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Entry
- #613254 - TUBEROUS SCLEROSIS 2; TSC2
- OMIM
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<span class="h4">#613254</span>
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/613254"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS191100"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#diagnosis">Diagnosis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=TUBEROUS SCLEROSIS" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="http://www.informatics.jax.org/disease/613254" 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>
</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>ORPHA:</strong> 805<br />
<strong>DO:</strong> 0080325<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>
613254
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
TUBEROUS SCLEROSIS 2; TSC2
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
TSC2 ANGIOMYOLIPOMAS, RENAL, MODIFIER OF, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/598?start=-3&limit=10&highlight=598">
12q15
</a>
</span>
</td>
<td>
<span class="mim-font">
{TSC2 angiomyolipomas, renal, modifier of}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613254"> 613254 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
IFNG
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147570"> 147570 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/93?start=-3&limit=10&highlight=93">
16p13.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Tuberous sclerosis-2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613254"> 613254 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
TSC2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191092"> 191092 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/613254" 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/PS191100" 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/613254" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/613254" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Achromatic retinal patches <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860710&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860710</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009727" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009727</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009727" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009727</a>]</span><br /> -
Retinal astrocytoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/255026000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">255026000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/416351002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">416351002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0339554&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0339554</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012778" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012778</a>]</span><br /> -
Optic gliomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254976006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254976006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0346326&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0346326</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009734" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009734</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">
- Pitted dental enamel <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860711&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860711</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009722" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009722</a>]</span><br /> -
Gingival fibroma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/58569000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">58569000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K06.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K06.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0016049&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0016049</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000169" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000169</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000169" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000169</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Wolf-Parkinson-White syndrome <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74390002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74390002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I45.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I45.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0043202&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0043202</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001716</a>]</span><br /> -
Cardiac rhabdomyoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1332852&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1332852</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009729" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009729</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009729" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009729</a>]</span><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> Lung </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Lymphangiomyomatosis, rare <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860721&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860721</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Renal cysts <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/722223000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">722223000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3887499&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887499</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000107</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000107" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000107</a>]</span><br /> -
Tumors of the kidney (may progress to malignancy in less than 2%) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/126880001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">126880001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0022665&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022665</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009726</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Cystic areas of bone rarefaction, esp. phalanges <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806076&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806076</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Facial angiofibroma (adenoma sebaceum) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3810411&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3810411</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36025004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36025004</a>]</span><br /> -
White ash leaf-shaped macules <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806077&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806077</a>]</span><br /> -
Shagreen patch <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254244007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254244007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0432363&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0432363</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009721" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009721</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009721" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009721</a>]</span><br /> -
Subcutaneous nodules <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95325000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95325000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151811&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151811</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001482" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001482</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001482" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001482</a>]</span><br /> -
Cafe-au-lait spots <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/201281002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">201281002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L81.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L81.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221263&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221263</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000957" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000957</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000957" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000957</a>]</span><br /> -
Subungual fibromata <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39295002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39295002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0266003&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0266003</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009724" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009724</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hamartomatous lesions of the brain <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1968957&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1968957</a>]</span><br /> -
Subependymal nodules <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1968958&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1968958</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009716</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009716</a>]</span><br /> -
Cortical tubers <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1968959&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1968959</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009717" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009717</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009717" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009717</a>]</span><br /> -
Infantile spasms <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/28055006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">28055006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G40.82" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G40.82</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/345.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">345.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3887898&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887898</a>, <a href="https://bioportal.bioontology.org/search?q=C0037769&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037769</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011097" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011097</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0012469" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012469</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012469" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012469</a>]</span><br /> -
Seizures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
Mental retardation (30%) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a>, <a href="https://bioportal.bioontology.org/search?q=C0025362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
Learning difficulties <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/161129001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">161129001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424939&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424939</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001328" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001328</a>]</span><br /> -
Intracranial calcification by x-ray or CT <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860708&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860708</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Attention deficit disorder <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7461003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7461003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35253001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35253001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/406506008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">406506008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F90.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F90.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F90.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F90.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/314.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314.01</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/314" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/314.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/314.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0339002&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0339002</a>, <a href="https://bioportal.bioontology.org/search?q=C0041671&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0041671</a>, <a href="https://bioportal.bioontology.org/search?q=C1263846&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1263846</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000752" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000752</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0007018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007018</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007018</a>]</span><br /> -
