ALPS. </p><p>Straus et al. (2001) found that 130 individuals in 39 families segregating ALPS had heterozygous germline FAS mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected. All 10 patients with FAS mutations had defective lymphocyte apoptosis and most had other features of ALPS. The average age of ALPS onset was 5 years, whereas the average age of lymphoma diagnosis was 28 years. The cases in which somatic alterations in FAS were described in lymphomas (e.g., Gronbaek et al., 1998) more typically arose later in life. Straus et al. (2001) stated that the mechanism by which FAS defects in ALPS predispose to lymphomas might involve several components. They suggested that the most obvious possibility is that a general expansion of the lymphoid pool provides a larger target cell population for other transforming events. </p><p>Lim et al. (2005) reported a case of bilateral uveitis in an 8-year old child with ALPS1A. The authors concluded that despite a Th2 immune predominance in ALPS, uveitis, a Th1-mediated disease, might still manifest in these patients. They hypothesized that the pathogenesis of uveitis in ALPS might differ from that of the systemic disease overall. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>ALPS is most often transmitted in an autosomal dominant manner. However, autosomal recessive inheritance of ALPS1A due to homozygous or compound heterozygous mutations in the FAS gene has been described. In addition, Dowdell et al. (2010) noted that one-third of patients may have somatic mutations in the FAS gene. </p><p>In a girl with severe ALPS1A, born of consanguineous parents, van der Burg et al. (2000) identified a homozygous 20-bp duplication in the FAS gene (134637.0013). The findings indicated that autosomal recessive inheritance. Van der Burg et al. (2000) noted that Rieux-Laucat et al. (1995) and Bettinardi et al. (1997) had reported similar patients with 2 FAS gene mutations (see 134637.0006 and 134637.0007). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p><strong><em>ALPS1A Due to Heterozygous Mutations in the FAS Gene</em></strong></p><p>
In 5 unrelated patients with ALPS1A, 1 of whom was reported by Sneller et al. (1992), Fisher et al. (1995) identified heterozygous mutations in the FAS gene (134637.0001-134637.0005). </p><p>In 2 patients with ALPS1A first reported by Canale and Smith (1967), Drappa et al. (1996) identified heterozygous mutations in the FAS gene (134637.0019; 134637.0020). </p><p><strong><em>ALPS1A Due to Biallelic Mutations in the FAS Gene</em></strong></p><p>
In a girl with severe ALPS1A, born of consanguineous parents, van der Burg et al. (2000) identified a homozygous 20-bp duplication in the FAS gene (134637.0013). Van der Burg et al. (2000) noted that Rieux-Laucat et al. (1995) and Bettinardi et al. (1997) had reported similar patients with 2 FAS gene mutations (see 134637.0006 and 134637.0007). </p><p><strong><em>ALPS1A Due to Heterozygous Germline and Additional Somatic Mutations in the FAS Gene</em></strong></p><p>
Dowdell et al. (2010) found that 12 (38.7%) of 31 ALPS patients who were negative for germline FAS mutations carried heterozygous somatic FAS mutations in their double-negative T cells. All of the 12 somatic mutations resulted in known or predicted functional loss of normal FAS signaling; 10 mutations led to a premature stop codon. Patients with somatic FAS mutations were clinically similar to those with germline FAS mutations, although they had a slightly lower incidence of splenectomy and lower lymphocyte counts. </p><p>Holzelova et al. (2004) reported 6 children with an unusual form of ALPS, characterized by elevated numbers of double-negative T cells and hypergammaglobulinemia, but normal Fas-mediated apoptosis of T cells in vitro. Double-negative T cells from all 6 patients showed heterozygous mutations in the FAS gene (see, e.g., 134637.0018). In 2 affected patients, FAS mutations were found in a fraction of CD4+ and CD8+ T cells, monocytes, and CD34+ hematopoietic precursors, but not in hair or mucosal epithelial cells, demonstrating somatic mosaicism. </p><p>Magerus-Chatinet et al. (2011) reported 7 unrelated patients with typical features of ALPS associated with heterozygous germline mutations in the FAS gene. Four of the patients had asymptomatic relatives who were heterozygous for the same mutation, suggesting incomplete penetrance. All 7 patients and the carrier relatives had low FAS-mediated T cell apoptosis in vitro compared to controls. However, only the symptomatic patients also had increased double-negative T cells, increased IL10 (124092), and increased FAS ligand (FASL; 134638). Three of the 7 symptomatic patients were subsequently found to carry a heterozygous somatic FAS mutation within double-negative T cells, whereas the remaining 4 symptomatic patients showed somatic loss of the wildtype allele. These somatic events were not found in any of the asymptomatic heterozygous carriers. The additional somatic event in the 7 patients led to a clear and profound TNFRSF6 expression defect in the majority of double-negative T cells in all patients except 1, who carried 2 missense mutations that were predicted to be nonfunctional. The double-mutant lymphocytes could not be killed by FAS ligand. These findings were similar to those observed in patients with biallelic TNFRS6 mutations, and supported the idea of a '2-hit' mechanism in which loss of both alleles in relevant cells causes symptomatic lymphoproliferation. </p><p><strong><em>ALPS1B Due to Mutations in the FASL Gene</em></strong></p><p>
