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<title>
Entry
- #242860 - IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1; ICF1
- OMIM
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<span class="h4">#242860</span>
<br />
<strong>Table of Contents</strong>
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<li role="presentation">
<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
<a href="/clinicalSynopsis/242860"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
<a href="/phenotypicSeries/PS242860"> <strong>Phenotypic Series</strong> </a>
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<li role="presentation">
<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#clinicalFeatures">Clinical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#clinicalManagement">Clinical Management</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</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="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#heterogeneity">Heterogeneity</a>
</li>
<li role="presentation">
<a href="#references"><strong>References</strong></a>
</li>
<li role="presentation">
<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
<a href="#creationDate"><strong>Creation Date</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
</h4>
</div>
</div>
<div id="mimExternalLinksFold" class="collapse in">
<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
<span class="panel-title">
<span class="small">
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9660;</div>
&nbsp;
<div style="display: table-cell;">Clinical Resources</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
<div class="panel-body small mim-panel-body">
<div><a href="https://clinicaltrials.gov/search?cond=(IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME) OR (DNMT3B)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=1018&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
<div><a href="https://www.diseaseinfosearch.org/x/3708" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=242860[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2268" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/4953d9fe-3321-4fb2-8fa8-14cc0e492f6b/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0090008" 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/242860" 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>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:242860" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</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> 234633000<br />
<strong>ORPHA:</strong> 2268<br />
<strong>DO:</strong> 0090008<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>
242860
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1; ICF1
</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">
IMMUNE DEFICIENCY, VARIABLE, WITH CENTROMERIC INSTABILITY OF CHROMOSOMES 1, 9, AND 16<br />
CENTROMERIC INSTABILITY, IMMUNODEFICIENCY SYNDROME; CIID<br />
IMMUNODEFICIENCY SYNDROME, VARIABLE
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/203?start=-3&limit=10&highlight=203">
20q11.21
</a>
</span>
</td>
<td>
<span class="mim-font">
Immunodeficiency-centromeric instability-facial anomalies syndrome 1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/242860"> 242860 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
DNMT3B
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602900"> 602900 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/242860" 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">
<a href="/phenotypicSeries/PS242860" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
<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/242860" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/242860" 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 recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Height </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Below the third percentile <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855764&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855764</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Weight </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Below the third percentile <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855764&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855764</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Other </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Head circumference below the third percentile <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855765&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855765</a>]</span><br /> -
Failure to thrive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/432788009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">432788009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54840006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54840006</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0015544&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0015544</a>, <a href="https://bioportal.bioontology.org/search?q=C2315100&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2315100</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001508</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Head </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Sinusitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36971009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36971009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J32" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J32</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0037199&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037199</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000246" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000246</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000246" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000246</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Flat face <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853241&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853241</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012368" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012368</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012368" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012368</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=9ba328482ffd2d39f0d1071965725b03" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Face,Flat-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=9ba328482ffd2d39f0d1071965725b03&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Epicanthal folds <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74824007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74824007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0678230&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0678230</a>, <a href="https://bioportal.bioontology.org/search?q=C0229249&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0229249</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000286</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000286</a>]</span><br /> -
Hypertelorism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22006008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22006008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q75.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q75.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/376.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">376.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020534&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020534</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000316" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000316</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000316" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000316</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=593a4d488f00bb03351a0ddffaf4ac9a" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Eyes,Widely_Spaced-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=593a4d488f00bb03351a0ddffaf4ac9a&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Low set ears <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95515009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95515009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q17.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q17.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239234&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239234</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000369" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000369</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000369" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000369</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Nose </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Flat nasal bridge <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836542&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836542</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005280</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005280" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005280</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=7043769fd21a78a413fd758918cdda17" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Nasal_Bridge,Depressed-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=7043769fd21a78a413fd758918cdda17&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Small upturned nose <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855766&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855766</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Mouth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Micrognathia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32958008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32958008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M26.04" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M26.04</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/524.04" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">524.04</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0025990&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025990</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000347</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000347</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=9149eccae19753e96defbd69602ab882" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Micrognathia-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=9149eccae19753e96defbd69602ab882&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Tongue protrusion <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249872000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249872000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/285503005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">285503005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241442&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241442</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010808</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010808</a>]</span><br /> -
Macroglossia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/25273001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">25273001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/270516002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">270516002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K14.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K14.8</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q38.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q38.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/750.15" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">750.15</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0024421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024421</a>, <a href="https://bioportal.bioontology.org/search?q=C0009677&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009677</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000158" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000158</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000158" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000158</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=ac5acf24e74116d49a4df85084887155" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Tongue,Large-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=ac5acf24e74116d49a4df85084887155&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> RESPIRATORY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Airways </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Chronic bronchitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/63480004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">63480004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J42" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J42</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/491.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">491.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/491" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">491</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0008677&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008677</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004469" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004469</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004469" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004469</a>]</span><br /> -
Bronchiectasis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/12295008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">12295008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/J47" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J47</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/J47.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">J47.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/494" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">494</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0006267&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0006267</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002110" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002110</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002110" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002110</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Lung </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pneumonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/233604007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">233604007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0032285&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0032285</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002090" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002090</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002090" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002090</a>]</span><br />
</span>
</div>
</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> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Diarrhea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267060006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267060006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/62315008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">62315008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R19.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R19.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011991&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011991</a>, <a href="https://bioportal.bioontology.org/search?q=C2169706&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2169706</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span><br /> -
Malabsorption <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/32230006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">32230006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/197476001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">197476001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K90.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K90.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K90</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/579.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">579.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/579" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">579</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0024523&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0024523</a>, <a href="https://bioportal.bioontology.org/search?q=C3714745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714745</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002024" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002024</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002024" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002024</a>]</span><br />
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<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
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<em> Central Nervous System </em>
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<span class="mim-font">
- Variable mental retardation ranging from severe neurodegeneration to mild mental retardation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855763&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855763</a>]</span><br />
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<strong> IMMUNOLOGY </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
- Reduced number of T cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2931322&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2931322</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005403" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005403</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005403" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005403</a>]</span><br /> -