Hyperactivity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44548000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44548000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424295&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424295</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000752" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000752</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000752" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000752</a>]</span><br /> -
Autism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35919005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35919005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/408857007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">408857007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43614003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43614003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F84.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F84.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F84" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F84</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F84.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F84.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/299" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">299</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/299.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">299.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/299.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">299.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0524528&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0524528</a>, <a href="https://bioportal.bioontology.org/search?q=C0004352&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004352</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000717" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000717</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000717" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000717</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ENDOCRINE FEATURES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Precocious puberty <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/400179000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">400179000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E30.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E30.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0034013&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0034013</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000826" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000826</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000826" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000826</a>]</span><br /> -
Hypothyroidism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40930008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40930008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E03.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E03.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/244.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">244.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020676&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020676</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000821" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000821</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000821" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000821</a>]</span><br />
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<div>
<div>
<span class="h5 mim-font">
<strong> NEOPLASIA </strong>
</span>
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<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Myocardial rhabdomyoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860713&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860713</a>]</span><br /> -
Multiple bilateral renal angiomyolipoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860714&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860714</a>]</span><br /> -
Ependymoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1186904005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1186904005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/443643007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">443643007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0014474&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014474</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002888" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002888</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002888" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002888</a>]</span><br /> -
Renal carcinoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/702391001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">702391001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/41607009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">41607009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1378703&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1378703</a>, <a href="https://bioportal.bioontology.org/search?q=C0007134&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007134</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009726" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009726</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0005584" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005584</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005584" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005584</a>]</span><br /> -
Giant cell astrocytoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860715&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860715</a>]</span><br /> -
Chordoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1156453008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1156453008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/50007008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">50007008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0008487&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008487</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010762" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010762</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010762" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010762</a>]</span><br /> -
Benign tumors of the eye, heart, and lungs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1968961&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1968961</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">
- Increased frequency of premature centromere disjunction (PCD) in cultured fibroblasts, esp. chromosome 3 <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860717&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860717</a>]</span><br /> -
Allelic loss on 16p13.3 in angiomyolipoma, cardiac rhabdomyoma, cortical tuber, and giant cell astrocytoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2750462&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2750462</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">
- Genetic heterogeneity (see <a href="/entry/191100">191100</a>) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0242960&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0242960</a>]</span><br /> -
Many studies have reported that the phenotype of tuberous sclerosis-2 (TSC2) is more severe than that of tuberous sclerosis-1 (e.g., lower IQ, more seizures, more macules, cust-like cortical tubers)<br /> -
Highly variable phenotype <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839039&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839039</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003812" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003812</a>]</span><br /> -
One-third of cases are familial<br /> -
Majority of cases are sporadic<br /> -
Prevalence of 1 in 6,000 to 1 in 10,000<br /> -
Frequent new mutations (~60%) and/or gonadal mosaicism in TSC2<br />
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<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
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<span class="mim-font">
- Caused by mutation in the tuberin gene (TSC2, <a href="/entry/191092#0001">191092.0001</a>)<br />
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<h5>
Tuberous sclerosis
- <a href="/phenotypicSeries/PS191100">PS191100</a>
- 3 Entries
</h5>
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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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<strong>Gene/Locus<br />MIM number</strong>
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<td>
<span class="mim-font">
<a href="/geneMap/9/601?start=-3&limit=10&highlight=601"> 9q34.13 </a>
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<span class="mim-font">
<a href="/entry/191100"> Tuberous sclerosis-1 </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/191100"> 191100 </a>
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<span class="mim-font">
<a href="/entry/605284"> TSC1 </a>
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<span class="mim-font">
<a href="/entry/605284"> 605284 </a>
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<span class="mim-font">
<a href="/geneMap/12/598?start=-3&limit=10&highlight=598"> 12q15 </a>
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<span class="mim-font">
<a href="/entry/613254"> {TSC2 angiomyolipomas, renal, modifier of} </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/613254"> 613254 </a>
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<span class="mim-font">
<a href="/entry/147570"> IFNG </a>
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</td>
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<span class="mim-font">
<a href="/entry/147570"> 147570 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/16/93?start=-3&limit=10&highlight=93"> 16p13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613254"> Tuberous sclerosis-2 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613254"> 613254 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191092"> TSC2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191092"> 191092 </a>
</span>
</td>
</tr>
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because tuberous sclerosis-2 (TSC2) is caused by heterozygous mutation in the TSC2 gene (<a href="/entry/191092">191092</a>) on chromosome 16p13. The TSC2 gene product is known as 'tuberin.'</p>
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<strong>Description</strong>
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<p>Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by hamartomas in multiple organ systems, including the brain, skin, heart, kidneys, and lung. These changes can result in epilepsy, learning difficulties, behavioral problems, and renal failure, among other complications (reviews by Crino et al., 2006 and Curatolo et al., 2008).</p><p>For a general phenotypic description and a discussion of genetic heterogeneity of tuberous sclerosis, see tuberous sclerosis-1 (<a href="/entry/191100">191100</a>), caused by mutation in the TSC1 gene (<a href="/entry/605284">605284</a>) on chromosome 9q34.</p><p>Approximately 10 to 30% of cases of tuberous sclerosis are due to mutations in the TSC1 gene: the frequency of cases due to mutations in the TSC2 gene is consistently higher. TSC2 mutations are associated with more severe disease (Crino et al., 2006) (see GENOTYPE/PHENOTYPE CORRELATIONS section).</p>
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<strong>Clinical Features</strong>
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<p><a href="#13" class="mim-tip-reference" title="Kumar, A., Wolpert, C., Kandt, R. S., Segal, J., Pufky, J., Roses, A. D., Pericak-Vance, M. A., Gilbert, J. R. &lt;strong&gt;A de novo frame-shift mutation in the tuberin gene.&lt;/strong&gt; Hum. Molec. Genet. 4: 1471-1472, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7581393/&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;7581393&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/4.8.1471&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="7581393">Kumar et al. (1995)</a> reported a 2-year-old Caucasian female with tuberous sclerosis-2. At birth, she had a hypopigmented patch on her left ankle and multiple hypopigmented patches on her back and trunk. She later developed facial plaques on her forehead but no facial angiofibromas or ungual fibromata. Onset of generalized seizures occurred at 7 months of age. CT scan of the brain demonstrated cerebral cortical tubers and subependymal nodules. Renal ultrasound showed multiple cysts in both kidneys. The parents were clinically normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7581393" 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="Vrtel, R., Verhoef, S., Bouman, K., Maheshwar, M. M., Nellist, M., van Essen, A. J., Bakker, P. L. G., Hermans, C. J., Bink-Boelkens, M. T. E., van Elburg, R. M., Hoff, M., Lindhout, D., Sampson, J., Halley, D. J. J., van den Ouweland, A. M. W. &lt;strong&gt;Identification of a nonsense mutation at the 5-prime end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex.&lt;/strong&gt; J. Med. Genet. 