Wu et al. (1996) reported an African American man with systemic lupus erythematosus (SLE; 152700) and lymphadenopathy who had a heterozygous mutation in the FASL gene (134638.0001). Peripheral blood mononuclear cells from this patient showed decreased FASL activity, decreased activation-induced cell death, and increased T-cell proliferation after activation. Although the patient did not have increased numbers of CD4-, CD8- T cells, Wu et al. (1996) suggested that the lymphadenopathy and autoimmune disease were consistent with an adult type of ALPS. Lenardo (1999) noted that although this patient satisfied the rheumatologic criteria for a diagnosis of SLE, the features were more consistent with ALPS. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
For discussion of a possible association between ALPS and variation in the RELA gene, see 164014.0002.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Nomenclature</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Vaishnaw et al. (1997) urged the use of the eponym 'Canale-Smith syndrome.' They argued that the term 'lymphoproliferative syndrome' connotes malignancy, but that lymphadenopathy associated with FAS mutations results primarily from the accumulation of lymphocytes due to the failure of FAS-mediated apoptosis. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Krammer (2000) and Nagata (1998) pointed out that the recessive lymphoproliferation (lpr) phenotype and the generalized lymphoproliferative disease (gld) phenotype are mouse models of aberrant T-cell accumulation. In lpr mice, a splicing defect in the Fas gene results in greatly decreased expression of Fas. In mice with the lpr/cg (complementing gld) allele, a point mutation in the intracellular death domain of Fas abolishes the transmission of the apoptotic signal. In gld mice, a point mutation in the C terminus of Fasl impairs its ability to interact successfully with its receptor. These mutations lead to a failure of apoptosis and complex immune disorders in lpr and gld mutant mice that are analogous to the human disorders ALPS1A and ALPS1B. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
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Canale, V. C., Smith, C. H.
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Fisher, G. H., Rosenberg, F. J., Straus, S. E., Dale, J. K., Middelton, L. A., Lin, A. Y., Strober, W., Lenardo, M. J., Puck, J. M.
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Gronbaek, K., Straten, P., Ralfkiaer, E., Ahrenkiel, V., Andersen, M. K., Hansen, N. E., Zeuthen, J., Hou-Jensen, K., Guldberg, P.
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Holzelova, E., Vonarbourg, C., Stolzenberg, M.-C., Arkwright, P. D., Selz, F., Prieur, A.-M., Blanche, S., Bartunkova, J., Vilmer, E., Fischer, A., Le Deist, F., Rieux-Laucat, F.
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Krammer, P. H.
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<p class="mim-text-font">
Lenardo, M. J.
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</p>
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Lim, W.-K., Ursea, R., Rao, K., Buggage, R. R., Suhler, E. B., Dugan, F., Chan, C.-C., Straus, S. E., Nussenblatt, R. B.
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<p class="mim-text-font">
Magerus-Chatinet, A., Neven, B., Stolzenberg, M.-C., Daussy, C., Arkwright, P. D., Lanzarotti, N., Schaffner, C., Cluet-Dennetiere, S., Haerynck, F., Michel, G., Bole-Feysot, C., Zarhrate, M.., Radford-Weiss, I., Romana, S. P., Picard, C., Fischer, A., Rieux-Laucat, F.
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Nagata, S.
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Puck, J. M., Straus, S. E.
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Rieux-Laucat, F., Le Deist, F., Hivroz, C., Roberts, I. A. G., Debatin, K. M., Fischer, A., de Villartay, J. P.
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Sneller, M. C., Straus, S. E., Jaffe, E. S., Jaffe, J. S., Fleisher, T. A., Stetler-Stevenson, M., Strober, W.
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[PubMed: 1386609]
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</p>
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Sneller, M. C., Wang, J., Dale, J. K., Strober, W., Middleton, L. A., Choi, Y., Fleisher, T. A., Lim, M. S., Jaffe, E. S., Puck, J. M., Lenardo, M. J., Straus, S. E.
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<p class="mim-text-font">
Straus, S. E., Jaffe, E. S., Puck, J. M., Dale, J. K., Elkon, K. B., Rosen-Wolff, A., Peters, A. M. J., Sneller, M. C., Hallahan, C. W., Wang, J., Fischer, R. E., Jackson, C. M., Lin, A. Y., Baumler, C., Siegert, E., Marx, A., Vaishnaw, A. K., Grodzicky, T., Fleisher, T. A., Lenardo, M. J.
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Straus, S. E., Lenardo, M., Puck, J. M.
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Teachey, D. T., Seif, A. E., Grupp, S. A.
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</p>
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van der Burg, M., de Groot, R., Comans-Bitter, W. M., den Hollander, J. C., Hooijkaas, H., Neijens, H. J., Berger, R. M. F., Oranje, A. P., Langerak, A. W., van Dongen, J. J. M.
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<p class="mim-text-font">
Wu, J., Wilson, J., He, J., Xiang, L., Schur, P. H., Mountz, J. D.
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</p>
</li>
</ol>
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