Reduced number of natural killer cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855767&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855767</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0040218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0040218</a>]</span><br />
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<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Reduced IgA <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855768&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855768</a>]</span><br /> -
Increased IgM <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239990&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239990</a>]</span><br />
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<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Centromeric instability of chromosomes 1, 9 and 16 with increased somatic recombination and formation of multibranched configurations<br />
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<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
- Caused by mutation in the DNA methyl-transferase 3B gene (DNMT3B, <a href="/entry/602900#0001">602900.0001</a>)<br />
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
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<h5>
Immunodeficiency-centromeric instability-facial anomalies
- <a href="/phenotypicSeries/PS242860">PS242860</a>
- 4 Entries
</h5>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<strong>Location</strong>
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<strong>Phenotype</strong>
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<strong>Inheritance</strong>
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<strong>Phenotype<br />mapping key</strong>
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<strong>Phenotype<br />MIM number</strong>
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<strong>Gene/Locus</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
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</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/783?start=-3&limit=10&highlight=783"> 2q31.1 </a>
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<td>
<span class="mim-font">
<a href="/entry/616910"> Immunodeficiency-centromeric instability-facial anomalies syndrome 3 </a>
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<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<td>
<span class="mim-font">
<a href="/entry/616910"> 616910 </a>
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</td>
<td>
<span class="mim-font">
<a href="/entry/609937"> CDCA7 </a>
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</td>
<td>
<span class="mim-font">
<a href="/entry/609937"> 609937 </a>
</span>
</td>
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<td>
<span class="mim-font">
<a href="/geneMap/6/767?start=-3&limit=10&highlight=767"> 6q21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614069"> Immunodeficiency-centromeric instability-facial anomalies syndrome 2 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614069"> 614069 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614064"> ZBTB24 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614064"> 614064 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/416?start=-3&limit=10&highlight=416"> 10q23.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616911"> Immunodeficiency-centromeric instability-facial anomalies syndrome 4 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
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<td>
<span class="mim-font">
<a href="/entry/616911"> 616911 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603946"> HELLS </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603946"> 603946 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/203?start=-3&limit=10&highlight=203"> 20q11.21 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/242860"> Immunodeficiency-centromeric instability-facial anomalies syndrome 1 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/242860"> 242860 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602900"> DNMT3B </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602900"> 602900 </a>
</span>
</td>
</tr>
</tbody>
</table>
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because immunodeficiency-centromeric instability-facial anomalies syndrome-1 is caused by homozygous or compound heterozygous mutation in the gene encoding DNA methyltransferase-3B (DNMT3B; <a href="/entry/602900">602900</a>) on chromosome 20q11.</p>
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</div>
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<div>
<a id="description" class="mim-anchor"></a>
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<strong>Description</strong>
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<p>Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare autosomal recessive disease characterized by facial dysmorphism, immunoglobulin deficiency, and branching of chromosomes 1, 9, and 16 after phytohemagglutinin (PHA) stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients that is explained by mutations in the DNMT3B gene in some, but not all, ICF patients (<a href="#11" class="mim-tip-reference" title="Hagleitner, M. M., Lankester, A., Maraschio, P., Hulten, M., Fryns, J. P., Schuetz, C., Gimelli, G., Davies, E. G., Gennery, A., Belohradsky, B. H., de Groot, R., Gerritsen, E. J. A., and 12 others. &lt;strong&gt;Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).&lt;/strong&gt; J. Med. Genet. 45: 93-99, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17893117/&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;17893117&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2007.053397&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="17893117">Hagleitner et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17893117" 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 Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome</em></strong></p><p>
See also ICF2 (<a href="/entry/614069">614069</a>), caused by mutation in the ZBTB24 gene (<a href="/entry/614064">614064</a>) on chromosome 6q21; ICF3 (<a href="/entry/616910">616910</a>), caused by mutation in the CDCA7 gene (<a href="/entry/609937">609937</a>) on chromosome 2q31; and ICF4 (<a href="/entry/616911">616911</a>), caused by mutation in the HELLS gene (<a href="/entry/603946">603946</a>) on chromosome 10q23.</p>
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<strong>Clinical Features</strong>
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</h4>
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<p>Variable immune deficiency in association with centromeric instability of chromosomes 1, 9, 16, and, rarely, 2, with an increased frequency of somatic recombination of the arms of these chromosomes and a marked tendency to formation of multibranched configurations, has been reported by <a href="#15" class="mim-tip-reference" title="Hulten, M. &lt;strong&gt;Selective somatic pairing and fragility at 1q12 in a boy with common variable immunodeficiency. (Abstract)&lt;/strong&gt; Clin. Genet. 14: 294 only, 1978."None>Hulten (1978)</a>, <a href="#35" class="mim-tip-reference" title="Tiepolo, L., Maraschio, P., Gimelli, G., Cuoco, C., Gargani, G. F., Romano, C. &lt;strong&gt;Multibranched chromosomes 1, 9 and 16 in a patient with combined IgA and IgE deficiency.&lt;/strong&gt; Hum. Genet. 51: 127-137, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/511139/&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;511139&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00287166&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="511139">Tiepolo et al. (1979)</a>, <a href="#8" class="mim-tip-reference" title="Fryns, J. P., Azou, M., Jaeken, J., Eggermont, E., Pedersen, J. C., Van den Berghe, H. &lt;strong&gt;Centromeric instability of chromosomes 1, 9, and 16 associated with combined immunodeficiency.&lt;/strong&gt; Hum. Genet. 57: 108-110, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7262865/&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;7262865&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00271181&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="7262865">Fryns et al. (1981)</a>, <a href="#14" class="mim-tip-reference" title="Howard, P. Y., Lewis, Y. J., Harris, F., Walker, S. &lt;strong&gt;Centromeric instability of chromosomes 1 and 16 with variable immune deficiency: a new syndrome.&lt;/strong&gt; Clin. Genet. 27: 501-505, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4006276/&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;4006276&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1985.tb00239.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="4006276">Howard et al. (1985)</a>, and <a href="#37" class="mim-tip-reference" title="Valkova, G., Ghenev, E., Tzancheva, M. &lt;strong&gt;Centromeric instability of chromosomes 1, 9 and 16 with variable immune deficiency: support of a new syndrome.&lt;/strong&gt; Clin. Genet. 31: 119-124, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3568436/&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;3568436&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1987.tb02781.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="3568436">Valkova et al. (1987)</a>. Three males and 2 females have been reported. The parents are clinically and cytogenetically normal. In 2 of the 5 families, those reported by <a href="#35" class="mim-tip-reference" title="Tiepolo, L., Maraschio, P., Gimelli, G., Cuoco, C., Gargani, G. F., Romano, C. &lt;strong&gt;Multibranched chromosomes 1, 9 and 16 in a patient with combined IgA and IgE deficiency.&lt;/strong&gt; Hum. Genet. 51: 127-137, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/511139/&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;511139&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00287166&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="511139">Tiepolo et al. (1979)</a> and <a href="#37" class="mim-tip-reference" title="Valkova, G., Ghenev, E., Tzancheva, M. &lt;strong&gt;Centromeric instability of chromosomes 1, 9 and 16 with variable immune deficiency: support of a new syndrome.&lt;/strong&gt; Clin. Genet. 31: 119-124, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3568436/&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;3568436&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1987.tb02781.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="3568436">Valkova et al. (1987)</a>, sibs were affected. The most frequent symptoms of the syndrome are facial dysmorphism, mental retardation, recurrent and prolonged respiratory infections, infections of the skin and digestive system, and variable immune deficiency with a constant decrease of IgA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7262865+511139+4006276+3568436" 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="#24" class="mim-tip-reference" title="Maraschio, P., Zuffardi, O., Dalla Fior, T., Tiepolo, L. &lt;strong&gt;Immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9, and 16, and facial anomalies: the ICF syndrome.&lt;/strong&gt; J. Med. Genet. 25: 173-180, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3351904/&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;3351904&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.25.3.173&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="3351904">Maraschio et al. (1988)</a> described ICF syndrome in a 4-year-old girl. From the age of 2 years she had suffered from recurrent pulmonary infections and from diarrhea in the summertime. The face was described as dysmorphic with hypertelorism, flat nasal bridge, low-set ears, and protrusion of the tongue. <a href="#23" class="mim-tip-reference" title="Maraschio, P., Tupler, R., Dainotti, E., Piantanida, M., Cazzola, G., Tiepolo, L. &lt;strong&gt;Differential expression of the ICF (immunodeficiency, centromeric heterochromatin, facial anomalies) mutation in lymphocytes and fibroblasts.&lt;/strong&gt; J. Med. Genet. 26: 452-456, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2746618/&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;2746618&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.26.7.452&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="2746618">Maraschio et al. (1989)</a> reported further clinical data on this child, who had severe chronic bronchitis with bronchiectasis, maxillary sinusitis, and otitis media. They demonstrated that, unlike lymphocytes, fibroblasts showed no major chromosomal anomalies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2746618+3351904" 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="#36" class="mim-tip-reference" title="Turleau, C., Cabanis, M.-O., Girault, D., Ledeist, F., Mettey, R., Puissant, H., Prieur, M., de Grouchy, J. &lt;strong&gt;Multibranched chromosomes in the ICF syndrome: immunodeficiency, centromeric instability, and facial anomalies.&lt;/strong&gt; Am. J. Med. Genet. 32: 420-424, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2729362/&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;2729362&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320320331&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="2729362">Turleau et al. (1989)</a> reported a patient with ICF syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2729362" 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="Haas, O. A. &lt;strong&gt;Centromeric heterochromatin instability of chromosomes 1, 9, and 16 in variable immunodeficiency syndrome--a virus-induced phenomenon?&lt;/strong&gt; Hum. Genet. 85: 244-246, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2196213/&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;2196213&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00193205&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="2196213">Haas (1990)</a> pointed to 8 reports of variable immunodeficiency associated with instability of the centromeric regions of chromosomes 1, 9, and 16. The children suffered from a serious variable immunodeficiency, mild developmental delay, and facial abnormalities with hypertelorism, a flat nasal bridge, epicanthal folds, protrusion of the tongue, and mild micrognathia. The severity of the disorder was indicated by the fact that 3 children died at ages 14, 12.5, and 2.5 years. They showed absence or severe reduction of at least 2 immunoglobulin classes with or without a defective cell-mediated immunity. Although no cytogenetically documented familial cases were reported, a genetic trait was suggested by the retrospective recognition of similar symptoms in deceased sibs of 2 of the patients (<a href="#35" class="mim-tip-reference" title="Tiepolo, L., Maraschio, P., Gimelli, G., Cuoco, C., Gargani, G. F., Romano, C. &lt;strong&gt;Multibranched chromosomes 1, 9 and 16 in a patient with combined IgA and IgE deficiency.&lt;/strong&gt; Hum. Genet. 51: 127-137, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/511139/&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;511139&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00287166&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="511139">Tiepolo et al., 1979</a>; <a href="#37" class="mim-tip-reference" title="Valkova, G., Ghenev, E., Tzancheva, M. &lt;strong&gt;Centromeric instability of chromosomes 1, 9 and 16 with variable immune deficiency: support of a new syndrome.&lt;/strong&gt; Clin. Genet. 31: 119-124, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3568436/&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;3568436&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1987.tb02781.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="3568436">Valkova et al., 1987</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3568436+511139+2196213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Fasth, A., Forestier, E., Holmberg, E., Holmgren, G., Nordenson, I., Soderstrom, T., Wahlstrom, J. &lt;strong&gt;Fragility of the centromeric region of chromosome 1 associated with combined immunodeficiency in siblings: a recessively inherited entity?&lt;/strong&gt; Acta Paediat. Scand. 79: 605-612, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2386052/&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;2386052&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1651-2227.1990.tb11524.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="2386052">Fasth et al. (1990)</a> observed instability of the centromeric region of chromosome 1 and multibranched configurations formed by the short and long arms in a brother and sister with facial dysmorphism, mental retardation, and recurrent infections. The parents, who were first cousins, showed no chromosomal abnormalities. A combined immunodeficiency characterized by a lack of immunoglobulin production, low numbers of T cells, and lack of cells with NK (natural killer) cell markers was found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2386052" 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="#9" class="mim-tip-reference" title="Gimelli, G., Varone, P., Pezzolo, A., Lerone, M., Pistoia, V. &lt;strong&gt;ICF syndrome with variable expression in sibs.&lt;/strong&gt; J. Med. Genet. 30: 429-432, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8320711/&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;8320711&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.30.5.429&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="8320711">Gimelli et al. (1993)</a> reported ICF syndrome in a 29-year-old woman and her 30-year-old brother. The proband showed mental retardation, facial anomalies, recurrent respiratory infections, combined deficit of IgM and IgE immunoglobulin classes, and paracentromeric heterochromatin instability of chromosomes 1, 9, and 16. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8320711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Smeets, D. F. C. M., Moog, U., Weemaes, C. M. R., Vaes-Peeters, G., Merkx, G. F. M., Niehof, J. P., Hamers, G. &lt;strong&gt;ICF syndrome: a new case and review of the literature .&lt;/strong&gt; Hum. Genet. 94: 240-246, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8076938/&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;8076938&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00208277&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="8076938">Smeets et al. (1994)</a> reported an affected boy with ICF syndrome and reviewed the 14 previously reported cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8076938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Brown, D. C., Grace, E., Sumner, A. T., Edmunds, A. T., Ellis, P. M. &lt;strong&gt;ICF syndrome (immunodeficiency, centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome.&lt;/strong&gt; Hum. Genet. 96: 411-416, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7557962/&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;7557962&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00191798&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="7557962">Brown et al. (1995)</a> described a 25-month-old girl with ICF syndrome. The proband's grandfathers were twin brothers and her grandmothers were sisters. Assuming that the twin grandfathers were monozygotic, the parents were related to each as half sibs, giving a coefficient of relationship of one-fourth; but they were also related to each other as first cousins, giving an additional coefficient of relatedness of one-eighth and a total coefficient of three-eighths. In other words, the parents were related as something half way between half sibs and full sibs. <a href="#3" class="mim-tip-reference" title="Brown, D. C., Grace, E., Sumner, A. T., Edmunds, A. T., Ellis, P. M. &lt;strong&gt;ICF syndrome (immunodeficiency, centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome.&lt;/strong&gt; Hum. Genet. 96: 411-416, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7557962/&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;7557962&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00191798&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="7557962">Brown et al. (1995)</a> reviewed the features of the 15 published ICF cases. All but 1 had facial anomalies, most often hypertelorism, flat nasal bridge, epicanthic folds, protrusion of the tongue, and micrognathia. Mental retardation was variable, from severe neurodegeneration to special educational needs without any delay in motor function. Their patient was typical in that speech development was delayed. Follow-up information was provided on the published cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7557962" 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="Franceschini, P., Martino, S., Ciocchini, M., Ciuti, E., Vardeu, M. P., Guala, A., Signorile, F., Camerano, P., Franceschini, D., Tovo, P. A. &lt;strong&gt;Variability of clinical and immunological phenotype in immunodeficiency-centromeric instability-facial anomalies syndrome: report of two new patients and review of the literature.&lt;/strong&gt; Europ. J. Pediat. 154: 840-846, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8529685/&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;8529685&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01959794&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="8529685">Franceschini et al. (1995)</a> reported 2 new patients and reviewed the literature. They commented on the marked phenotypic variability in the 15 affected individuals reported to that time. Both of their patients were boys found to have hypogammaglobulinemia. Both of them were described as having bipartite nipples. One had shawl scrotum and the other had cryptorchidism and hypospadias. The photographs showed striking similarity of facies in the 2 boys. They showed abnormal mitotic configurations, involving chromosomes 1, 16, and to a lesser extent, 9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8529685" 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="De Ravel, T. J. L., Deckers, E., Alliet, P. L. O., Petit, P., Fryns, J. P. &lt;strong&gt;The ICF syndrome: new case and update.&lt;/strong&gt; Genet. Counsel. 12: 379-385, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11837609/&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;11837609&lt;/a&gt;]" pmid="11837609">De Ravel et al. (2001)</a> found reports of 32 cases of this rare disorder. They reported findings in a young patient who received appropriate early therapy, with a good outcome. The published photograph showed hypertelorism, low-set ears, and high forehead as facial features. Starting at the age of 7 months, gammaglobulin was periodically administered intravenously, with no serious infections occurring. Despite nasogastric feeding, malnutrition was a problem, requiring continuous gastrostomy feeding from 19 to 28 months of age. A verbal IQ of 104 and a performance IQ of 90 was observed at 4 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11837609" 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="Hagleitner, M. M., Lankester, A., Maraschio, P., Hulten, M., Fryns, J. P., Schuetz, C., Gimelli, G., Davies, E. G., Gennery, A., Belohradsky, B. H., de Groot, R., Gerritsen, E. J. A., and 12 others. &lt;strong&gt;Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).&lt;/strong&gt; J. Med. Genet. 45: 93-99, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17893117/&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;17893117&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2007.053397&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="17893117">Hagleitner et al. (2008)</a> reviewed the clinical features of 45 patients with ICF syndrome. Facial dysmorphism, including epicanthic folds, hypertelorism, flat nasal bridge, and low-set ears, was commonly present. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (39 of 44), and opportunistic infections were seen in several patients, indicating T-cell dysfunction. However, there was phenotypic variability in that not all patients had obvious facial dysmorphism, and 39% had normal intelligence. Life expectancy was poor: 17 (40.5%) patients died at a mean age of 8 years, predominantly due to severe respiratory tract infections, sepsis, and failure to thrive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17893117" 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="clinicalManagement" class="mim-anchor"></a>
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<strong>Clinical Management</strong>
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<p><a href="#11" class="mim-tip-reference" title="Hagleitner, M. M., Lankester, A., Maraschio, P., Hulten, M., Fryns, J. P., Schuetz, C., Gimelli, G., Davies, E. G., Gennery, A., Belohradsky, B. H., de Groot, R., Gerritsen, E. J. A., and 12 others. &lt;strong&gt;Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).&lt;/strong&gt; J. Med. Genet. 45: 93-99, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17893117/&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;17893117&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2007.053397&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="17893117">Hagleitner et al. (2008)</a> emphasized that early diagnosis of ICF syndrome is critical since early immunoglobulin supplementation can improve the course of disease. Allogeneic stem cell transplantation should also be considered as a therapeutic option in patients with severe infections or failure to thrive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17893117" 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="cytogenetics" class="mim-anchor"></a>
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<strong>Cytogenetics</strong>
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<p><a href="#10" class="mim-tip-reference" title="Haas, O. A. &lt;strong&gt;Centromeric heterochromatin instability of chromosomes 1, 9, and 16 in variable immunodeficiency syndrome--a virus-induced phenomenon?&lt;/strong&gt; Hum. Genet. 85: 244-246, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2196213/&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;2196213&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00193205&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="2196213">Haas (1990)</a> noted that the chromosome alterations in ICF syndrome affected the heterochromatic regions of chromosomes 1, 9, and 16 and consisted of despiralization, chromatid and chromosome breaks, somatic pairing, and interchanges between homologous and nonhomologous chromosomes. In general, the abnormalities were restricted to peripheral blood lymphocytes. <a href="#10" class="mim-tip-reference" title="Haas, O. A. &lt;strong&gt;Centromeric heterochromatin instability of chromosomes 1, 9, and 16 in variable immunodeficiency syndrome--a virus-induced phenomenon?&lt;/strong&gt; Hum. Genet. 85: 244-246, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2196213/&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;2196213&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00193205&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="2196213">Haas (1990)</a> suggested that instability of these chromosomes is a virus-induced effect appearing in genetically predisposed individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2196213" 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>By nonisotopic in situ hybridization, using a satellite II-related probe, <a href="#22" class="mim-tip-reference" title="Maraschio, P., Cortinovis, M., Dainotti, E., Tupler, R., Tiepolo, L. &lt;strong&gt;Interphase cytogenetics of the ICF syndrome.&lt;/strong&gt; Ann. Hum. Genet. 56: 273-278, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1449239/&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;1449239&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1469-1809.1992.tb01152.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="1449239">Maraschio et al. (1992)</a> found evidence for interphase somatic pairing in ICF lymphocytes at a frequency higher than that found in normal cells. Lymphocytes of ICF patients showed nuclear protrusions and micronuclei and these nuclear abnormalities consistently involved a hybridization signal. Somatic pairing was also present in fibroblasts but with frequencies similar in normal and ICF subjects. Fibroblasts did not have the major chromosomal abnormalities found in lymphocytes. The degree of heterochromatin condensation in fibroblasts was lower than that in lymphocytes, prompting <a href="#22" class="mim-tip-reference" title="Maraschio, P., Cortinovis, M., Dainotti, E., Tupler, R., Tiepolo, L. &lt;strong&gt;Interphase cytogenetics of the ICF syndrome.&lt;/strong&gt; Ann. Hum. Genet. 56: 273-278, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1449239/&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;1449239&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1469-1809.1992.tb01152.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="1449239">Maraschio et al. (1992)</a> to postulate that the more decondensed state of chromocenters in the fibroblasts explains the absence of major chromosomal abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1449239" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Smeets, D. F. C. M., Moog, U., Weemaes, C. M. R., Vaes-Peeters, G., Merkx, G. F. M., Niehof, J. P., Hamers, G. &lt;strong&gt;ICF syndrome: a new case and review of the literature .&lt;/strong&gt; Hum. Genet. 94: 240-246, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8076938/&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;8076938&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00208277&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="8076938">Smeets et al. (1994)</a> reported an affected boy with ICF syndrome and reviewed the 14 previously reported cases. Their patient showed a normal male karyotype; however, half of his GTG-banded cells showed aberrations of chromosomes 1 and/or 16. These aberrations were recognized as breaks, deletions, isochromosomes, triradial figures, interchanges between pericentromeric regions of chromosomes 1 and 16, and multiradial configurations. In all aberrant cells, 2 short arms of both chromosomes 1 and chromosomes 16 were present, with a variable number of long arms of these 2 chromosomes, indicating that breaks occurred just below the centromere within the heterochromatin region on the proximal long arm. <a href="#29" class="mim-tip-reference" title="Smeets, D. F. C. M., Moog, U., Weemaes, C. M. R., Vaes-Peeters, G., Merkx, G. F. M., Niehof, J. P., Hamers, G. &lt;strong&gt;ICF syndrome: a new case and review of the literature .&lt;/strong&gt; Hum. Genet. 94: 240-246, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8076938/&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;8076938&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00208277&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="8076938">Smeets et al. (1994)</a> could demonstrate no hypersensitivity to physical and/or chemical agents and no increased incidence of neoplasia and skin abnormalities, indicating that ICF syndrome is not a chromosome breakage syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8076938" 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="#27" class="mim-tip-reference" title="Sawyer, J. R., Swanson, C. M., Wheeler, G., Cunniff, C. &lt;strong&gt;Chromosome instability in ICF syndrome: formation of micronuclei from multibranched chromosomes 1 demonstrated by fluorescence in situ hybridization.&lt;/strong&gt; Am. J. Med. Genet. 56: 203-209, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7625446/&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;7625446&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320560218&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="7625446">Sawyer et al. (1995)</a> examined a patient with ICF syndrome and found through traditional cytogenetic methods that the chromosomal aberrations of ICF primarily involve the centromeric regions of chromosomes 1 and 16. Undercondensation of heterochromatic blocks of chromosomes 1, 9, and 16 are involved. The undercondensation of the heterochromatic blocks appears to be restricted to a portion of phytohemagglutinin-stimulated T cells. Patients with this syndrome also show an increase in micronucleus formation. <a href="#30" class="mim-tip-reference" title="Stacey, M., Bennett, M. S., Hulten, M. &lt;strong&gt;FISH analysis on spontaneously arising micronuclei in the ICF syndrome.&lt;/strong&gt; J. Med. Genet. 32: 502-508, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7562960/&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;7562960&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.32.7.502&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="7562960">Stacey et al. (1995)</a> used dual-color fluorescence in situ hybridization to investigate the chromosomal content of these micronuclei in PHA-stimulated peripheral blood cultures, an EBV-transformed B-cell line, and also in micronuclei observed in vivo from peripheral blood smears. Chromosome 1 appeared to be present in a high proportion of micronuclei compared to chromosomes 9 and 16 in both a PHA-stimulated culture and an EBV-transformed cell line. An 18-centromeric probe showed no signal in any of the micronuclei observed. The implications of the findings were that the heterochromatic instability in ICF syndrome is manifested not only in T but also in B cells and that it is present in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7625446+7562960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Brown, D. C., Grace, E., Sumner, A. T., Edmunds, A. T., Ellis, P. M. &lt;strong&gt;ICF syndrome (immunodeficiency, centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome.&lt;/strong&gt; Hum. Genet. 96: 411-416, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7557962/&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;7557962&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00191798&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="7557962">Brown et al. (1995)</a> presented scanning electron micrographs of the heterochromatin abnormalities of an ICF patient's chromosomes 1, 9, and 16. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7557962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using fluorescence in situ hybridization analysis, <a href="#31" class="mim-tip-reference" title="Sumner, A. T., Mitchell, A. R., Ellis, P. M. &lt;strong&gt;A FISH study of chromosome fusion in the ICF syndrome: involvement of paracentric heterochromatin but not of the centromeres themselves.&lt;/strong&gt; J. Med. Genet. 35: 833-835, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9783707/&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;9783707&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.35.10.833&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="9783707">Sumner et al. (1998)</a> showed that it is always the paracentromeric heterochromatin of the relevant chromosomes that becomes decondensed and which fuses to produce multiradial configurations in ICF syndrome. The centromeric regions appear never to become decondensed and always remain outside the regions of chromosome fusion in the multiradials. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9783707" 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="#40" class="mim-tip-reference" title="Wijmenga, C., van den Heuvel, L. P. W. J., Strengman, E., Luyten, J. A. F. M., van der Burgt, I. J. A. M., de Groot, R., Smeets, D. F. C. M., Draaisma, J. M. T., van Dongen, J. J., De Abreu, R. A., Pearson, P. L., Sandkuijl, L. A., Weemaes, C. M. R. &lt;strong&gt;Localization of the ICF syndrome to chromosome 20 by homozygosity mapping.&lt;/strong&gt; Am. J. Hum. Genet. 63: 803-809, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9718351/&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;9718351&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302021&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="9718351">Wijmenga et al. (1998)</a> used DNA from 3 consanguineous families with a total of 4 ICF patients to localize the ICF syndrome gene by homozygosity mapping. One chromosomal region, 20q11-q13, was consistently found to be homozygous in ICF patients, whereas all healthy sibs showed heterozygosity. Comparison of the regions of homozygosity in the 4 patients localized the ICF locus to a 9-cM region between D20S477 and D20S850. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9718351" 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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<strong>Inheritance</strong>