33: 47-51, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8825048/&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;8825048&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.1.47&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="8825048">Vrtel et al. (1996)</a> reported a father and his son with tuberous sclerosis-2. The family was ascertained through a discovery of fetal bradycardia and arrhythmia in the proband at 20 weeks' gestation. At 24 weeks' gestation, an intracardiac mass suspected of being a rhabdomyosarcoma was detected by fetal ultrasound and the diagnosis of tuberous sclerosis was suggested. A boy, weighing 2,500 g, was delivered at 39 weeks. Postnatal ECG showed intermittent second and third degree atrioventricular block. Echography of the brain, liver, and kidneys showed no abnormalities, and the studies of the retina were also normal. At 3 months of age a hypomelanotic macule, 25 x 15 mm, was noted on the buttock using Woods light. The 30-year-old father showed no abnormalities on study of the brain, heart, skin, and retina, and the most questionable changes in the kidneys. All tooth surfaces showed pit-shaped enamel defects, corresponding to the dental pits described in patients with tuberous sclerosis. In addition, 2 gingival fibromas were found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8825048" 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="Khare, L., Strizheva, G. D., Bailey, J. N., Au, K.-S., Northrup, H., Smith, M., Smalley, S. L., Henske, E. P. &lt;strong&gt;A novel missense mutation in the GTPase activating protein homology region of TSC2 in two large families with tuberous sclerosis complex.&lt;/strong&gt; J. Med. Genet. 38: 347-349, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11403047/&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;11403047&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.38.5.347&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="11403047">Khare et al. (2001)</a> reported a 4-generation family with mild physical features of tuberous sclerosis-2, but in which there was significant clustering of neuropsychiatric disorders including mood disorder, anxiety disorder, and autism among affected individuals. A second family also had mild physical features of tuberous sclerosis, but no neuropsychiatric assessment had been performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11403047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Martin, N., Zugge, K., Brandt, R., Friebel, D., Janssen, B., Zimmerhackl, L. B. &lt;strong&gt;Discordant clinical manifestations in monozygotic twins with the identical mutation in the TSC2 gene. (Letter)&lt;/strong&gt; Clin. Genet. 63: 427-430, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12752578/&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;12752578&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1034/j.1399-0004.2003.00073.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="12752578">Martin et al. (2003)</a> reported a pair of twin boys discordant for tuberous sclerosis-2 in whom marker studies supported a probability of monozygosity greater than 99.9%. The twins had similar CNS features, as both were severely mentally retarded with motor delay. Obvious differences were seen in the skin, heart, and kidneys. Whereas twin T had a shagreen patch of the skin and a heart rhabdomyoma, twin M had none. Twin M was diagnosed early (at the age of 3 years) with renal lesions, namely, angiomyolipomas and cystic alterations. At 6 years of age, twin T also started to have the same types of renal lesions as twin M. <a href="#16" class="mim-tip-reference" title="Martin, N., Zugge, K., Brandt, R., Friebel, D., Janssen, B., Zimmerhackl, L. B. &lt;strong&gt;Discordant clinical manifestations in monozygotic twins with the identical mutation in the TSC2 gene. (Letter)&lt;/strong&gt; Clin. Genet. 63: 427-430, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12752578/&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;12752578&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1034/j.1399-0004.2003.00073.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="12752578">Martin et al. (2003)</a> suggested that the Knudson hypothesis (<a href="#12" class="mim-tip-reference" title="Knudson, A. G., Jr. &lt;strong&gt;Mutation and cancer: statistical study of retinoblastoma.&lt;/strong&gt; Proc. Nat. Acad. Sci. 68: 820-823, 1971.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5279523/&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;5279523&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.68.4.820&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="5279523">Knudson, 1971</a>) explained the difference, assuming that many of the features such as the skin, cardiac, and renal alterations present a 2-hit phenomenon, the second hit depending on a random somatic event. Genetic analysis identified a germline mutation in the TSC2 gene (<a href="/entry/191092#0012">191092.0012</a>) in both boys. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12752578+5279523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Jansen, A. C., Sancak, O., D&#x27;Agostino, M. D., Badhwar, A., Roberts, P., Gobbi, G., Wilkinson, R., Melanson, D., Tampieri, D., Koenekoop, R., Gans, M., Maat-Kievit, A., and 12 others. &lt;strong&gt;Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation.&lt;/strong&gt; Ann. Neurol. 60: 528-539, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17120248/&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;17120248&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21037&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="17120248">Jansen et al. (2006)</a> reported a large 5-generation French Canadian family with a mild form of tuberous sclerosis-2 due to a heterozygous mutation in the TSC2 gene (R905Q; <a href="/entry/191092#0013">191092.0013</a>). The proband was a 25-year-old man who started having seizures at age 8 years. Family studies showed that 25 individuals carried the mutation, but only 5 had definite TSC according to diagnostic criteria and 11 did not meet any diagnostic criteria. Examination of mutation carriers showed hypomelanotic macules in 92%, epilepsy in 60%, learning difficulties or mild cognitive impairment in 52%, and brain imaging abnormalities (white matter lesions, subependymal nodule, or subependymal giant cell astrocytoma) in 24%. None had cortical tubers. Renal lesions were found in 8% and retinal abnormalities in 4%. Five additional families with the same mutation were found, and all had a similarly mild phenotype, although cortical tubers were present in some. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17120248" 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 retrospective review, <a href="#17" class="mim-tip-reference" title="McMaster, M. L., Goldstein, A. M., Parry, D. M. &lt;strong&gt;Clinical features distinguish childhood chordoma associated with tuberous sclerosis complex (TSC) from chordoma in the general paediatric population.&lt;/strong&gt; J. Med. Genet. 48: 444-449, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21266383/&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;21266383&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21266383[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/10.1136/jmg.2010.085092&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="21266383">McMaster et al. (2011)</a> identified 10 cases of chordoma associated with tuberous sclerosis complex, although only 3 patients had documented mutations: 2 in the TSC1 gene and 1 in the TSC2 gene. The median age at onset in TSC-associated chordoma was 6.2 months (range 0 to 16 years), with only 1 patient diagnosed with chordoma after age 5. Chordomas were skull-based in 50% and sacral-based in 40%; the 16-year-old had a spinal-based tumor. The 5-year survival was 83%. Molecular and immunohistochemical studies of the chordomas from 2 patients with identified mutations in the TSC1 and TSC2 genes, respectively, demonstrated that 1 tumor had loss of heterozygosity (LOH) for the wildtype TSC1 allele, while the other tumor had LOH for the wildtype TSC2 allele, suggesting a pathogenetic role for the TSC1/TSC2 genes in these chordomas. Comparison with 65 cases of non-TSC-associated pediatric chordoma (<a href="/entry/215400">215400</a>) showed important clinical differences. The latter patients had onset between ages 0 and 18 years (median age at diagnosis was 12 years). Most (64.1%) were intracranial, 26.6% were spinal, and 9.4% were sacral. Chordomas were exclusively skull-based in the youngest age tertile, while sacral chordomas were confined to patients in the oldest tertile. Survival was poorer, at 68.2% at 5 years and 53.1% at 20 years. The findings suggested that TSC-associated chordoma has an unusually early onset and/or rapid growth, and that chordoma can be a rare pediatric manifestation of TSC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21266383" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The tuberous sclerosis complex consensus conference (<a href="#21" class="mim-tip-reference" title="Roach, E. S., Gomez, M. R., Northrup, H. &lt;strong&gt;Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria.&lt;/strong&gt; J. Child Neurol. 13: 624-628, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9881533/&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;9881533&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1177/088307389801301206&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="9881533">Roach et al., 1998</a>) proposed major and minor diagnostic criteria. Since no single feature is diagnostic, an evaluation that includes consideration of all clinical features is necessary to make a correct diagnosis. The clinical manifestations of TSC appear at distinct developmental points, which may further complicate the clinical diagnosis. Major criteria include retinal hamartomas, renal angiomyolipomas, facial angiofibromas, and cortical tubers, among other features. Minor criteria include dental pits, bone cysts, and cerebral white-matter radial migration lines, among other features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9881533" 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="#2" class="mim-tip-reference" title="Brackley, K. J., Farndon, P. A., Weaver, J. B., Dow, D. J., Chapman, S., Kilby, M. D. &lt;strong&gt;Prenatal diagnosis of tuberous sclerosis with intracerebral signs at 14 weeks&#x27; gestation.&lt;/strong&gt; Prenatal Diag. 19: 575-579, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10416977/&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;10416977&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1097-0223(199906)19:6&lt;575::aid-pd580&gt;3.0.co;2-r&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="10416977">Brackley et al. (1999)</a> reported detection by ultrasound of cranial abnormalities at 14 weeks' gestation in a fetus subsequently confirmed as having tuberous sclerosis using DNA linkage analysis within the affected family. The presence of asymmetric ventricular enlargement persisted antenatally. MRI at 26 weeks indicated the possibility of poor gyral formation consistent with a neuronal migration disorder. Cardiac rhabdomyomata were not visualized on ultrasound scan until 30 weeks' gestation. Postnatal cranial ultrasound confirmed the significant neuropathology that was manifested by severe developmental delay and intractable fits in the child. The right fundus of the patient showed multiple peripheral pigmented areas and a persistent pupillary membrane also consistent with TSC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10416977" 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="#15" class="mim-tip-reference" title="Liang, N., Zhang, C., Dill, P., Panasyuk, G., Pion, D., Koka, V., Gallazzini, M., Olson, E. N., Lam, H., Henske, E. P., Dong, Z., Apte, U., Pallet, N., Johnson, R. L., Terzi, F., Kwiatkowski, D. J., Scoazec, J.-Y., Martignoni, G., Pende, M. &lt;strong&gt;Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex.&lt;/strong&gt; J. Exp. Med. 211: 2249-2263, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25288394/&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;25288394&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25288394[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/10.1084/jem.20140341&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="25288394">Liang et al. (2014)</a> generated a mosaic Tsc1-knockout mouse model in which mutant mice developed renal mesenchymal lesions that recapitulated perivascular epithelioid cell tumors (PEComas) found in patients with TSC. The authors found that YAP (YAP1; <a href="/entry/606608">606608</a>) was upregulated by MTOR (<a href="/entry/601231">601231</a>) in mouse and human PEComas. Genetic or pharmacologic inhibition of Yap blunted abnormal proliferation and induced apoptosis of mouse Tsc1/Tsc2-deficient cells in culture and in mosaic Tsc1-knockout mice. Yap accumulated in cells lacking Tsc1/Tsc2 due to impaired degradation of Yap by autophagy in an Mtor-dependent manner. <a href="#15" class="mim-tip-reference" title="Liang, N., Zhang, C., Dill, P., Panasyuk, G., Pion, D., Koka, V., Gallazzini, M., Olson, E. N., Lam, H., Henske, E. P., Dong, Z., Apte, U., Pallet, N., Johnson, R. L., Terzi, F., Kwiatkowski, D. J., Scoazec, J.-Y., Martignoni, G., Pende, M. &lt;strong&gt;Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex.&lt;/strong&gt; J. Exp. Med. 211: 2249-2263, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25288394/&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;25288394&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25288394[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/10.1084/jem.20140341&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="25288394">Liang et al. (2014)</a> proposed that YAP is a potential therapeutic target for TSC and other disease with dysregulated MTOR activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25288394" 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>Most patients with tuberous sclerosis-2 have de novo heterozygous mutations in the TSC2 gene. Patients with tuberous sclerosis-2 generally have more severe disease than patients with tuberous sclerosis-1, thus reducing the chance of these patients having a family (<a href="#5" class="mim-tip-reference" title="Curatolo, P., Bombardieri, R., Jozwiak, S. &lt;strong&gt;Tuberous sclerosis.&lt;/strong&gt; Lancet 372: 657-668, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18722871/&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;18722871&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(08)61279-9&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="18722871">Curatolo et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18722871" 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>Mosaicism</em></strong></p><p>
<a href="#27" class="mim-tip-reference" title="Verhoef, S., Vrtel, R., van Essen, T., Bakker, L., Sikkens, E., Halley, D., Lindhout, D., van den Ouweland, A. &lt;strong&gt;Somatic mosaicism and clinical variation in tuberous sclerosis complex.&lt;/strong&gt; Lancet 345: 202 only, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7823706/&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;7823706&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(95)90213-9&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="7823706">Verhoef et al. (1995)</a> reported somatic mosaicism in the father of a 2-year-old boy with tuberous sclerosis 2: the father had subclinical signs of TSC and an apparently low proportion of cells with the TSC2 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7823706" 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="Verhoef, S., Bakker, L., Tempelaars, A. M. P., Hesseling-Janssen, A. L. W., Mazurczak, T., Jozwiak, S., Fois, A., Bartalini, G., Zonnenberg, B. A., van Essen, A. J., Lindhout, D., Halley, D. J. J., van den Ouweland, A. M. W. &lt;strong&gt;High rate of mosaicism in tuberous sclerosis complex.&lt;/strong&gt; Am. J. Hum. Genet. 64: 1632-1637, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10330349/&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;10330349&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302412&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="10330349">Verhoef et al. (1999)</a> identified 6 families with mosaicism in a series of 62 unrelated families with a mutation in either the TSC1 or the TSC2 gene. In 5 families, somatic mosaicism was present in the mildly affected parent of an index patient. In 1 family with clinically unaffected parents, gonadal mosaicism was detected after tuberous sclerosis was found in 3 children. The detection of mosaicism has obvious consequences for genetic counseling. Clinical investigation of the parents of patients with seemingly sporadic mutations is essential to determine their residual chance of gonadal and/or somatic mosaicism, unless a mosaic pattern is detected in the index patient, proving a de novo event. In the data set of <a href="#26" class="mim-tip-reference" title="Verhoef, S., Bakker, L., Tempelaars, A. M. P., Hesseling-Janssen, A. L. W., Mazurczak, T., Jozwiak, S., Fois, A., Bartalini, G., Zonnenberg, B. A., van Essen, A. J., Lindhout, D., Halley, D. J. J., van den Ouweland, A. M. W. &lt;strong&gt;High rate of mosaicism in tuberous sclerosis complex.&lt;/strong&gt; Am. J. Hum. Genet. 64: 1632-1637, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10330349/&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;10330349&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302412&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="10330349">Verhoef et al. (1999)</a>, the exclusion of signs of tuberous sclerosis in the parents of a patient with tuberous sclerosis reduced the chance of one of the parents to be a mosaic mutation carrier from 10% to 2%. In the 5 families with somatic mosaicism, the parent was given the diagnosis after the diagnosis was made in the child. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10330349" 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>During TSC2 mutational analysis, <a href="#22" class="mim-tip-reference" title="Roberts, P. S., Chung, J., Jozwiak, S., Dabora, S. L., Franz, D. N., Thiele, E. A., Kwiatkowski, D. J. &lt;strong&gt;SNP identification, haplotype analysis, and parental origin of mutations in TSC2.&lt;/strong&gt; Hum. Genet. 111: 96-101, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12136241/&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;12136241&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-002-0738-y&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="12136241">Roberts et al. (2002)</a> identified 10 single-nucleotide polymorphisms (SNPs) that occur within or close to exon boundaries at minor allele frequencies greater than 5%. The authors determined the haplotypes for 6 of these SNPs and the microsatellite marker kg8 in the 3-prime region of TSC2 in a set of 40 parent-child trios. The most common haplotypes accounted for 53%, 11%, 6%, and 5% of chromosomes. Thirty-eight TSC2 mutation-bearing haplotypes had a similar distribution, indicating that there was no haplotype that predisposed to mutation in this region in TSC2. Family analysis was possible in 12 sporadic cases, and indicated that the mother was the parent of origin in 7 cases (3 point mutations, 2 small deletions, 2 large deletions), while the father was the parent of origin in 5 cases (2 point mutations, 3 small deletions). <a href="#22" class="mim-tip-reference" title="Roberts, P. S., Chung, J., Jozwiak, S., Dabora, S. L., Franz, D. N., Thiele, E. A., Kwiatkowski, D. J. &lt;strong&gt;SNP identification, haplotype analysis, and parental origin of mutations in TSC2.&lt;/strong&gt; Hum. Genet. 111: 96-101, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12136241/&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;12136241&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-002-0738-y&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="12136241">Roberts et al. (2002)</a> concluded that TSC2 mutations occur at substantial frequency on both the maternally and paternally derived TSC alleles, in contrast to many other genetic diseases. There was no major age effect for mutations of paternal origin. The observation was considered significant to genetic counseling of parents of a sporadic TSC case; each parent should be considered the potential parent of origin, and some alternative reproductive choices such as use of a sperm donor only or egg donor only are not guaranteed to prevent recurrence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12136241" 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="mapping" class="mim-anchor"></a>
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<p>Using tuberous sclerosis families in which linkage to the TSC1 locus on chromosome 9 had been excluded, <a href="#10" class="mim-tip-reference" title="Kandt, R. S., Haines, J. L., Smith, M., Northrup, H., Gardner, R. J. M., Short, M. P., Dumars, K., Roach, E. S., Steingold, S., Wall, S., Blanton, S. H., Flodman, P., Kwiatkowski, D. J., Jewell, A., Weber, J. L., Roses, A. D., Pericak-Vance, M. A. &lt;strong&gt;Linkage of a major gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 51 (suppl.): A4, 1992."None>Kandt et al. (1992)</a> demonstrated linkage with D16S283, the closest marker on the proximal side of the locus for polycystic kidney disease type 1 (<a href="/entry/173900">173900</a>), on chromosome 16p13. A lod score of 9.50 at theta = 0.02 was observed; 1 family independently presented a lod score of 4.44 at theta = 0.05. <a href="#10" class="mim-tip-reference" title="Kandt, R. S., Haines, J. L., Smith, M., Northrup, H., Gardner, R. J. M., Short, M. P., Dumars, K., Roach, E. S., Steingold, S., Wall, S., Blanton, S. H., Flodman, P., Kwiatkowski, D. J., Jewell, A., Weber, J. L., Roses, A. D., Pericak-Vance, M. A. &lt;strong&gt;Linkage of a major gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 51 (suppl.): A4, 1992."None>Kandt et al. (1992)</a> estimated that about 40% of tuberous sclerosis families are linked to chromosome 9, and most of the rest, the majority, to chromosome 16. No clear evidence for a locus on other chromosomes was found. Confirmation of a tuberous sclerosis locus on chromosome 16 (TSC2) was provided by <a href="#19" class="mim-tip-reference" title="Pericak-Vance, M. A., Gardner, R. J. M., Steingold, S., Wall, S. L., Carter, S., DiMario, F. J., Vance, J. M., Reeders, S., Roses, A. D., Kandt, R. S. &lt;strong&gt;Confirmation of linkage of tuberous sclerosis to chromosome 16p. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 51 (suppl.): A198, 1992."None>Pericak-Vance et al. (1992)</a>, <a href="#24" class="mim-tip-reference" title="Short, M. P., Haines, J. L., Bove, C., Henske, E. P., Guillemette, W., Sitsma, M., Amos, J., Andermann, E., Gusella, J. F., Kwiatkowski, D. J. &lt;strong&gt;Linkage and heterogeneity in tuberous sclerosis: linkage to chromosome 16 and resolution of old problems. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 51 (suppl.): A201, 1992."None>Short et al. (1992)</a> and <a href="#25" class="mim-tip-reference" title="Smith, M., Handa, K., Sokolov, G., Postle, S., Flodman, P., Spence, M. A. &lt;strong&gt;Further evidence for a tuberous sclerosis gene locus on chromosome 16p13. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 51 (suppl.): A201, 1992."None>Smith et al. (1992)</a>.</p><p><a href="#20" class="mim-tip-reference" title="Povey, S., Burley, M. W., Attwood, J., Benham, F., Hunt, D., Jeremiah, S. J., Franklin, D., Gillett, G., Malas, S., Robson, E. B., Tippett, P., Edwards, J. H., Kwiatkowski, D. J., Super, M., Mueller, R., Fryer, A., Clarke, A., Webb, D., Osborne, J. &lt;strong&gt;Two loci for tuberous sclerosis: one on 9q34 and one on 16p13.&lt;/strong&gt; Ann. Hum. Genet. 58: 107-127, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7979156/&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;7979156&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1469-1809.1994.tb01881.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="7979156">Povey et al. (1994)</a> did linkage studies in 32 families of tuberous sclerosis, using genetic markers on chromosomes 9, 11, 12, and 16. Approximately half the families appeared to be linked to TSC1 on chromosome 9 between ASS1 (<a href="/entry/603470">603470</a>) and D9S298 and half to TSC2 on chromosome 16 close to D16S291. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7979156" 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>Approximately 10 to 30% of tuberous sclerosis cases are due to TSC1 mutations, whereas the frequency of TSC2 mutations is consistently higher. TSC1 mutations account for 15 to 30% of familial cases and 10 to 15% of sporadic cases. The frequency of TSC2 mutations in sporadic cases ranges from 75 to 80%. About 15 to 20% of patients have no identifiable mutations, which may be due to mosaicism (<a href="#4" class="mim-tip-reference" title="Crino, P. B., Nathanson, K. L., Henske, E. P. &lt;strong&gt;The tuberous sclerosis complex.&lt;/strong&gt; New Eng. J. Med. 355: 1345-1356, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17005952/&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;17005952&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMra055323&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="17005952">Crino et al., 2006</a>; <a href="#5" class="mim-tip-reference" title="Curatolo, P., Bombardieri, R., Jozwiak, S. &lt;strong&gt;Tuberous sclerosis.&lt;/strong&gt; Lancet 372: 657-668, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18722871/&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;18722871&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(08)61279-9&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="18722871">Curatolo et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18722871+17005952" 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 patient with tuberous sclerosis-2, <a href="#13" class="mim-tip-reference" title="Kumar, A., Wolpert, C., Kandt, R. S., Segal, J., Pufky, J., Roses, A. D., Pericak-Vance, M. A., Gilbert, J. R. &lt;strong&gt;A de novo frame-shift mutation in the tuberin gene.&lt;/strong&gt; Hum. Molec. Genet. 4: 1471-1472, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7581393/&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;7581393&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/4.8.1471&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="7581393">Kumar et al. (1995)</a> identified a de novo 1-bp deletion in the TSC2 gene (<a href="/entry/191092#0001">191092.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7581393" 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 father and son with tuberous sclerosis-2, <a href="#28" class="mim-tip-reference" title="Vrtel, R., Verhoef, S., Bouman, K., Maheshwar, M. M., Nellist, M., van Essen, A. J., Bakker, P. L. G., Hermans, C. J., Bink-Boelkens, M. T. E., van Elburg, R. M., Hoff, M., Lindhout, D., Sampson, J., Halley, D. J. J., van den Ouweland, A. M. W. &lt;strong&gt;Identification of a nonsense mutation at the 5-prime end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex.&lt;/strong&gt; J. Med. Genet. 33: 47-51, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8825048/&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;8825048&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.1.47&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="8825048">Vrtel et al. (1996)</a> identified a truncating mutation in the TSC2 gene (K12X; <a href="/entry/191092#0003">191092.0003</a>). The father had a milder phenotype, and was only diagnosed after his son was diagnosed. Flanking markers suggested that the mutated chromosome was of grandmaternal origin. The authors noted that it is possible that the mildly affected father was mosaic (although this was not detected), with the new mutation occurring by chance on the chromosome 16 he received from his mother. <a href="#28" class="mim-tip-reference" title="Vrtel, R., Verhoef, S., Bouman, K., Maheshwar, M. M., Nellist, M., van Essen, A. J., Bakker, P. L. G., Hermans, C. J., Bink-Boelkens, M. T. E., van Elburg, R. M., Hoff, M., Lindhout, D., Sampson, J., Halley, D. J. J., van den Ouweland, A. M. W. &lt;strong&gt;Identification of a nonsense mutation at the 5-prime end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex.&lt;/strong&gt; J. Med. Genet. 33: 47-51, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8825048/&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;8825048&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.33.1.47&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="8825048">Vrtel et al. (1996)</a> stated that the case illustrated the usefulness of mutation analysis in the diagnosis of families with an incomplete phenotype of tuberous sclerosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8825048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated families with tuberous sclerosis-2, <a href="#11" class="mim-tip-reference" title="Khare, L., Strizheva, G. D., Bailey, J. N., Au, K.-S., Northrup, H., Smith, M., Smalley, S. L., Henske, E. P. &lt;strong&gt;A novel missense mutation in the GTPase activating protein homology region of TSC2 in two large families with tuberous sclerosis complex.&lt;/strong&gt; J. Med. Genet. 38: 347-349, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11403047/&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;11403047&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.38.5.347&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="11403047">Khare et al. (2001)</a> identified a missense mutation in the TSC2 gene (Q1503P; <a href="/entry/191092#0011">191092.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11403047" 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 6 families with a mild form of tuberous sclerosis, <a href="#8" class="mim-tip-reference" title="Jansen, A. C., Sancak, O., D&#x27;Agostino, M. D., Badhwar, A., Roberts, P., Gobbi, G., Wilkinson, R., Melanson, D., Tampieri, D., Koenekoop, R., Gans, M., Maat-Kievit, A., and 12 others. &lt;strong&gt;Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation.&lt;/strong&gt; Ann. Neurol. 60: 528-539, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17120248/&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;17120248&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21037&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="17120248">Jansen et al. (2006)</a> identified a heterozygous mutation in the TSC2 gene (R905Q; <a href="/entry/191092#0013">191092.0013</a>). The authors identified 2 additional mutations in the same codon, R905W (<a href="/entry/191092#0014">191092.0014</a>) and R905G (<a href="/entry/191092#0015">191092.0015</a>), in other families with a more severe phenotype, including cortical tubers, seizures, cognitive impairment, and severe skin lesions. <a href="#8" class="mim-tip-reference" title="Jansen, A. C., Sancak, O., D&#x27;Agostino, M. D., Badhwar, A., Roberts, P., Gobbi, G., Wilkinson, R., Melanson, D., Tampieri, D., Koenekoop, R., Gans, M., Maat-Kievit, A., and 12 others. &lt;strong&gt;Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation.&lt;/strong&gt; Ann. Neurol. 60: 528-539, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17120248/&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;17120248&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21037&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="17120248">Jansen et al. (2006)</a> noted that the R905W and R905G substitutions resulted in the incorporation of nonpolar amino acids into the sequence, whereas the R905Q substitution introduced a polar amino acid with an amido functional group. <a href="#8" class="mim-tip-reference" title="Jansen, A. C., Sancak, O., D&#x27;Agostino, M. D., Badhwar, A., Roberts, P., Gobbi, G., Wilkinson, R., Melanson, D., Tampieri, D., Koenekoop, R., Gans, M., Maat-Kievit, A., and 12 others. &lt;strong&gt;Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation.&lt;/strong&gt; Ann. Neurol. 60: 528-539, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17120248/&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;17120248&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.21037&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="17120248">Jansen et al. (2006)</a> emphasized that patients with a mild form of tuberous sclerosis may not meet established diagnostic criteria, but can still have detrimental mutations in disease-associated genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17120248" 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>Modifier of TSC2 Renal Angiomyolipomas</em></strong></p><p>
Because interferon-gamma (IFNG; <a href="/entry/147570">147570</a>) is a useful mediator of tumor regression in animal models of kidney tumors and because there is a polymorphism within intron 1 of the IFNG gene for which 1 common allele (allele 2, with 12 CA repeats; <a href="/entry/147570#0001">147570.0001</a>) is associated with a higher expression of interferon-gamma in humans, <a href="#7" class="mim-tip-reference" title="Dabora, S. L., Roberts, P., Nieto, A., Perez, R., Jozwiak, S., Franz, D., Bissler, J., Thiele, E. A., Sims, K., Kwiatkowski, D. J. &lt;strong&gt;Association between a high-expressing interferon-gamma allele and a lower frequency of kidney angiomyolipomas in TSC2 patients.&lt;/strong&gt; Am. J. Hum. Genet. 71: 750-758, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12192641/&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;12192641&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/342718&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="12192641">Dabora et al. (2002)</a> examined the relationship between the IFNG genotype and the severity of renal disease in patients with tuberous sclerosis who had TSC2 mutations. Patients were genotyped for the IFNG microsatellite polymorphism, allele 2, and its association with the development of kidney angiomyolipomas (which the authors called KAMLs) was examined. Both chi square analysis and the transmission/disequilibrium test (TDT) suggested an association between allele 2 and the absence of KAMLs in patients with known TSC2 mutations. Among the 127 patients who were more than 5 years old, KAMLs were present in 95 (75%) and absent in 32 (25%). In the group with KAMLs, the frequency of allele 2 was 56%; in the group without KAMLs, the frequency of allele 2 was significantly higher, at 78%. Family-based TDT analysis gave similar results. Subgroup analyses showed that both age and gender may influence the impact of this association. This study suggested that modifier genes play a role in the variable expression of tuberous sclerosis and also suggested a potential therapy for KAMLs in patients with tuberous sclerosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12192641" 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="#14" class="mim-tip-reference" title="Lewis, J. C., Thomas, H. V., Murphy, K. C., Sampson, J. R. &lt;strong&gt;Genotype and psychological phenotype in tuberous sclerosis. (Letter)&lt;/strong&gt; J. Med. Genet. 41: 203-207, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14985384/&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;14985384&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2003.012757&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="14985384">Lewis et al. (2004)</a> used validated tools measuring intellectual function, depression, anxiety, and autistic and behavioral disorders to study the relationships between genotype, seizures, mental retardation, and behaviors in a cohort of 92 patients with mutations in the TSC1 or TSC2 genes. TSC2 but not TSC1 mutations were associated with autistic disorder (p = 0.001), infantile spasms (p = 0.001), and higher risk of low IQ (p = 0.0004) even after adjustment for a history of infantile spasms using logistical regression (OR, 3.50; 95% CI, 1.03-11.95). Previously unrecognized anxiety was frequently diagnosed in patients with mutations in either gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14985384" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Au, K. S., Williams, A. T., Roach, E. S., Batchelor, L., Sparagana, S. P., Delgado, M. R., Wheless, J. W., Baumgartner, J. E., Roa, B. B., Wilson, C. M., Smith-Knuppel, T. K., Cheung, M.-Y. C., Whittemore, V. H., King, T. M., Northrup, H. &lt;strong&gt;Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.&lt;/strong&gt; Genet. Med. 9: 88-100, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17304050/&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;17304050&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/gim.0b013e31803068c7&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="17304050">Au et al. (2007)</a> performed mutation analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. The authors identified mutations in 72% (199 of 257) of de novo and 77% (53 of 68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in 2 previous large studies. <a href="#1" class="mim-tip-reference" title="Au, K. S., Williams, A. T., Roach, E. S., Batchelor, L., Sparagana, S. P., Delgado, M. R., Wheless, J. W., Baumgartner, J. E., Roa, B. B., Wilson, C. M., Smith-Knuppel, T. K., Cheung, M.-Y. C., Whittemore, V. H., King, T. M., Northrup, H. &lt;strong&gt;Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.&lt;/strong&gt; Genet. Med. 9: 88-100, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17304050/&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;17304050&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/gim.0b013e31803068c7&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="17304050">Au et al. (2007)</a> showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. The authors also observed results consistent with 2 similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing metaanalyses of their data and the other 2 large studies in the literature (<a href="#6" class="mim-tip-reference" title="Dabora, S. L., Jozwiak, S., Franz, D. N., Roberts, P. S., Nieto, A., Chung, J., Choy, Y.-S., Reeve, M. P., Thiele, E., Egelhoff, J. C., Kasprzyk-Obara, J., Domanska-Pakiela, D., Kwiatkowski, D. J. &lt;strong&gt;Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.&lt;/strong&gt; Am. J. Hum. Genet. 68: 64-80, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11112665/&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;11112665&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11112665[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/10.1086/316951&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="11112665">Dabora et al., 2001</a>; <a href="#23" class="mim-tip-reference" title="Sancak, O., Nellist, M., Goedbloed, M., Elfferich, P., Wouters, C., Maat-Kievit, A., Zonnenberg, B., Verhoef, S., Halley, D., van den Ouweland, A. &lt;strong&gt;Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex.&lt;/strong&gt; Europ. J. Hum. Genet. 13: 731-741, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15798777/&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;15798777&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.ejhg.5201402&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="15798777">Sancak et al., 2005</a>), <a href="#1" class="mim-tip-reference" title="Au, K. S., Williams, A. T., Roach, E. S., Batchelor, L., Sparagana, S. P., Delgado, M. R., Wheless, J. W., Baumgartner, J. E., Roa, B. B., Wilson, C. M., Smith-Knuppel, T. K., Cheung, M.-Y. C., Whittemore, V. H., King, T. M., Northrup, H. &lt;strong&gt;Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.&lt;/strong&gt; Genet. Med. 9: 88-100, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17304050/&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;17304050&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/gim.0b013e31803068c7&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="17304050">Au et al. (2007)</a> found significant correlations for several features that individual studies did not have sufficient power to conclude. Male patients showed more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11112665+15798777+17304050" 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="Jansen, F. E., Braams, O., Vincken, K. L., Algra, A., Anbeek, P., Jennekens-Schinkel, A., Halley, D., Zonnenberg, B. A., van den Ouweland, A., van Huffelen, A. C., van Nieuwenhuizen, O., Nellist, M. &lt;strong&gt;Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations.&lt;/strong&gt; Neurology 70: 908-915, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18032745/&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;18032745&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000280578.99900.96&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="18032745">Jansen et al. (2008)</a> compared the clinical features of 17 TS patients with mutations in the TSC1 gene and 31 patients with mutations in the TSC2 gene. Patients with TSC2 mutations tended to have an earlier onset of seizures, a higher incidence of infantile spasms, and lower cognition scores compared to those with TSC1 mutations. Patients with TSC2 mutations had more tubers and more tubers per brain proportion than those with TSC1 mutations, but the ranges overlapped. Patients with a mutation deleting or inactivating the GTPase-activating protein domain had more tubers than those with intact GTPase-activating domains. Despite some of these small differences, <a href="#9" class="mim-tip-reference" title="Jansen, F. E., Braams, O., Vincken, K. L., Algra, A., Anbeek, P., Jennekens-Schinkel, A., Halley, D., Zonnenberg, B. A., van den Ouweland, A., van Huffelen, A. C., van Nieuwenhuizen, O., Nellist, M. &lt;strong&gt;Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations.&lt;/strong&gt; Neurology 70: 908-915, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18032745/&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;18032745&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000280578.99900.96&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="18032745">Jansen et al. (2008)</a> concluded that there was considerable overlap between the groups and that prediction of the phenotype in patients with tuberous sclerosis should not be based on their particular TSC1 or TSC2 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18032745" 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>Some patients with tuberous sclerosis develop pulmonary lymphangioleiomyomatosis (LAM; <a href="/entry/606690">606690</a>), also known as pulmonary lymphangiomyomatosis, which has been reported in 34 to 39% of asymptomatic women and in some men with tuberous sclerosis. In a retrospective review of the chest CT scans of 45 female and 20 male patients with tuberous sclerosis, <a href="#18" class="mim-tip-reference" title="Muzykewicz, D. A., Sharma, A., Muse, V., Numis, A. L., Rajagopal, J., Thiele, E. A. &lt;strong&gt;TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. (Letter)&lt;/strong&gt; J. Med. Genet. 46: 465-468, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19419980/&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;19419980&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2008.065342&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="19419980">Muzykewicz et al. (2009)</a> found cysts consistent with LAM in 22 (49%) women and 2 (10%) men. Among the women, changes consistent with LAM were observed in 6 (40%) of 15 with TSC1 mutations, 11 (48%) of 23 with TSC2 mutations, and 5 (71%) of 7 with no mutation identified. While the predominant size of cysts did not differ across these 3 groups, LAM women with TSC2 mutations had a significantly greater number of cysts than did women with TSC1 mutations. Some of the same mutations were identified in patients with LAM and in those without LAM. These findings suggested a higher rate of LAM in patients with TSC1 than previously recognized, as well as a fundamental difference in CT presentation between individuals with TSC1 and TSC2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19419980" 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 retrospective chart review of brain MRI scans of 173 patients with TSC, <a href="#3" class="mim-tip-reference" title="Chu-Shore, C. J., Major, P., Montenegro, M., Thiele, E. &lt;strong&gt;Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex.&lt;/strong&gt; Neurology 72: 1165-1169, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19332694/&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;19332694&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000345365.92821.86&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="19332694">Chu-Shore et al. (2009)</a> found that 46% of patients had at least 1 cyst-like cortical tuber. The tubers are called cyst-like because they presumably lack the inner endothelial lining seen in true cysts. Patients with TSC2 mutations were more likely to have a cyst-like tuber than patients with TSC1 mutation (p = 0.002) or patients with no mutation identified (p = 0.039). Patients with at least 1 cyst-like cortical tuber were more likely to have a history of infantile spasms (p = 0.00005; relative risk, 2.18), epilepsy (p = 0.0038; relative risk, 1.22), and refractory epilepsy (p = 0.0007; relative risk, 1.47) than patients without a cyst-like cortical tuber. <a href="#3" class="mim-tip-reference" title="Chu-Shore, C. J., Major, P., Montenegro, M., Thiele, E. &lt;strong&gt;Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex.&lt;/strong&gt; Neurology 72: 1165-1169, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19332694/&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;19332694&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/01.wnl.0000345365.92821.86&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="19332694">Chu-Shore et al. (2009)</a> concluded that cyst-like cortical tubers are strongly associated with TSC2 gene mutations and a more aggressive seizure phenotype in patients with tuberous sclerosis complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19332694" 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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Au, K. S., Williams, A. T., Roach, E. S., Batchelor, L., Sparagana, S. P., Delgado, M. R., Wheless, J. W., Baumgartner, J. E., Roa, B. B., Wilson, C. M., Smith-Knuppel, T. K., Cheung, M.-Y. C., Whittemore, V. H., King, T. M., Northrup, H.
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[<a href="https://doi.org/10.1097/gim.0b013e31803068c7" target="_blank">Full Text</a>]
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<a id="Brackley1999" class="mim-anchor"></a>
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Brackley, K. J., Farndon, P. A., Weaver, J. B., Dow, D. J., Chapman, S., Kilby, M. D.
<strong>Prenatal diagnosis of tuberous sclerosis with intracerebral signs at 14 weeks' gestation.</strong>
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[<a href="https://doi.org/10.1002/(sici)1097-0223(199906)19:6&lt;575::aid-pd580&gt;3.0.co;2-r" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
<a id="Chu-Shore2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Chu-Shore, C. J., Major, P., Montenegro, M., Thiele, E.
<strong>Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex.</strong>
Neurology 72: 1165-1169, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19332694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19332694</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19332694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/01.wnl.0000345365.92821.86" target="_blank">Full Text</a>]
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<a id="Crino2006" class="mim-anchor"></a>
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Crino, P. B., Nathanson, K. L., Henske, E. P.
<strong>The tuberous sclerosis complex.</strong>
New Eng. J. Med. 355: 1345-1356, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17005952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17005952</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17005952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMra055323" target="_blank">Full Text</a>]
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Curatolo, P., Bombardieri, R., Jozwiak, S.
<strong>Tuberous sclerosis.</strong>
Lancet 372: 657-668, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18722871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18722871</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18722871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/S0140-6736(08)61279-9" target="_blank">Full Text</a>]
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<a id="Dabora2001" class="mim-anchor"></a>
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Dabora, S. L., Jozwiak, S., Franz, D. N., Roberts, P. S., Nieto, A., Chung, J., Choy, Y.-S., Reeve, M. P., Thiele, E., Egelhoff, J. C., Kasprzyk-Obara, J., Domanska-Pakiela, D., Kwiatkowski, D. J.
<strong>Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.</strong>
Am. J. Hum. Genet. 68: 64-80, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11112665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11112665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11112665[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11112665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/316951" target="_blank">Full Text</a>]
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<a id="Dabora2002" class="mim-anchor"></a>
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Dabora, S. L., Roberts, P., Nieto, A., Perez, R., Jozwiak, S., Franz, D., Bissler, J., Thiele, E. A., Sims, K., Kwiatkowski, D. J.
<strong>Association between a high-expressing interferon-gamma allele and a lower frequency of kidney angiomyolipomas in TSC2 patients.</strong>
Am. J. Hum. Genet. 71: 750-758, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12192641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12192641</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12192641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/342718" target="_blank">Full Text</a>]
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<a id="Jansen2006" class="mim-anchor"></a>
<div class="">
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Jansen, A. C., Sancak, O., D'Agostino, M. D., Badhwar, A., Roberts, P., Gobbi, G., Wilkinson, R., Melanson, D., Tampieri, D., Koenekoop, R., Gans, M., Maat-Kievit, A., and 12 others.
<strong>Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17120248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17120248</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17120248" 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/ana.21037" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
<a id="Jansen2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Jansen, F. E., Braams, O., Vincken, K. L., Algra, A., Anbeek, P., Jennekens-Schinkel, A., Halley, D., Zonnenberg, B. A., van den Ouweland, A., van Huffelen, A. C., van Nieuwenhuizen, O., Nellist, M.
<strong>Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations.</strong>
Neurology 70: 908-915, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18032745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18032745</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18032745" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1212/01.wnl.0000280578.99900.96" target="_blank">Full Text</a>]
</p>
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<a id="10" class="mim-anchor"></a>
<a id="Kandt1992" class="mim-anchor"></a>
<div class="">
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Kandt, R. S., Haines, J. L., Smith, M., Northrup, H., Gardner, R. J. M., Short, M. P., Dumars, K., Roach, E. S., Steingold, S., Wall, S., Blanton, S. H., Flodman, P., Kwiatkowski, D. J., Jewell, A., Weber, J. L., Roses, A. D., Pericak-Vance, M. A.
<strong>Linkage of a major gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. (Abstract)</strong>
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<a id="Khare2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Khare, L., Strizheva, G. D., Bailey, J. N., Au, K.-S., Northrup, H., Smith, M., Smalley, S. L., Henske, E. P.
<strong>A novel missense mutation in the GTPase activating protein homology region of TSC2 in two large families with tuberous sclerosis complex.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11403047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11403047</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11403047" 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.38.5.347" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
<a id="Knudson1971" class="mim-anchor"></a>
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Knudson, A. G., Jr.
<strong>Mutation and cancer: statistical study of retinoblastoma.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5279523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5279523</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5279523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.68.4.820" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
<a id="Kumar1995" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kumar, A., Wolpert, C., Kandt, R. S., Segal, J., Pufky, J., Roses, A. D., Pericak-Vance, M. A., Gilbert, J. R.
<strong>A de novo frame-shift mutation in the tuberin gene.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581393</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7581393" 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/4.8.1471" target="_blank">Full Text</a>]
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<a id="14" class="mim-anchor"></a>
<a id="Lewis2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lewis, J. C., Thomas, H. V., Murphy, K. C., Sampson, J. R.
<strong>Genotype and psychological phenotype in tuberous sclerosis. (Letter)</strong>
J. Med. Genet. 41: 203-207, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14985384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14985384</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14985384" 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.2003.012757" target="_blank">Full Text</a>]
</p>
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<a id="Liang2014" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Liang, N., Zhang, C., Dill, P., Panasyuk, G., Pion, D., Koka, V., Gallazzini, M., Olson, E. N., Lam, H., Henske, E. P., Dong, Z., Apte, U., Pallet, N., Johnson, R. L., Terzi, F., Kwiatkowski, D. J., Scoazec, J.-Y., Martignoni, G., Pende, M.
<strong>Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25288394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25288394</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25288394[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25288394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1084/jem.20140341" target="_blank">Full Text</a>]
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<a id="Martin2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Martin, N., Zugge, K., Brandt, R., Friebel, D., Janssen, B., Zimmerhackl, L. B.
<strong>Discordant clinical manifestations in monozygotic twins with the identical mutation in the TSC2 gene. (Letter)</strong>
Clin. Genet. 63: 427-430, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12752578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12752578</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12752578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1034/j.1399-0004.2003.00073.x" target="_blank">Full Text</a>]
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<a id="McMaster2011" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
McMaster, M. L., Goldstein, A. M., Parry, D. M.