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<p>The transmission pattern of ICF1 in the families reported by <a href="#41" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc&#x27;his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. &lt;strong&gt;Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.&lt;/strong&gt; Nature 402: 187-191, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10647011/&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;10647011&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/46052&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="10647011">Xu et al. (1999)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" 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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<strong>Molecular Genetics</strong>
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<p><a href="#41" class="mim-tip-reference" title="Xu, G.-L., Bestor, T. H., Bourc&#x27;his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E. &lt;strong&gt;Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.&lt;/strong&gt; Nature 402: 187-191, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10647011/&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;10647011&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/46052&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="10647011">Xu et al. (1999)</a> demonstrated homozygous or compound heterozygous mutations in the DNMT3B gene (e.g., <a href="/entry/602900#0001">602900.0001</a>) in 5 unrelated ICF patients. All mutations affected residues invariant in DNMT3A (<a href="/entry/602769">602769</a>) and DNMT3B of mouse and human, and in an uncategorized zebrafish Dnmt3 family member. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Okano, M., Bell, D. W., Haber, D. A., Li, E. &lt;strong&gt;DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.&lt;/strong&gt; Cell 99: 247-257, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10555141/&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;10555141&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0092-8674(00)81656-6&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="10555141">Okano et al. (1999)</a> identified compound heterozygous mutations in the DNMT3B gene in DNA from a lymphoblastoid cell line derived from an individual with ICF syndrome and her parents. One of the 2 mutations was de novo (not present in the parents), and neither was found in 100 normal alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10555141" 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="genotypePhenotypeCorrelations" class="mim-anchor"></a>
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<p>Among 44 patients with a clinical diagnosis of ICF, <a href="#38" class="mim-tip-reference" title="Weemaes, C. M. R., van Tol, M. J. D., Wang, J., van Ostaijen-ten Dam, M. M., van Eggermond, M. C. J. A., Thijssen, P. E., Aytekin, C., Brunetti-Pierri, N., van der Burg, M., Graham Davies, E., Ferster, A., Furthner, D., and 11 others. &lt;strong&gt;Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects.&lt;/strong&gt; Europ. J. Hum. Genet. 21: 1219-1225, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23486536/&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;23486536&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ejhg.2013.40&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="23486536">Weemaes et al. (2013)</a> found that 23 (52%) had mutations in the DNMT3B gene and 13 (30%) had mutations in the ZBTB24 gene. A genetic defect was not identified in 8 patients. Although the phenotype was relatively homogeneous, systematic phenotypic evaluation showed that humoral immunodeficiency was generally more pronounced in ICF1 patients and that ICF2 patients had a significantly higher incidence of intellectual disability. Both T- and B-cell compartments were involved in ICF1 and ICF2. A few patients from both groups had congenital malformations including cardiac defects, cleft lip, clinodactyly, choanal stenosis, hip dislocation, and cerebral malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23486536" 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="pathogenesis" class="mim-anchor"></a>
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<strong>Pathogenesis</strong>
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<p><a href="#16" class="mim-tip-reference" title="Jeanpierre, M., Turleau, C., Aurias, A., Prieur, M., Ledeist, F., Fischer, A., Viegas-Pequignot, E. &lt;strong&gt;An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome.&lt;/strong&gt; Hum. Molec. Genet. 2: 731-735, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8102570/&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;8102570&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/2.6.731&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="8102570">Jeanpierre et al. (1993)</a> reported undermethylation of classical satellite DNA, but not of alpha-satellite DNA, in 4 patients with ICF syndrome. Classical satellite DNA is located in the pericentromeric regions of chromosomes 1, 9, and 16, and on the distal long arm of the Y chromosome. Methylation of these sequences, normally almost complete in leukocyte DNA, is reduced or absent in ICF patients, thus mimicking the germinal and embryonic pattern of undermethylation. Why there are no abnormalities in the Y chromosome is not known. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8102570" 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>Further study of alpha-satellite DNA methylation at 10 sites in 4 ICF patients by <a href="#25" class="mim-tip-reference" title="Miniou, P., Jeanpierre, M., Bourc&#x27;his, D., Coutinho Barbosa, A. C., Blanquet, V., Viegas-Pequignot, E. &lt;strong&gt;Alpha-satellite DNA methylation in normal individuals and in ICF patients: heterogeneous methylation of constitutive heterochromatin in adult and fetal tissues.&lt;/strong&gt; Hum. Genet. 99: 738-745, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9187666/&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;9187666&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004390050441&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="9187666">Miniou et al. (1997)</a> revealed undermethylation at all 10 sites in only 1 individual. In another patient, undermethylation was limited to only 2 alpha satellites, while in a third, alpha-satellite methylation was unchanged compared with controls. In the fourth patient, a 20-week fetus with ICF, alpha-satellite methylation was uninformative, as normal fetal tissue showed undermethylation of these satellites at this gestational age. Analysis of alpha-satellite methylation in normal somatic and fetal tissues revealed variable methylation, with the alpha satellites of chromosomes 13 and 21 being less methylated than those of metacentric and submetacentric chromosomes. In normal fetal tissue at 20 weeks gestation, alpha satellites were all undermethylated, while classical satellites showed the same methylation pattern as in normal somatic tissues, demonstrating asynchrony in timing of methylation during development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9187666" 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="#20" class="mim-tip-reference" title="Kondo, T., Bobek, M. P., Kuick, R., Lamb, B., Zhu, X., Narayan, A., Bourc&#x27;his, D., Viegas-Pequignot, E., Ehrlich, M., Hanash, S. M. &lt;strong&gt;Whole-genome methylation scan in ICF syndrome: hypomethylation of non-satellite DNA repeats D4Z4 and NBL2.&lt;/strong&gt; Hum. Molec. Genet. 9: 597-604, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10699183/&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;10699183&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/9.4.597&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="10699183">Kondo et al. (2000)</a> investigated the methylation abnormalities in CpG islands of B cell lines from 4 ICF patients and their unaffected parents. Using CpG methylation-sensitive restriction digestion and 2-dimensional DNA gel electrophoresis, ICF DNA digests displayed multicopy fragments which were absent in controls. In particular, the nonsatellite repeats D4Z4 and NBL2 were strongly hypomethylated in all 4 patients, as compared with their unaffected parents. Deletion of D4Z4 has been implicated in the pathogenesis of facioscapulohumeral muscular dystrophy (FSHMD1A; <a href="/entry/158900">158900</a>), and the NBL2 locus had been previously shown to be demethylated in DNA from neuroblastoma cells (<a href="#34" class="mim-tip-reference" title="Thoraval, D., Asakawa, J., Wimmer, K., Kuick, R., Lamb, B., Richardson, B., Ambros, P., Glover, T., Hanash, S. &lt;strong&gt;Demethylation of repetitive DNA sequences in neuroblastoma.&lt;/strong&gt; Genes Chromosomes Cancer 17: 234-244, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8946205/&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;8946205&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-2264(199612)17:4&lt;234::AID-GCC5&gt;3.0.CO;2-4&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="8946205">Thoraval et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8946205+10699183" 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="#12" class="mim-tip-reference" title="Hansen, R. S., Stoger, R., Wijmenga, C., Stanek, A. M., Canfield, T. K., Luo, P., Matarazzo, M. R., D&#x27;Esposito, M., Feil, R., Gimelli, G., Weemaes, C. M. R., Laird, C. D., Gartler, S. M. &lt;strong&gt;Escape from gene silencing in ICF syndrome: evidence for advanced replication time as a major determinant.&lt;/strong&gt; Hum. Molec. Genet. 9: 2575-2587, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11063717/&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;11063717&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/9.18.2575&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="11063717">Hansen et al. (2000)</a> reported several examples of extensive hypomethylation that were associated with advanced replication time, nuclease hypersensitivity, and a variable escape from silencing for genes on the inactive X and Y chromosomes of ICF cells. Their data suggested that all genes on the inactive X chromosome may be extremely hypomethylated at their 5-prime CpG islands. Abnormal escape from X chromosome inactivation of G6PD (<a href="/entry/305900">305900</a>) and SYBL1 (<a href="/entry/300053">300053</a>) was noted in untransformed female ICF fibroblasts. SYBL1 silencing was also disrupted on the Y chromosome in male ICF cells. Increased chromatin sensitivity to nuclease was found at all hypomethylated promoters examined, including those of silenced genes. The persistence of inactivation in these latter cases appeared to depend critically on delayed replication of DNA, since escape from silencing was only seen when replication was advanced to an active X-like pattern. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11063717" 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="#13" class="mim-tip-reference" title="Hendrich, B., Bickmore, W. &lt;strong&gt;Human diseases with underlying defects in chromatin structure and modification.&lt;/strong&gt; Hum. Molec. Genet. 10: 2233-2242, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11673406/&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;11673406&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.20.2233&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="11673406">Hendrich and Bickmore (2001)</a> reviewed human disorders which share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders (<a href="/entry/301040">301040</a>), ICF syndrome, Rett syndrome (<a href="/entry/312750">312750</a>), Rubinstein-Taybi syndrome (<a href="/entry/180849">180849</a>), and Coffin-Lowry syndrome (<a href="/entry/303600">303600</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11673406" 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="Ehrlich, M., Buchanan, K. L., Tsien, F., Jiang, G., Sun, B., Uicker, W., Weemaes, C. M. R., Smeets, D., Sperling, K., Belohradsky, B. H., Tommerup, N., Misek, D. E., Rouillard, J.-M., Kuick, R., Hanash, S. M. &lt;strong&gt;DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes.&lt;/strong&gt; Hum. Molec. Genet. 10: 2917-2931, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11741835/&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;11741835&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.25.2917&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="11741835">Ehrlich et al. (2001)</a> performed microarray expression analysis on B-cell lymphoblastoid cell lines from 5 ICF patients with diverse DNMT3B mutations and on control lymphoblastoid cell lines. They employed oligonucleotide arrays for approximately 5,600 different genes, 510 of which showed a lymphoid lineage-restricted expression pattern among several different lineages tested. A set of 32 genes, half of which are thought to play a role in immune function, had consistent and significant ICF-specific changes in RNA levels. ICF-specific increases in immunoglobulin (Ig) heavy constant mu- and delta-RNA and cell surface IgM and IgD, decreases in Ig-gamma and Ig-alpha RNA, and surface IgG and IgA suggested inhibition of the later steps of lymphocyte maturation. ICF-specific increases were seen in RNA for RGS1 (<a href="/entry/600323">600323</a>), a B-cell specific inhibitor of G-protein signaling implicated in negative regulation of B-cell migration, and in RNA for the proapoptotic protein kinase C eta gene (<a href="/entry/605437">605437</a>). ICF-associated decreases were observed in RNAs encoding proteins involved in activation, migration, or survival of lymphoid cells, namely, transcription factor negative regulator ID3 (<a href="/entry/600277">600277</a>), the enhancer-binding MEF2C (<a href="/entry/600662">600662</a>), the iron regulatory TFRC (<a href="/entry/190010">190010</a>), integrin beta-7 (ITGB7; <a href="/entry/147559">147559</a>), the stress protein heme oxygenase (HMOX1; <a href="/entry/141250">141250</a>), and the lymphocyte-specific tumor necrosis factor receptor family members 7 and 17 (TNFRSF7, <a href="/entry/186711">186711</a>; TNFRSF17, <a href="/entry/109545">109545</a>). No differences in promoter methylation were seen between ICF and normal lymphoblastoid cell lines for 3 ICF upregulated genes and 1 downregulated gene by a quantitative methylation assay. The authors hypothesized that DNMT3B mutations in the ICF syndrome may cause lymphogenesis-associated gene dysregulation by indirect effects on gene expression that interfere with normal lymphocyte signaling, maturation, and migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a model EBV-based system and 3 members of the unique cellular cancer-testis gene family, <a href="#32" class="mim-tip-reference" title="Tao, Q., Huang, H., Geiman, T. M., Lim, C. Y., Fu, L., Qiu, G.-H., Robertson, K. D. &lt;strong&gt;Defective de novo methylation of viral and cellular DNA sequences in ICF syndrome cells.&lt;/strong&gt; Hum. Molec. Genet. 11: 2091-2102, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12189161/&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;12189161&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/11.18.2091&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="12189161">Tao et al. (2002)</a> determined that de novo methylation of newly introduced viral sequences is defective in ICF cells. Limited de novo methylation capacity was retained in ICF cells, suggesting that the mutations in DNMT3B may not be complete loss-of-function mutations, or that other DNMTs may cooperate with DNMT3B. Analysis of 3 cancer-testis genes (2 on the X chromosome and 1 autosomal) revealed that loss of methylation from cellular gene sequences was heterogeneous, with both autosomal and X chromosome-based genes demonstrating sensitivity to mutations in DNMT3B. Aberrant hypomethylation at a number of loci examined correlated with altered gene expression levels. However, no consistent changes in the protein levels of the DNA methyltransferases were noted when normal and ICF cell lines were compared. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of genetic disorders associated with aberrant chromatin structure, <a href="#1" class="mim-tip-reference" title="Bickmore, W. A., van der Maarel, S. M. &lt;strong&gt;Perturbations of chromatin structure in human genetic disease: recent advances.&lt;/strong&gt; Hum. Molec. Genet. 12: R207-R213, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12915455/&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;12915455&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddg260&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="12915455">Bickmore and van der Maarel (2003)</a> discussed altered heterochromatin structure, DNA methylation, and gene expression in ICF syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Jin, B., Tao, Q., Peng, J., Soo, H. M., Wu, W., Ying, J., Fields, C. R., Delmas, A. L., Liu, X., Qiu, J., Robertson, K. D. &lt;strong&gt;DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function.&lt;/strong&gt; Hum. Molec. Genet. 