<strong>Clinical features distinguish childhood chordoma associated with tuberous sclerosis complex (TSC) from chordoma in the general paediatric population.</strong>
J. Med. Genet. 48: 444-449, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21266383/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21266383</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21266383[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21266383" 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.2010.085092" target="_blank">Full Text</a>]
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<a id="18" class="mim-anchor"></a>
<a id="Muzykewicz2009" class="mim-anchor"></a>
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Muzykewicz, D. A., Sharma, A., Muse, V., Numis, A. L., Rajagopal, J., Thiele, E. A.
<strong>TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. (Letter)</strong>
J. Med. Genet. 46: 465-468, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19419980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19419980</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19419980" 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.2008.065342" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
<a id="Pericak-Vance1992" class="mim-anchor"></a>
<div class="">
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Pericak-Vance, M. A., Gardner, R. J. M., Steingold, S., Wall, S. L., Carter, S., DiMario, F. J., Vance, J. M., Reeders, S., Roses, A. D., Kandt, R. S.
<strong>Confirmation of linkage of tuberous sclerosis to chromosome 16p. (Abstract)</strong>
Am. J. Hum. Genet. 51 (suppl.): A198, 1992.
</p>
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<a id="20" class="mim-anchor"></a>
<a id="Povey1994" class="mim-anchor"></a>
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<p class="mim-text-font">
Povey, S., Burley, M. W., Attwood, J., Benham, F., Hunt, D., Jeremiah, S. J., Franklin, D., Gillett, G., Malas, S., Robson, E. B., Tippett, P., Edwards, J. H., Kwiatkowski, D. J., Super, M., Mueller, R., Fryer, A., Clarke, A., Webb, D., Osborne, J.
<strong>Two loci for tuberous sclerosis: one on 9q34 and one on 16p13.</strong>
Ann. Hum. Genet. 58: 107-127, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7979156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7979156</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7979156" 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.1469-1809.1994.tb01881.x" target="_blank">Full Text</a>]
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<a id="Roach1998" class="mim-anchor"></a>
<div class="">
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Roach, E. S., Gomez, M. R., Northrup, H.
<strong>Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria.</strong>
J. Child Neurol. 13: 624-628, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9881533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9881533</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9881533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1177/088307389801301206" target="_blank">Full Text</a>]
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<a id="22" class="mim-anchor"></a>
<a id="Roberts2002" class="mim-anchor"></a>
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<p class="mim-text-font">
Roberts, P. S., Chung, J., Jozwiak, S., Dabora, S. L., Franz, D. N., Thiele, E. A., Kwiatkowski, D. J.
<strong>SNP identification, haplotype analysis, and parental origin of mutations in TSC2.</strong>
Hum. Genet. 111: 96-101, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12136241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12136241</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12136241" 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/s00439-002-0738-y" target="_blank">Full Text</a>]
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<a id="Sancak2005" class="mim-anchor"></a>
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Sancak, O., Nellist, M., Goedbloed, M., Elfferich, P., Wouters, C., Maat-Kievit, A., Zonnenberg, B., Verhoef, S., Halley, D., van den Ouweland, A.
<strong>Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex.</strong>
Europ. J. Hum. Genet. 13: 731-741, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15798777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15798777</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15798777" 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/sj.ejhg.5201402" target="_blank">Full Text</a>]
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<a id="24" class="mim-anchor"></a>
<a id="Short1992" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Short, M. P., Haines, J. L., Bove, C., Henske, E. P., Guillemette, W., Sitsma, M., Amos, J., Andermann, E., Gusella, J. F., Kwiatkowski, D. J.
<strong>Linkage and heterogeneity in tuberous sclerosis: linkage to chromosome 16 and resolution of old problems. (Abstract)</strong>
Am. J. Hum. Genet. 51 (suppl.): A201, 1992.
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<a id="25" class="mim-anchor"></a>
<a id="Smith1992" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Smith, M., Handa, K., Sokolov, G., Postle, S., Flodman, P., Spence, M. A.
<strong>Further evidence for a tuberous sclerosis gene locus on chromosome 16p13. (Abstract)</strong>
Am. J. Hum. Genet. 51 (suppl.): A201, 1992.
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<a id="26" class="mim-anchor"></a>
<a id="Verhoef1999" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Verhoef, S., Bakker, L., Tempelaars, A. M. P., Hesseling-Janssen, A. L. W., Mazurczak, T., Jozwiak, S., Fois, A., Bartalini, G., Zonnenberg, B. A., van Essen, A. J., Lindhout, D., Halley, D. J. J., van den Ouweland, A. M. W.
<strong>High rate of mosaicism in tuberous sclerosis complex.</strong>
Am. J. Hum. Genet. 64: 1632-1637, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330349</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10330349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/302412" target="_blank">Full Text</a>]
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<a id="Verhoef1995" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Verhoef, S., Vrtel, R., van Essen, T., Bakker, L., Sikkens, E., Halley, D., Lindhout, D., van den Ouweland, A.
<strong>Somatic mosaicism and clinical variation in tuberous sclerosis complex.</strong>
Lancet 345: 202 only, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7823706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7823706</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7823706" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0140-6736(95)90213-9" target="_blank">Full Text</a>]
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<a id="Vrtel1996" class="mim-anchor"></a>
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<p class="mim-text-font">
Vrtel, R., Verhoef, S., Bouman, K., Maheshwar, M. M., Nellist, M., van Essen, A. J., Bakker, P. L. G., Hermans, C. J., Bink-Boelkens, M. T. E., van Elburg, R. M., Hoff, M., Lindhout, D., Sampson, J., Halley, D. J. J., van den Ouweland, A. M. W.
<strong>Identification of a nonsense mutation at the 5-prime end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex.</strong>
J. Med. Genet. 33: 47-51, 1996.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825048</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8825048" 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.33.1.47" target="_blank">Full Text</a>]
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Paul J. Converse - updated : 02/12/2015
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Cassandra L. Kniffin - updated : 8/9/2011
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Cassandra L. Kniffin : 2/16/2010
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mgross : 02/12/2015
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carol : 2/19/2014<br>alopez : 8/17/2011<br>ckniffin : 8/9/2011<br>ckniffin : 2/19/2010<br>carol : 2/18/2010<br>carol : 2/18/2010<br>ckniffin : 2/17/2010
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<strong>#</strong> 613254
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<span class="mim-font">
TUBEROUS SCLEROSIS 2; TSC2
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Other entities represented in this entry:
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TSC2 ANGIOMYOLIPOMAS, RENAL, MODIFIER OF, INCLUDED
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<strong>ORPHA:</strong> 805; &nbsp;
<strong>DO:</strong> 0080325; &nbsp;
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<h4>
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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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<span class="mim-font">
12q15
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<span class="mim-font">
{TSC2 angiomyolipomas, renal, modifier of}
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613254
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Autosomal dominant
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<span class="mim-font">
3
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<span class="mim-font">
IFNG
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<span class="mim-font">
147570
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16p13.3
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Tuberous sclerosis-2
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613254
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Autosomal dominant
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3
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TSC2
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191092
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because tuberous sclerosis-2 (TSC2) is caused by heterozygous mutation in the TSC2 gene (191092) on chromosome 16p13. The TSC2 gene product is known as 'tuberin.'</p>
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<strong>Description</strong>
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<p>Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by hamartomas in multiple organ systems, including the brain, skin, heart, kidneys, and lung. These changes can result in epilepsy, learning difficulties, behavioral problems, and renal failure, among other complications (reviews by Crino et al., 2006 and Curatolo et al., 2008).</p><p>For a general phenotypic description and a discussion of genetic heterogeneity of tuberous sclerosis, see tuberous sclerosis-1 (191100), caused by mutation in the TSC1 gene (605284) on chromosome 9q34.</p><p>Approximately 10 to 30% of cases of tuberous sclerosis are due to mutations in the TSC1 gene: the frequency of cases due to mutations in the TSC2 gene is consistently higher. TSC2 mutations are associated with more severe disease (Crino et al., 2006) (see GENOTYPE/PHENOTYPE CORRELATIONS section).</p>
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<strong>Clinical Features</strong>