17: 690-709, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18029387/&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;18029387&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddm341&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="18029387">Jin et al. (2008)</a> used global expression profiling to analyze and compare gene expression patterns in lymphoblastoid cell lines from 3 patients with ICF syndrome and 5 healthy controls. There were significant changes, both up- and downregulation, of genes involved in immune function, signal transduction, mRNA transcription, development, and neurogenesis between the 2 groups that were highly relevant to the ICF phenotype. Loss of DNMT3B function in ICF cells resulted in loss of methylation at promoter regions in several genes, such as LHX2 (<a href="/entry/603759">603759</a>), compared to normal cells. These changes were associated with histone modifications, particularly H3K27 trimethylation, and gains in transcriptionally active H3K9 acetylation and H3K4 trimethylation marks. There was a consistent loss of binding of the SUZ12 (<a href="/entry/606245">606245</a>) component of the PRC2 polycomb repression complex and DNMT3B to derepressed genes, including a number of homeobox genes critical for immune system, brain, and craniofacial development. The findings indicated that genes upregulated in ICF cells lose histone modifications characteristic of repressed chromatin and gain modifications characteristic of transcriptionally active chromatin. <a href="#18" class="mim-tip-reference" title="Jin, B., Tao, Q., Peng, J., Soo, H. M., Wu, W., Ying, J., Fields, C. R., Delmas, A. L., Liu, X., Qiu, J., Robertson, K. D. &lt;strong&gt;DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function.&lt;/strong&gt; Hum. Molec. Genet. 17: 690-709, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18029387/&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;18029387&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddm341&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="18029387">Jin et al. (2008)</a> suggested that their results showed the interrelatedness of DNA methylation and histone modifications and the importance of DNMT3B in DNA methylation and repression of transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18029387" 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="#39" class="mim-tip-reference" title="Wijmenga, C., Hansen, R. S., Gimelli, G., Bjorck, E. J., Davies, E. G., Valentine, D., Belohradsky, B. H., van Dongen, J. J., Smeets, D. F. C. M., van den Heuvel, L. P. W. J., Luyten, J. A. F. M., Strengman, E., Weemaes, C., Pearson, P. L. &lt;strong&gt;Genetic variation in ICF syndrome: evidence for genetic heterogeneity.&lt;/strong&gt; Hum. Mutat. 16: 509-517, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11102980/&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;11102980&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1098-1004(200012)16:6&lt;509::AID-HUMU8&gt;3.0.CO;2-V&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="11102980">Wijmenga et al. (2000)</a> found mutations in the DNMT3B gene in only 9 of 14 ICF patients. Moreover, 2 ICF patients from consanguineous families who did not show homozygosity by descent for the DNMT3B locus did not have DNMT3B mutations, suggesting genetic heterogeneity for this disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11102980" 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="Kubota, T., Furuumi, H., Kamoda, T., Iwasaki, N., Tobita, N., Fujiwara, N., Goto, Y., Matsui, A., Sasaki, H., Kajii, T. &lt;strong&gt;ICF syndrome in a girl with DNA hypomethylation but without detectable DNMT3B mutation.&lt;/strong&gt; Am. J. Med. Genet. 129A: 290-293, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15326630/&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;15326630&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30135&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="15326630">Kubota et al. (2004)</a> described a 3-year-old girl with phenotypic and cytogenetic characteristics of ICF syndrome and DNA hypomethylation but without a detectable mutation in the DNMT3B gene. Indeed, from an analysis of 17 patients, <a href="#17" class="mim-tip-reference" title="Jiang, Y. L., Rigolet, M., Bourc&#x27;his, D., Nigon, F., Bokesoy, I., Fryns, J. P., Hulten, M., Jonveaux, P., Maraschio, P., Megarbane, A., Moncla, A., Viegas-Pequignot, E. &lt;strong&gt;DNMT3B mutations and DNA methylation defect define two types of ICF syndrome.&lt;/strong&gt; Hum. Mutat. 25: 56-63, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15580563/&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;15580563&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20113&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="15580563">Jiang et al. (2005)</a> suggested that there are 2 types of clinically indistinguishable ICF syndrome: type 1 is characterized by DNMT3B mutations and normal methylation of alpha satellites; type 2 lacks DNMT3B mutations and shows hypomethylation of alpha satellites. Both show characteristic heterochromatin abnormalities and undermethylation of classic satellites 2 and 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15326630+15580563" 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="#19" class="mim-tip-reference" title="Kloeckener-Gruissem, B., Betts, D. R., Zankl, A., Berger, W., Gungor, T. &lt;strong&gt;A new and a reclassified ICF patient without mutations in DNMT3B and its interacting proteins SUMO-1 and UBC9.&lt;/strong&gt; Am. J. Med. Genet. 136A: 31-37, 2005. Note: Erratum: Am. J. Med. Genet. 138A: 195 only, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15952214/&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;15952214&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30767&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="15952214">Kloeckener-Gruissem et al. (2005)</a> reported a Turkish boy (patient 1), born of consanguineous parents, with ICF syndrome. He had hypertelorism, hypospadias, severe hypogammaglobulinemia with normal T-cell function, delayed speech development, and bilateral suspected focal cortical heterotopy. An affected brother had died at age 4.5 years. Cytogenetic and Southern blot analysis showed that the patient had hypomethylation and centromeric instability of chromosomes 1 and 16, although he did not have mutations in the DNMT3B gene or in genes encoding the DNMT3B-interacting proteins SUMO1 (<a href="/entry/601912">601912</a>) and UBC9 (UBE2I; <a href="/entry/601661">601661</a>). Including this study, <a href="#19" class="mim-tip-reference" title="Kloeckener-Gruissem, B., Betts, D. R., Zankl, A., Berger, W., Gungor, T. &lt;strong&gt;A new and a reclassified ICF patient without mutations in DNMT3B and its interacting proteins SUMO-1 and UBC9.&lt;/strong&gt; Am. J. Med. Genet. 136A: 31-37, 2005. Note: Erratum: Am. J. Med. Genet. 138A: 195 only, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15952214/&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;15952214&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30767&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="15952214">Kloeckener-Gruissem et al. (2005)</a> estimated that approximately 40% of reported patients with ICF lack mutations in the DNMT3B coding region, suggesting genetic heterogeneity. A second patient reported by <a href="#19" class="mim-tip-reference" title="Kloeckener-Gruissem, B., Betts, D. R., Zankl, A., Berger, W., Gungor, T. &lt;strong&gt;A new and a reclassified ICF patient without mutations in DNMT3B and its interacting proteins SUMO-1 and UBC9.&lt;/strong&gt; Am. J. Med. Genet. 136A: 31-37, 2005. Note: Erratum: Am. J. Med. Genet. 138A: 195 only, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15952214/&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;15952214&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30767&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="15952214">Kloeckener-Gruissem et al. (2005)</a> (patient 2), previously reported by <a href="#2" class="mim-tip-reference" title="Braegger, C., Bottani, A., Halle, F., Giedion, A., Leumann, E., Seger, R., Willi, U., Schinzel, A. &lt;strong&gt;Unknown syndrome: ischiadic hypoplasia, renal dysfunction, immunodeficiency, and a pattern of minor congenital anomalies.&lt;/strong&gt; J. Med. Genet. 28: 56-59, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1999836/&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;1999836&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.28.1.56&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="1999836">Braegger et al. (1991)</a>, was found by <a href="#33" class="mim-tip-reference" title="Thijssen, P. E., Ito, Y., Grillo, G., Wang, J., Velasco, G., Nitta, H., Unoki, M., Yoshihara, M., Suyama, M., Sun, Y., Lemmers, R. J. L. F., de Greef, J. C., and 17 others. &lt;strong&gt;Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome.&lt;/strong&gt; Nature Commun. 6: 7870, 2015. Note: Electronic Article. Erratum: Nature Commun. 7: 12003, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26216346/&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;26216346&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26216346[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/10.1038/ncomms8870&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="26216346">Thijssen et al. (2015)</a> to have ICF3 (<a href="/entry/616910">616910</a>), caused by a homozygous mutation in the CDCA7 gene (<a href="/entry/609937#0001">609937.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26216346+1999836+15952214" 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="#28" class="mim-tip-reference" title="Schuetz, C., Barbi, G., Barth, T. F. E., Hoenig, M., Schulz, A., Moeller, P., Smeets, D., de Greef, J. C., van der Maarel, S. M., Vogel, W., Debatin, K.-M., Friedrich, W. &lt;strong&gt;ICF syndrome: high variability of the chromosomal phenotype and association with classical Hodgkin lymphoma.&lt;/strong&gt; Am. J. Med. Genet. 143A: 2052-2057, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17702009/&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;17702009&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31885&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="17702009">Schuetz et al. (2007)</a> described a brother and sister with ICF syndrome. The brother had a history of multiple infections, mild facial dysmorphism, delayed development, and hypogammaglobulinemia (absent IgM and low IgG). At age 7, the boy presented with hemiplegia secondary to tumorous invasion of the right brachial plexus. Immunohistochemistry confirmed the diagnosis of classic Hodgkin lymphoma of the lymphocyte depleted subtype. Following surgery, the boy had sudden cardiac arrest and died. The younger sister has similar dysmorphic features, hypogammaglobulinemia, and psychomotor retardation. No mutation was found in the DNMT3B gene. DNA of the affected sister was tested for the presence of hypomethylation of repetitive DNA by Southern blot analysis; hypomethylation of alpha-satellite DNA and classic satellite 2, characteristic of ICF type 2, was observed. <a href="#28" class="mim-tip-reference" title="Schuetz, C., Barbi, G., Barth, T. F. E., Hoenig, M., Schulz, A., Moeller, P., Smeets, D., de Greef, J. C., van der Maarel, S. M., Vogel, W., Debatin, K.-M., Friedrich, W. &lt;strong&gt;ICF syndrome: high variability of the chromosomal phenotype and association with classical Hodgkin lymphoma.&lt;/strong&gt; Am. J. Med. Genet. 143A: 2052-2057, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17702009/&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;17702009&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31885&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="17702009">Schuetz et al. (2007)</a> suggested that clinical follow-up for children with ICF include surveillance for neoplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17702009" 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="Hagleitner, M. M., Lankester, A., Maraschio, P., Hulten, M., Fryns, J. P., Schuetz, C., Gimelli, G., Davies, E. G., Gennery, A., Belohradsky, B. H., de Groot, R., Gerritsen, E. J. A., and 12 others. &lt;strong&gt;Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).&lt;/strong&gt; J. Med. Genet. 45: 93-99, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17893117/&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;17893117&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2007.053397&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="17893117">Hagleitner et al. (2008)</a> identified DNMT3B mutations in only 20 (57%) of 34 ICF patients tested, suggesting genetic heterogeneity. No genotype/phenotype correlations were found between patients with and without DNMT3B mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17893117" 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="Bickmore2003" class="mim-anchor"></a>
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<p class="mim-text-font">
Bickmore, W. A., van der Maarel, S. M.
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[<a href="https://doi.org/10.1093/hmg/ddg260" target="_blank">Full Text</a>]
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<a id="Braegger1991" class="mim-anchor"></a>
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<p class="mim-text-font">
Braegger, C., Bottani, A., Halle, F., Giedion, A., Leumann, E., Seger, R., Willi, U., Schinzel, A.
<strong>Unknown syndrome: ischiadic hypoplasia, renal dysfunction, immunodeficiency, and a pattern of minor congenital anomalies.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1999836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1999836</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1999836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.28.1.56" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
<a id="Brown1995" class="mim-anchor"></a>
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Brown, D. C., Grace, E., Sumner, A. T., Edmunds, A. T., Ellis, P. M.
<strong>ICF syndrome (immunodeficiency, centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome.</strong>
Hum. Genet. 96: 411-416, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7557962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7557962</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7557962" 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/BF00191798" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
<a id="De Ravel2001" class="mim-anchor"></a>
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<p class="mim-text-font">
De Ravel, T. J. L., Deckers, E., Alliet, P. L. O., Petit, P., Fryns, J. P.
<strong>The ICF syndrome: new case and update.</strong>
Genet. Counsel. 12: 379-385, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11837609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11837609</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11837609" 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="5" class="mim-anchor"></a>
<a id="Ehrlich2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ehrlich, M., Buchanan, K. L., Tsien, F., Jiang, G., Sun, B., Uicker, W., Weemaes, C. M. R., Smeets, D., Sperling, K., Belohradsky, B. H., Tommerup, N., Misek, D. E., Rouillard, J.-M., Kuick, R., Hanash, S. M.
<strong>DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes.</strong>
Hum. Molec. Genet. 10: 2917-2931, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741835</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/10.25.2917" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
<a id="Fasth1990" class="mim-anchor"></a>
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Fasth, A., Forestier, E., Holmberg, E., Holmgren, G., Nordenson, I., Soderstrom, T., Wahlstrom, J.
<strong>Fragility of the centromeric region of chromosome 1 associated with combined immunodeficiency in siblings: a recessively inherited entity?</strong>
Acta Paediat. Scand. 79: 605-612, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2386052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2386052</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2386052" 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.1651-2227.1990.tb11524.x" target="_blank">Full Text</a>]
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<a id="Franceschini1995" class="mim-anchor"></a>
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Franceschini, P., Martino, S., Ciocchini, M., Ciuti, E., Vardeu, M. P., Guala, A., Signorile, F., Camerano, P., Franceschini, D., Tovo, P. A.
<strong>Variability of clinical and immunological phenotype in immunodeficiency-centromeric instability-facial anomalies syndrome: report of two new patients and review of the literature.</strong>
Europ. J. Pediat. 154: 840-846, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8529685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8529685</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8529685" 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/BF01959794" target="_blank">Full Text</a>]
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<a id="Fryns1981" class="mim-anchor"></a>
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<p class="mim-text-font">
Fryns, J. P., Azou, M., Jaeken, J., Eggermont, E., Pedersen, J. C., Van den Berghe, H.
<strong>Centromeric instability of chromosomes 1, 9, and 16 associated with combined immunodeficiency.</strong>
Hum. Genet. 57: 108-110, 1981.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7262865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7262865</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7262865" 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/BF00271181" target="_blank">Full Text</a>]
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<a id="Gimelli1993" class="mim-anchor"></a>
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Gimelli, G., Varone, P., Pezzolo, A., Lerone, M., Pistoia, V.
<strong>ICF syndrome with variable expression in sibs.</strong>
J. Med. Genet. 30: 429-432, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8320711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8320711</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8320711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.30.5.429" target="_blank">Full Text</a>]
</p>
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<a id="Haas1990" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Haas, O. A.
<strong>Centromeric heterochromatin instability of chromosomes 1, 9, and 16 in variable immunodeficiency syndrome--a virus-induced phenomenon?</strong>
Hum. Genet. 85: 244-246, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2196213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2196213</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2196213" 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/BF00193205" target="_blank">Full Text</a>]
</p>
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<a id="11" class="mim-anchor"></a>
<a id="Hagleitner2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hagleitner, M. M., Lankester, A., Maraschio, P., Hulten, M., Fryns, J. P., Schuetz, C., Gimelli, G., Davies, E. G., Gennery, A., Belohradsky, B. H., de Groot, R., Gerritsen, E. J. A., and 12 others.
<strong>Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).</strong>
J. Med. Genet. 45: 93-99, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17893117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17893117</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17893117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.2007.053397" target="_blank">Full Text</a>]
</p>
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<a id="Hansen2000" class="mim-anchor"></a>
<div class="">
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Hansen, R. S., Stoger, R., Wijmenga, C., Stanek, A. M., Canfield, T. K., Luo, P., Matarazzo, M. R., D'Esposito, M., Feil, R., Gimelli, G., Weemaes, C. M. R., Laird, C. D., Gartler, S. M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11063717/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11063717</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11063717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/9.18.2575" target="_blank">Full Text</a>]
</p>
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<a id="13" class="mim-anchor"></a>
<a id="Hendrich2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hendrich, B., Bickmore, W.
<strong>Human diseases with underlying defects in chromatin structure and modification.</strong>
Hum. Molec. Genet. 10: 2233-2242, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11673406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11673406</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11673406" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/10.20.2233" target="_blank">Full Text</a>]
</p>
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<a id="14" class="mim-anchor"></a>
<a id="Howard1985" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Howard, P. Y., Lewis, Y. J., Harris, F., Walker, S.
<strong>Centromeric instability of chromosomes 1 and 16 with variable immune deficiency: a new syndrome.</strong>
Clin. Genet. 27: 501-505, 1985.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4006276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4006276</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4006276" 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.1399-0004.1985.tb00239.x" target="_blank">Full Text</a>]
</p>
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<a id="15" class="mim-anchor"></a>
<a id="Hulten1978" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Hulten, M.
<strong>Selective somatic pairing and fragility at 1q12 in a boy with common variable immunodeficiency. (Abstract)</strong>
Clin. Genet. 14: 294 only, 1978.
</p>
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<a id="16" class="mim-anchor"></a>
<a id="Jeanpierre1993" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Jeanpierre, M., Turleau, C., Aurias, A., Prieur, M., Ledeist, F., Fischer, A., Viegas-Pequignot, E.
<strong>An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome.</strong>
Hum. Molec. Genet. 2: 731-735, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8102570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8102570</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8102570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/2.6.731" target="_blank">Full Text</a>]
</p>
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<a id="17" class="mim-anchor"></a>
<a id="Jiang2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Jiang, Y. L., Rigolet, M., Bourc'his, D., Nigon, F., Bokesoy, I., Fryns, J. P., Hulten, M., Jonveaux, P., Maraschio, P., Megarbane, A., Moncla, A., Viegas-Pequignot, E.
<strong>DNMT3B mutations and DNA methylation defect define two types of ICF syndrome.</strong>
Hum. Mutat. 25: 56-63, 2005.
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[<a href="https://doi.org/10.1002/humu.20113" target="_blank">Full Text</a>]
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<strong>DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function.</strong>
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[<a href="https://doi.org/10.1093/hmg/ddm341" target="_blank">Full Text</a>]
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<strong>A new and a reclassified ICF patient without mutations in DNMT3B and its interacting proteins SUMO-1 and UBC9.</strong>
Am. J. Med. Genet. 136A: 31-37, 2005. Note: Erratum: Am. J. Med. Genet. 138A: 195 only, 2005.
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[<a href="https://doi.org/10.1002/ajmg.a.30767" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.4.597" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30135" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.1992.tb01152.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.26.7.452" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.25.3.173" target="_blank">Full Text</a>]
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<strong>Alpha-satellite DNA methylation in normal individuals and in ICF patients: heterogeneous methylation of constitutive heterochromatin in adult and fetal tissues.</strong>
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[<a href="https://doi.org/10.1007/s004390050441" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)81656-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320560218" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31885" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00208277" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.32.7.502" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.35.10.833" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.18.2091" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00287166" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320320331" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1987.tb02781.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ejhg.2013.40" target="_blank">Full Text</a>]
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<a id="39" class="mim-anchor"></a>
<a id="Wijmenga2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wijmenga, C., Hansen, R. S., Gimelli, G., Bjorck, E. J., Davies, E. G., Valentine, D., Belohradsky, B. H., van Dongen, J. J., Smeets, D. F. C. M., van den Heuvel, L. P. W. J., Luyten, J. A. F. M., Strengman, E., Weemaes, C., Pearson, P. L.
<strong>Genetic variation in ICF syndrome: evidence for genetic heterogeneity.</strong>
Hum. Mutat. 16: 509-517, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11102980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11102980</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11102980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/1098-1004(200012)16:6&lt;509::AID-HUMU8&gt;3.0.CO;2-V" target="_blank">Full Text</a>]
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<a id="40" class="mim-anchor"></a>
<a id="Wijmenga1998" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wijmenga, C., van den Heuvel, L. P. W. J., Strengman, E., Luyten, J. A. F. M., van der Burgt, I. J. A. M., de Groot, R., Smeets, D. F. C. M., Draaisma, J. M. T., van Dongen, J. J., De Abreu, R. A., Pearson, P. L., Sandkuijl, L. A., Weemaes, C. M. R.
<strong>Localization of the ICF syndrome to chromosome 20 by homozygosity mapping.</strong>
Am. J. Hum. Genet. 63: 803-809, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9718351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9718351</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9718351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/302021" target="_blank">Full Text</a>]
</p>
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<a id="41" class="mim-anchor"></a>
<a id="Xu1999" class="mim-anchor"></a>
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Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E.
<strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong>
Nature 402: 187-191, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10647011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10647011</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10647011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/46052" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<span class="mim-text-font">
Cassandra L. Kniffin - updated : 4/19/2016
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Cassandra L. Kniffin - updated : 12/4/2013<br>Cassandra L. Kniffin - updated : 4/13/2010<br>Matthew B. Gross - reorganized : 2/20/2009<br>Cassandra L. Kniffin - updated : 6/25/2008<br>Kelly A. Przylepa - updated : 11/6/2007<br>Cassandra L. Kniffin - updated : 10/31/2005<br>George E. Tiller - updated : 9/30/2005<br>Victor A. McKusick - updated : 2/4/2005<br>Victor A. McKusick - updated : 9/22/2004<br>George E. Tiller - updated : 9/17/2003<br>George E. Tiller - updated : 8/15/2002<br>Victor A. McKusick - updated : 3/7/2002<br>George E. Tiller - updated : 2/12/2002<br>George E. Tiller - updated : 1/24/2001<br>George E. Tiller - updated : 4/14/2000<br>Stylianos E. Antonarakis - updated : 11/12/1999<br>Ada Hamosh - updated : 11/11/1999<br>Michael J. Wright - updated : 11/9/1998<br>Victor A. McKusick - updated : 9/16/1998<br>Michael J. Wright - updated : 8/25/1997
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Creation Date:
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Victor A. McKusick : 4/14/1987
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 11/04/2022
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carol : 05/14/2019<br>alopez : 04/10/2019<br>alopez : 04/21/2016<br>ckniffin : 4/19/2016<br>carol : 12/16/2013<br>carol : 12/13/2013<br>ckniffin : 12/4/2013<br>carol : 7/6/2011<br>wwang : 7/5/2011<br>ckniffin : 6/30/2011<br>wwang : 4/22/2011<br>wwang : 5/17/2010<br>ckniffin : 4/13/2010<br>ckniffin : 3/10/2009<br>mgross : 2/20/2009<br>mgross : 2/20/2009<br>wwang : 7/22/2008<br>ckniffin : 6/25/2008<br>carol : 11/6/2007<br>wwang : 11/2/2005<br>ckniffin : 10/31/2005<br>alopez : 9/30/2005<br>wwang : 2/16/2005<br>wwang : 2/11/2005<br>terry : 2/4/2005<br>tkritzer : 9/23/2004<br>terry : 9/22/2004<br>carol : 11/6/2003<br>cwells : 9/17/2003<br>cwells : 8/15/2002<br>cwells : 3/18/2002<br>cwells : 3/14/2002<br>terry : 3/7/2002<br>cwells : 2/18/2002<br>cwells : 2/12/2002<br>terry : 6/5/2001<br>carol : 2/1/2001<br>mcapotos : 2/1/2001<br>mcapotos : 1/24/2001<br>mcapotos : 9/7/2000<br>terry : 4/14/2000<br>yemi : 2/18/2000<br>yemi : 2/18/2000<br>mgross : 11/12/1999<br>alopez : 11/11/1999<br>terry : 11/11/1999<br>alopez : 12/11/1998<br>terry : 11/9/1998<br>carol : 9/24/1998<br>alopez : 9/21/1998<br>alopez : 9/18/1998<br>terry : 9/16/1998<br>terry : 9/4/1997<br>terry : 8/25/1997<br>terry : 11/9/1995<br>mark : 10/6/1995<br>carol : 12/19/1994<br>mimadm : 2/19/1994<br>carol : 11/18/1993<br>carol : 7/9/1993
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<strong>#</strong> 242860
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<span class="mim-font">
IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1; ICF1
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<em>Alternative titles; symbols</em>
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IMMUNE DEFICIENCY, VARIABLE, WITH CENTROMERIC INSTABILITY OF CHROMOSOMES 1, 9, AND 16<br />
CENTROMERIC INSTABILITY, IMMUNODEFICIENCY SYNDROME; CIID<br />
IMMUNODEFICIENCY SYNDROME, VARIABLE
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<strong>SNOMEDCT:</strong> 234633000; &nbsp;
<strong>ORPHA:</strong> 2268; &nbsp;
<strong>DO:</strong> 0090008; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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20q11.21
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Immunodeficiency-centromeric instability-facial anomalies syndrome 1
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242860
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Autosomal recessive
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3
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DNMT3B
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602900
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because immunodeficiency-centromeric instability-facial anomalies syndrome-1 is caused by homozygous or compound heterozygous mutation in the gene encoding DNA methyltransferase-3B (DNMT3B; 602900) on chromosome 20q11.</p>
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<strong>Description</strong>
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<p>Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare autosomal recessive disease characterized by facial dysmorphism, immunoglobulin deficiency, and branching of chromosomes 1, 9, and 16 after phytohemagglutinin (PHA) stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients that is explained by mutations in the DNMT3B gene in some, but not all, ICF patients (Hagleitner et al., 2008). </p><p><strong><em>Genetic Heterogeneity of Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome</em></strong></p><p>
See also ICF2 (614069), caused by mutation in the ZBTB24 gene (614064) on chromosome 6q21; ICF3 (616910), caused by mutation in the CDCA7 gene (609937) on chromosome 2q31; and ICF4 (616911), caused by mutation in the HELLS gene (603946) on chromosome 10q23.</p>
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<strong>Clinical Features</strong>
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<p>Variable immune deficiency in association with centromeric instability of chromosomes 1, 9, 16, and, rarely, 2, with an increased frequency of somatic recombination of the arms of these chromosomes and a marked tendency to formation of multibranched configurations, has been reported by Hulten (1978), Tiepolo et al. (1979), Fryns et al. (1981), Howard et al. (1985), and Valkova et al. (1987). Three males and 2 females have been reported. The parents are clinically and cytogenetically normal. In 2 of the 5 families, those reported by Tiepolo et al. (1979) and Valkova et al. (1987), sibs were affected. The most frequent symptoms of the syndrome are facial dysmorphism, mental retardation, recurrent and prolonged respiratory infections, infections of the skin and digestive system, and variable immune deficiency with a constant decrease of IgA. </p><p>Maraschio et al. (1988) described ICF syndrome in a 4-year-old girl. From the age of 2 years she had suffered from recurrent pulmonary infections and from diarrhea in the summertime. The face was described as dysmorphic with hypertelorism, flat nasal bridge, low-set ears, and protrusion of the tongue. Maraschio et al. (1989) reported further clinical data on this child, who had severe chronic bronchitis with bronchiectasis, maxillary sinusitis, and otitis media. They demonstrated that, unlike lymphocytes, fibroblasts showed no major chromosomal anomalies. </p><p>Turleau et al. (1989) reported a patient with ICF syndrome. </p><p>Haas (1990) pointed to 8 reports of variable immunodeficiency associated with instability of the centromeric regions of chromosomes 1, 9, and 16. The children suffered from a serious variable immunodeficiency, mild developmental delay, and facial abnormalities with hypertelorism, a flat nasal bridge, epicanthal folds, protrusion of the tongue, and mild micrognathia. The severity of the disorder was indicated by the fact that 3 children died at ages 14, 12.5, and 2.5 years. They showed absence or severe reduction of at least 2 immunoglobulin classes with or without a defective cell-mediated immunity. Although no cytogenetically documented familial cases were reported, a genetic trait was suggested by the retrospective recognition of similar symptoms in deceased sibs of 2 of the patients (Tiepolo et al., 1979; Valkova et al., 1987). </p><p>Fasth et al. (1990) observed instability of the centromeric region of chromosome 1 and multibranched configurations formed by the short and long arms in a brother and sister with facial dysmorphism, mental retardation, and recurrent infections. The parents, who were first cousins, showed no chromosomal abnormalities. A combined immunodeficiency characterized by a lack of immunoglobulin production, low numbers of T cells, and lack of cells with NK (natural killer) cell markers was found. </p><p>Gimelli et al. (1993) reported ICF syndrome in a 29-year-old woman and her 30-year-old brother. The proband showed mental retardation, facial anomalies, recurrent respiratory infections, combined deficit of IgM and IgE immunoglobulin classes, and paracentromeric heterochromatin instability of chromosomes 1, 9, and 16. </p><p>Smeets et al. (1994) reported an affected boy with ICF syndrome and reviewed the 14 previously reported cases. </p><p>Brown et al. (1995) described a 25-month-old girl with ICF syndrome. The proband's grandfathers were twin brothers and her grandmothers were sisters. Assuming that the twin grandfathers were monozygotic, the parents were related to each as half sibs, giving a coefficient of relationship of one-fourth; but they were also related to each other as first cousins, giving an additional coefficient of relatedness of one-eighth and a total coefficient of three-eighths. In other words, the parents were related as something half way between half sibs and full sibs. Brown et al. (1995) reviewed the features of the 15 published ICF cases. All but 1 had facial anomalies, most often hypertelorism, flat nasal bridge, epicanthic folds, protrusion of the tongue, and micrognathia. Mental retardation was variable, from severe neurodegeneration to special educational needs without any delay in motor function. Their patient was typical in that speech development was delayed. Follow-up information was provided on the published cases. </p><p>Franceschini et al. (1995) reported 2 new patients and reviewed the literature. They commented on the marked phenotypic variability in the 15 affected individuals reported to that time. Both of their patients were boys found to have hypogammaglobulinemia. Both of them were described as having bipartite nipples. One had shawl scrotum and the other had cryptorchidism and hypospadias. The photographs showed striking similarity of facies in the 2 boys. They showed abnormal mitotic configurations, involving chromosomes 1, 16, and to a lesser extent, 9. </p><p>De Ravel et al. (2001) found reports of 32 cases of this rare disorder. They reported findings in a young patient who received appropriate early therapy, with a good outcome. The published photograph showed hypertelorism, low-set ears, and high forehead as facial features. Starting at the age of 7 months, gammaglobulin was periodically administered intravenously, with no serious infections occurring. Despite nasogastric feeding, malnutrition was a problem, requiring continuous gastrostomy feeding from 19 to 28 months of age. A verbal IQ of 104 and a performance IQ of 90 was observed at 4 years of age. </p><p>Hagleitner et al. (2008) reviewed the clinical features of 45 patients with ICF syndrome. Facial dysmorphism, including epicanthic folds, hypertelorism, flat nasal bridge, and low-set ears, was commonly present. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (39 of 44), and opportunistic infections were seen in several patients, indicating T-cell dysfunction. However, there was phenotypic variability in that not all patients had obvious facial dysmorphism, and 39% had normal intelligence. Life expectancy was poor: 17 (40.5%) patients died at a mean age of 8 years, predominantly due to severe respiratory tract infections, sepsis, and failure to thrive. </p>
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<strong>Clinical Management</strong>
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<p>Hagleitner et al. (2008) emphasized that early diagnosis of ICF syndrome is critical since early immunoglobulin supplementation can improve the course of disease. Allogeneic stem cell transplantation should also be considered as a therapeutic option in patients with severe infections or failure to thrive. </p>
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<strong>Cytogenetics</strong>
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<p>Haas (1990) noted that the chromosome alterations in ICF syndrome affected the heterochromatic regions of chromosomes 1, 9, and 16 and consisted of despiralization, chromatid and chromosome breaks, somatic pairing, and interchanges between homologous and nonhomologous chromosomes. In general, the abnormalities were restricted to peripheral blood lymphocytes. Haas (1990) suggested that instability of these chromosomes is a virus-induced effect appearing in genetically predisposed individuals. </p><p>By nonisotopic in situ hybridization, using a satellite II-related probe, Maraschio et al. (1992) found evidence for interphase somatic pairing in ICF lymphocytes at a frequency higher than that found in normal cells. Lymphocytes of ICF patients showed nuclear protrusions and micronuclei and these nuclear abnormalities consistently involved a hybridization signal. Somatic pairing was also present in fibroblasts but with frequencies similar in normal and ICF subjects. Fibroblasts did not have the major chromosomal abnormalities found in lymphocytes. The degree of heterochromatin condensation in fibroblasts was lower than that in lymphocytes, prompting Maraschio et al. (1992) to postulate that the more decondensed state of chromocenters in the fibroblasts explains the absence of major chromosomal abnormalities. </p><p>Smeets et al. (1994) reported an affected boy with ICF syndrome and reviewed the 14 previously reported cases. Their patient showed a normal male karyotype; however, half of his GTG-banded cells showed aberrations of chromosomes 1 and/or 16. These aberrations were recognized as breaks, deletions, isochromosomes, triradial figures, interchanges between pericentromeric regions of chromosomes 1 and 16, and multiradial configurations. In all aberrant cells, 2 short arms of both chromosomes 1 and chromosomes 16 were present, with a variable number of long arms of these 2 chromosomes, indicating that breaks occurred just below the centromere within the heterochromatin region on the proximal long arm. Smeets et al. (1994) could demonstrate no hypersensitivity to physical and/or chemical agents and no increased incidence of neoplasia and skin abnormalities, indicating that ICF syndrome is not a chromosome breakage syndrome. </p><p>Sawyer et al. (1995) examined a patient with ICF syndrome and found through traditional cytogenetic methods that the chromosomal aberrations of ICF primarily involve the centromeric regions of chromosomes 1 and 16. Undercondensation of heterochromatic blocks of chromosomes 1, 9, and 16 are involved. The undercondensation of the heterochromatic blocks appears to be restricted to a portion of phytohemagglutinin-stimulated T cells. Patients with this syndrome also show an increase in micronucleus formation. Stacey et al. (1995) used dual-color fluorescence in situ hybridization to investigate the chromosomal content of these micronuclei in PHA-stimulated peripheral blood cultures, an EBV-transformed B-cell line, and also in micronuclei observed in vivo from peripheral blood smears. Chromosome 1 appeared to be present in a high proportion of micronuclei compared to chromosomes 9 and 16 in both a PHA-stimulated culture and an EBV-transformed cell line. An 18-centromeric probe showed no signal in any of the micronuclei observed. The implications of the findings were that the heterochromatic instability in ICF syndrome is manifested not only in T but also in B cells and that it is present in vivo. </p><p>Brown et al. (1995) presented scanning electron micrographs of the heterochromatin abnormalities of an ICF patient's chromosomes 1, 9, and 16. </p><p>Using fluorescence in situ hybridization analysis, Sumner et al. (1998) showed that it is always the paracentromeric heterochromatin of the relevant chromosomes that becomes decondensed and which fuses to produce multiradial configurations in ICF syndrome. The centromeric regions appear never to become decondensed and always remain outside the regions of chromosome fusion in the multiradials. </p>
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<span class="mim-font">
<strong>Mapping</strong>
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<p>Wijmenga et al. (1998) used DNA from 3 consanguineous families with a total of 4 ICF patients to localize the ICF syndrome gene by homozygosity mapping. One chromosomal region, 20q11-q13, was consistently found to be homozygous in ICF patients, whereas all healthy sibs showed heterozygosity. Comparison of the regions of homozygosity in the 4 patients localized the ICF locus to a 9-cM region between D20S477 and D20S850. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of ICF1 in the families reported by Xu et al. (1999) was consistent with autosomal recessive inheritance. </p>
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<span class="mim-font">
<strong>Molecular Genetics</strong>
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<p>Xu et al. (1999) demonstrated homozygous or compound heterozygous mutations in the DNMT3B gene (e.g., 602900.0001) in 5 unrelated ICF patients. All mutations affected residues invariant in DNMT3A (602769) and DNMT3B of mouse and human, and in an uncategorized zebrafish Dnmt3 family member. </p><p>Okano et al. (1999) identified compound heterozygous mutations in the DNMT3B gene in DNA from a lymphoblastoid cell line derived from an individual with ICF syndrome and her parents. One of the 2 mutations was de novo (not present in the parents), and neither was found in 100 normal alleles. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Among 44 patients with a clinical diagnosis of ICF, Weemaes et al. (2013) found that 23 (52%) had mutations in the DNMT3B gene and 13 (30%) had mutations in the ZBTB24 gene. A genetic defect was not identified in 8 patients. Although the phenotype was relatively homogeneous, systematic phenotypic evaluation showed that humoral immunodeficiency was generally more pronounced in ICF1 patients and that ICF2 patients had a significantly higher incidence of intellectual disability. Both T- and B-cell compartments were involved in ICF1 and ICF2. A few patients from both groups had congenital malformations including cardiac defects, cleft lip, clinodactyly, choanal stenosis, hip dislocation, and cerebral malformations. </p>
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<strong>Pathogenesis</strong>
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<span class="mim-text-font">
<p>Jeanpierre et al. (1993) reported undermethylation of classical satellite DNA, but not of alpha-satellite DNA, in 4 patients with ICF syndrome. Classical satellite DNA is located in the pericentromeric regions of chromosomes 1, 9, and 16, and on the distal long arm of the Y chromosome. Methylation of these sequences, normally almost complete in leukocyte DNA, is reduced or absent in ICF patients, thus mimicking the germinal and embryonic pattern of undermethylation. Why there are no abnormalities in the Y chromosome is not known. </p><p>Further study of alpha-satellite DNA methylation at 10 sites in 4 ICF patients by Miniou et al. (1997) revealed undermethylation at all 10 sites in only 1 individual. In another patient, undermethylation was limited to only 2 alpha satellites, while in a third, alpha-satellite methylation was unchanged compared with controls. In the fourth patient, a 20-week fetus with ICF, alpha-satellite methylation was uninformative, as normal fetal tissue showed undermethylation of these satellites at this gestational age. Analysis of alpha-satellite methylation in normal somatic and fetal tissues revealed variable methylation, with the alpha satellites of chromosomes 13 and 21 being less methylated than those of metacentric and submetacentric chromosomes. In normal fetal tissue at 20 weeks gestation, alpha satellites were all undermethylated, while classical satellites showed the same methylation pattern as in normal somatic tissues, demonstrating asynchrony in timing of methylation during development. </p><p>Kondo et al. (2000) investigated the methylation abnormalities in CpG islands of B cell lines from 4 ICF patients and their unaffected parents. Using CpG methylation-sensitive restriction digestion and 2-dimensional DNA gel electrophoresis, ICF DNA digests displayed multicopy fragments which were absent in controls. In particular, the nonsatellite repeats D4Z4 and NBL2 were strongly hypomethylated in all 4 patients, as compared with their unaffected parents. Deletion of D4Z4 has been implicated in the pathogenesis of facioscapulohumeral muscular dystrophy (FSHMD1A; 158900), and the NBL2 locus had been previously shown to be demethylated in DNA from neuroblastoma cells (Thoraval et al., 1996). </p><p>Hansen et al. (2000) reported several examples of extensive hypomethylation that were associated with advanced replication time, nuclease hypersensitivity, and a variable escape from silencing for genes on the inactive X and Y chromosomes of ICF cells. Their data suggested that all genes on the inactive X chromosome may be extremely hypomethylated at their 5-prime CpG islands. Abnormal escape from X chromosome inactivation of G6PD (305900) and SYBL1 (300053) was noted in untransformed female ICF fibroblasts. SYBL1 silencing was also disrupted on the Y chromosome in male ICF cells. Increased chromatin sensitivity to nuclease was found at all hypomethylated promoters examined, including those of silenced genes. The persistence of inactivation in these latter cases appeared to depend critically on delayed replication of DNA, since escape from silencing was only seen when replication was advanced to an active X-like pattern. </p><p>Hendrich and Bickmore (2001) reviewed human disorders which share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders (301040), ICF syndrome, Rett syndrome (312750), Rubinstein-Taybi syndrome (180849), and Coffin-Lowry syndrome (303600). </p><p>Ehrlich et al. (2001) performed microarray expression analysis on B-cell lymphoblastoid cell lines from 5 ICF patients with diverse DNMT3B mutations and on control lymphoblastoid cell lines. They employed oligonucleotide arrays for approximately 5,600 different genes, 510 of which showed a lymphoid lineage-restricted expression pattern among several different lineages tested. A set of 32 genes, half of which are thought to play a role in immune function, had consistent and significant ICF-specific changes in RNA levels. ICF-specific increases in immunoglobulin (Ig) heavy constant mu- and delta-RNA and cell surface IgM and IgD, decreases in Ig-gamma and Ig-alpha RNA, and surface IgG and IgA suggested inhibition of the later steps of lymphocyte maturation. ICF-specific increases were seen in RNA for RGS1 (600323), a B-cell specific inhibitor of G-protein signaling implicated in negative regulation of B-cell migration, and in RNA for the proapoptotic protein kinase C eta gene (605437). ICF-associated decreases were observed in RNAs encoding proteins involved in activation, migration, or survival of lymphoid cells, namely, transcription factor negative regulator ID3 (600277), the enhancer-binding MEF2C (600662), the iron regulatory TFRC (190010), integrin beta-7 (ITGB7; 147559), the stress protein heme oxygenase (HMOX1; 141250), and the lymphocyte-specific tumor necrosis factor receptor family members 7 and 17 (TNFRSF7, 186711; TNFRSF17, 109545). No differences in promoter methylation were seen between ICF and normal lymphoblastoid cell lines for 3 ICF upregulated genes and 1 downregulated gene by a quantitative methylation assay. The authors hypothesized that DNMT3B mutations in the ICF syndrome may cause lymphogenesis-associated gene dysregulation by indirect effects on gene expression that interfere with normal lymphocyte signaling, maturation, and migration. </p><p>Using a model EBV-based system and 3 members of the unique cellular cancer-testis gene family, Tao et al. (2002) determined that de novo methylation of newly introduced viral sequences is defective in ICF cells. Limited de novo methylation capacity was retained in ICF cells, suggesting that the mutations in DNMT3B may not be complete loss-of-function mutations, or that other DNMTs may cooperate with DNMT3B. Analysis of 3 cancer-testis genes (2 on the X chromosome and 1 autosomal) revealed that loss of methylation from cellular gene sequences was heterogeneous, with both autosomal and X chromosome-based genes demonstrating sensitivity to mutations in DNMT3B. Aberrant hypomethylation at a number of loci examined correlated with altered gene expression levels. However, no consistent changes in the protein levels of the DNA methyltransferases were noted when normal and ICF cell lines were compared. </p><p>In a review of genetic disorders associated with aberrant chromatin structure, Bickmore and van der Maarel (2003) discussed altered heterochromatin structure, DNA methylation, and gene expression in ICF syndrome. </p><p>Jin et al. (2008) used global expression profiling to analyze and compare gene expression patterns in lymphoblastoid cell lines from 3 patients with ICF syndrome and 5 healthy controls. There were significant changes, both up- and downregulation, of genes involved in immune function, signal transduction, mRNA transcription, development, and neurogenesis between the 2 groups that were highly relevant to the ICF phenotype. Loss of DNMT3B function in ICF cells resulted in loss of methylation at promoter regions in several genes, such as LHX2 (603759), compared to normal cells. These changes were associated with histone modifications, particularly H3K27 trimethylation, and gains in transcriptionally active H3K9 acetylation and H3K4 trimethylation marks. There was a consistent loss of binding of the SUZ12 (606245) component of the PRC2 polycomb repression complex and DNMT3B to derepressed genes, including a number of homeobox genes critical for immune system, brain, and craniofacial development. The findings indicated that genes upregulated in ICF cells lose histone modifications characteristic of repressed chromatin and gain modifications characteristic of transcriptionally active chromatin. Jin et al. (2008) suggested that their results showed the interrelatedness of DNA methylation and histone modifications and the importance of DNMT3B in DNA methylation and repression of transcription. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Heterogeneity</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Wijmenga et al. (2000) found mutations in the DNMT3B gene in only 9 of 14 ICF patients. Moreover, 2 ICF patients from consanguineous families who did not show homozygosity by descent for the DNMT3B locus did not have DNMT3B mutations, suggesting genetic heterogeneity for this disease. </p><p>Kubota et al. (2004) described a 3-year-old girl with phenotypic and cytogenetic characteristics of ICF syndrome and DNA hypomethylation but without a detectable mutation in the DNMT3B gene. Indeed, from an analysis of 17 patients, Jiang et al. (2005) suggested that there are 2 types of clinically indistinguishable ICF syndrome: type 1 is characterized by DNMT3B mutations and normal methylation of alpha satellites; type 2 lacks DNMT3B mutations and shows hypomethylation of alpha satellites. Both show characteristic heterochromatin abnormalities and undermethylation of classic satellites 2 and 3. </p><p>Kloeckener-Gruissem et al. (2005) reported a Turkish boy (patient 1), born of consanguineous parents, with ICF syndrome. He had hypertelorism, hypospadias, severe hypogammaglobulinemia with normal T-cell function, delayed speech development, and bilateral suspected focal cortical heterotopy. An affected brother had died at age 4.5 years. Cytogenetic and Southern blot analysis showed that the patient had hypomethylation and centromeric instability of chromosomes 1 and 16, although he did not have mutations in the DNMT3B gene or in genes encoding the DNMT3B-interacting proteins SUMO1 (601912) and UBC9 (UBE2I; 601661). Including this study, Kloeckener-Gruissem et al. (2005) estimated that approximately 40% of reported patients with ICF lack mutations in the DNMT3B coding region, suggesting genetic heterogeneity. A second patient reported by Kloeckener-Gruissem et al. (2005) (patient 2), previously reported by Braegger et al. (1991), was found by Thijssen et al. (2015) to have ICF3 (616910), caused by a homozygous mutation in the CDCA7 gene (609937.0001). </p><p>Schuetz et al. (2007) described a brother and sister with ICF syndrome. The brother had a history of multiple infections, mild facial dysmorphism, delayed development, and hypogammaglobulinemia (absent IgM and low IgG). At age 7, the boy presented with hemiplegia secondary to tumorous invasion of the right brachial plexus. Immunohistochemistry confirmed the diagnosis of classic Hodgkin lymphoma of the lymphocyte depleted subtype. Following surgery, the boy had sudden cardiac arrest and died. The younger sister has similar dysmorphic features, hypogammaglobulinemia, and psychomotor retardation. No mutation was found in the DNMT3B gene. DNA of the affected sister was tested for the presence of hypomethylation of repetitive DNA by Southern blot analysis; hypomethylation of alpha-satellite DNA and classic satellite 2, characteristic of ICF type 2, was observed. Schuetz et al. (2007) suggested that clinical follow-up for children with ICF include surveillance for neoplasia. </p><p>Hagleitner et al. (2008) identified DNMT3B mutations in only 20 (57%) of 34 ICF patients tested, suggesting genetic heterogeneity. No genotype/phenotype correlations were found between patients with and without DNMT3B mutations. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
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[PubMed: 2729362]
[Full Text: https://doi.org/10.1002/ajmg.1320320331]
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</li>
<li>
<p class="mim-text-font">
Valkova, G., Ghenev, E., Tzancheva, M.
<strong>Centromeric instability of chromosomes 1, 9 and 16 with variable immune deficiency: support of a new syndrome.</strong>
Clin. Genet. 31: 119-124, 1987.
[PubMed: 3568436]
[Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb02781.x]
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</li>
<li>
<p class="mim-text-font">
Weemaes, C. M. R., van Tol, M. J. D., Wang, J., van Ostaijen-ten Dam, M. M., van Eggermond, M. C. J. A., Thijssen, P. E., Aytekin, C., Brunetti-Pierri, N., van der Burg, M., Graham Davies, E., Ferster, A., Furthner, D., and 11 others.
<strong>Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects.</strong>
Europ. J. Hum. Genet. 21: 1219-1225, 2013.
[PubMed: 23486536]
[Full Text: https://doi.org/10.1038/ejhg.2013.40]
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<li>
<p class="mim-text-font">
Wijmenga, C., Hansen, R. S., Gimelli, G., Bjorck, E. J., Davies, E. G., Valentine, D., Belohradsky, B. H., van Dongen, J. J., Smeets, D. F. C. M., van den Heuvel, L. P. W. J., Luyten, J. A. F. M., Strengman, E., Weemaes, C., Pearson, P. L.
<strong>Genetic variation in ICF syndrome: evidence for genetic heterogeneity.</strong>
Hum. Mutat. 16: 509-517, 2000.
[PubMed: 11102980]
[Full Text: https://doi.org/10.1002/1098-1004(200012)16:6&lt;509::AID-HUMU8&gt;3.0.CO;2-V]
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<li>
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Wijmenga, C., van den Heuvel, L. P. W. J., Strengman, E., Luyten, J. A. F. M., van der Burgt, I. J. A. M., de Groot, R., Smeets, D. F. C. M., Draaisma, J. M. T., van Dongen, J. J., De Abreu, R. A., Pearson, P. L., Sandkuijl, L. A., Weemaes, C. M. R.
<strong>Localization of the ICF syndrome to chromosome 20 by homozygosity mapping.</strong>
Am. J. Hum. Genet. 63: 803-809, 1998.
[PubMed: 9718351]
[Full Text: https://doi.org/10.1086/302021]
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<li>
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Xu, G.-L., Bestor, T. H., Bourc'his, D., Hsieh, C.-L., Tommerup, N., Bugge, M., Hulten, M., Qu, X., Russo, J. J., Viegas-Pequignot, E.
<strong>Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.</strong>
Nature 402: 187-191, 1999.
[PubMed: 10647011]
[Full Text: https://doi.org/10.1038/46052]
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Cassandra L. Kniffin - updated : 4/19/2016<br>Cassandra L. Kniffin - updated : 12/4/2013<br>Cassandra L. Kniffin - updated : 4/13/2010<br>Matthew B. Gross - reorganized : 2/20/2009<br>Cassandra L. Kniffin - updated : 6/25/2008<br>Kelly A. Przylepa - updated : 11/6/2007<br>Cassandra L. Kniffin - updated : 10/31/2005<br>George E. Tiller - updated : 9/30/2005<br>Victor A. McKusick - updated : 2/4/2005<br>Victor A. McKusick - updated : 9/22/2004<br>George E. Tiller - updated : 9/17/2003<br>George E. Tiller - updated : 8/15/2002<br>Victor A. McKusick - updated : 3/7/2002<br>George E. Tiller - updated : 2/12/2002<br>George E. Tiller - updated : 1/24/2001<br>George E. Tiller - updated : 4/14/2000<br>Stylianos E. Antonarakis - updated : 11/12/1999<br>Ada Hamosh - updated : 11/11/1999<br>Michael J. Wright - updated : 11/9/1998<br>Victor A. McKusick - updated : 9/16/1998<br>Michael J. Wright - updated : 8/25/1997
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Victor A. McKusick : 4/14/1987
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