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<p>Kumar et al. (1995) reported a 2-year-old Caucasian female with tuberous sclerosis-2. At birth, she had a hypopigmented patch on her left ankle and multiple hypopigmented patches on her back and trunk. She later developed facial plaques on her forehead but no facial angiofibromas or ungual fibromata. Onset of generalized seizures occurred at 7 months of age. CT scan of the brain demonstrated cerebral cortical tubers and subependymal nodules. Renal ultrasound showed multiple cysts in both kidneys. The parents were clinically normal. </p><p>Vrtel et al. (1996) reported a father and his son with tuberous sclerosis-2. The family was ascertained through a discovery of fetal bradycardia and arrhythmia in the proband at 20 weeks' gestation. At 24 weeks' gestation, an intracardiac mass suspected of being a rhabdomyosarcoma was detected by fetal ultrasound and the diagnosis of tuberous sclerosis was suggested. A boy, weighing 2,500 g, was delivered at 39 weeks. Postnatal ECG showed intermittent second and third degree atrioventricular block. Echography of the brain, liver, and kidneys showed no abnormalities, and the studies of the retina were also normal. At 3 months of age a hypomelanotic macule, 25 x 15 mm, was noted on the buttock using Woods light. The 30-year-old father showed no abnormalities on study of the brain, heart, skin, and retina, and the most questionable changes in the kidneys. All tooth surfaces showed pit-shaped enamel defects, corresponding to the dental pits described in patients with tuberous sclerosis. In addition, 2 gingival fibromas were found. </p><p>Khare et al. (2001) reported a 4-generation family with mild physical features of tuberous sclerosis-2, but in which there was significant clustering of neuropsychiatric disorders including mood disorder, anxiety disorder, and autism among affected individuals. A second family also had mild physical features of tuberous sclerosis, but no neuropsychiatric assessment had been performed. </p><p>Martin et al. (2003) reported a pair of twin boys discordant for tuberous sclerosis-2 in whom marker studies supported a probability of monozygosity greater than 99.9%. The twins had similar CNS features, as both were severely mentally retarded with motor delay. Obvious differences were seen in the skin, heart, and kidneys. Whereas twin T had a shagreen patch of the skin and a heart rhabdomyoma, twin M had none. Twin M was diagnosed early (at the age of 3 years) with renal lesions, namely, angiomyolipomas and cystic alterations. At 6 years of age, twin T also started to have the same types of renal lesions as twin M. Martin et al. (2003) suggested that the Knudson hypothesis (Knudson, 1971) explained the difference, assuming that many of the features such as the skin, cardiac, and renal alterations present a 2-hit phenomenon, the second hit depending on a random somatic event. Genetic analysis identified a germline mutation in the TSC2 gene (191092.0012) in both boys. </p><p>Jansen et al. (2006) reported a large 5-generation French Canadian family with a mild form of tuberous sclerosis-2 due to a heterozygous mutation in the TSC2 gene (R905Q; 191092.0013). The proband was a 25-year-old man who started having seizures at age 8 years. Family studies showed that 25 individuals carried the mutation, but only 5 had definite TSC according to diagnostic criteria and 11 did not meet any diagnostic criteria. Examination of mutation carriers showed hypomelanotic macules in 92%, epilepsy in 60%, learning difficulties or mild cognitive impairment in 52%, and brain imaging abnormalities (white matter lesions, subependymal nodule, or subependymal giant cell astrocytoma) in 24%. None had cortical tubers. Renal lesions were found in 8% and retinal abnormalities in 4%. Five additional families with the same mutation were found, and all had a similarly mild phenotype, although cortical tubers were present in some. </p><p>In a retrospective review, McMaster et al. (2011) identified 10 cases of chordoma associated with tuberous sclerosis complex, although only 3 patients had documented mutations: 2 in the TSC1 gene and 1 in the TSC2 gene. The median age at onset in TSC-associated chordoma was 6.2 months (range 0 to 16 years), with only 1 patient diagnosed with chordoma after age 5. Chordomas were skull-based in 50% and sacral-based in 40%; the 16-year-old had a spinal-based tumor. The 5-year survival was 83%. Molecular and immunohistochemical studies of the chordomas from 2 patients with identified mutations in the TSC1 and TSC2 genes, respectively, demonstrated that 1 tumor had loss of heterozygosity (LOH) for the wildtype TSC1 allele, while the other tumor had LOH for the wildtype TSC2 allele, suggesting a pathogenetic role for the TSC1/TSC2 genes in these chordomas. Comparison with 65 cases of non-TSC-associated pediatric chordoma (215400) showed important clinical differences. The latter patients had onset between ages 0 and 18 years (median age at diagnosis was 12 years). Most (64.1%) were intracranial, 26.6% were spinal, and 9.4% were sacral. Chordomas were exclusively skull-based in the youngest age tertile, while sacral chordomas were confined to patients in the oldest tertile. Survival was poorer, at 68.2% at 5 years and 53.1% at 20 years. The findings suggested that TSC-associated chordoma has an unusually early onset and/or rapid growth, and that chordoma can be a rare pediatric manifestation of TSC. </p>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The tuberous sclerosis complex consensus conference (Roach et al., 1998) proposed major and minor diagnostic criteria. Since no single feature is diagnostic, an evaluation that includes consideration of all clinical features is necessary to make a correct diagnosis. The clinical manifestations of TSC appear at distinct developmental points, which may further complicate the clinical diagnosis. Major criteria include retinal hamartomas, renal angiomyolipomas, facial angiofibromas, and cortical tubers, among other features. Minor criteria include dental pits, bone cysts, and cerebral white-matter radial migration lines, among other features. </p><p>Brackley et al. (1999) reported detection by ultrasound of cranial abnormalities at 14 weeks' gestation in a fetus subsequently confirmed as having tuberous sclerosis using DNA linkage analysis within the affected family. The presence of asymmetric ventricular enlargement persisted antenatally. MRI at 26 weeks indicated the possibility of poor gyral formation consistent with a neuronal migration disorder. Cardiac rhabdomyomata were not visualized on ultrasound scan until 30 weeks' gestation. Postnatal cranial ultrasound confirmed the significant neuropathology that was manifested by severe developmental delay and intractable fits in the child. The right fundus of the patient showed multiple peripheral pigmented areas and a persistent pupillary membrane also consistent with TSC. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Liang et al. (2014) generated a mosaic Tsc1-knockout mouse model in which mutant mice developed renal mesenchymal lesions that recapitulated perivascular epithelioid cell tumors (PEComas) found in patients with TSC. The authors found that YAP (YAP1; 606608) was upregulated by MTOR (601231) in mouse and human PEComas. Genetic or pharmacologic inhibition of Yap blunted abnormal proliferation and induced apoptosis of mouse Tsc1/Tsc2-deficient cells in culture and in mosaic Tsc1-knockout mice. Yap accumulated in cells lacking Tsc1/Tsc2 due to impaired degradation of Yap by autophagy in an Mtor-dependent manner. Liang et al. (2014) proposed that YAP is a potential therapeutic target for TSC and other disease with dysregulated MTOR activity. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Most patients with tuberous sclerosis-2 have de novo heterozygous mutations in the TSC2 gene. Patients with tuberous sclerosis-2 generally have more severe disease than patients with tuberous sclerosis-1, thus reducing the chance of these patients having a family (Curatolo et al., 2008). </p><p><strong><em>Mosaicism</em></strong></p><p>
Verhoef et al. (1995) reported somatic mosaicism in the father of a 2-year-old boy with tuberous sclerosis 2: the father had subclinical signs of TSC and an apparently low proportion of cells with the TSC2 mutation. </p><p>Verhoef et al. (1999) identified 6 families with mosaicism in a series of 62 unrelated families with a mutation in either the TSC1 or the TSC2 gene. In 5 families, somatic mosaicism was present in the mildly affected parent of an index patient. In 1 family with clinically unaffected parents, gonadal mosaicism was detected after tuberous sclerosis was found in 3 children. The detection of mosaicism has obvious consequences for genetic counseling. Clinical investigation of the parents of patients with seemingly sporadic mutations is essential to determine their residual chance of gonadal and/or somatic mosaicism, unless a mosaic pattern is detected in the index patient, proving a de novo event. In the data set of Verhoef et al. (1999), the exclusion of signs of tuberous sclerosis in the parents of a patient with tuberous sclerosis reduced the chance of one of the parents to be a mosaic mutation carrier from 10% to 2%. In the 5 families with somatic mosaicism, the parent was given the diagnosis after the diagnosis was made in the child. </p><p>During TSC2 mutational analysis, Roberts et al. (2002) identified 10 single-nucleotide polymorphisms (SNPs) that occur within or close to exon boundaries at minor allele frequencies greater than 5%. The authors determined the haplotypes for 6 of these SNPs and the microsatellite marker kg8 in the 3-prime region of TSC2 in a set of 40 parent-child trios. The most common haplotypes accounted for 53%, 11%, 6%, and 5% of chromosomes. Thirty-eight TSC2 mutation-bearing haplotypes had a similar distribution, indicating that there was no haplotype that predisposed to mutation in this region in TSC2. Family analysis was possible in 12 sporadic cases, and indicated that the mother was the parent of origin in 7 cases (3 point mutations, 2 small deletions, 2 large deletions), while the father was the parent of origin in 5 cases (2 point mutations, 3 small deletions). Roberts et al. (2002) concluded that TSC2 mutations occur at substantial frequency on both the maternally and paternally derived TSC alleles, in contrast to many other genetic diseases. There was no major age effect for mutations of paternal origin. The observation was considered significant to genetic counseling of parents of a sporadic TSC case; each parent should be considered the potential parent of origin, and some alternative reproductive choices such as use of a sperm donor only or egg donor only are not guaranteed to prevent recurrence. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Using tuberous sclerosis families in which linkage to the TSC1 locus on chromosome 9 had been excluded, Kandt et al. (1992) demonstrated linkage with D16S283, the closest marker on the proximal side of the locus for polycystic kidney disease type 1 (173900), on chromosome 16p13. A lod score of 9.50 at theta = 0.02 was observed; 1 family independently presented a lod score of 4.44 at theta = 0.05. Kandt et al. (1992) estimated that about 40% of tuberous sclerosis families are linked to chromosome 9, and most of the rest, the majority, to chromosome 16. No clear evidence for a locus on other chromosomes was found. Confirmation of a tuberous sclerosis locus on chromosome 16 (TSC2) was provided by Pericak-Vance et al. (1992), Short et al. (1992) and Smith et al. (1992).</p><p>Povey et al. (1994) did linkage studies in 32 families of tuberous sclerosis, using genetic markers on chromosomes 9, 11, 12, and 16. Approximately half the families appeared to be linked to TSC1 on chromosome 9 between ASS1 (603470) and D9S298 and half to TSC2 on chromosome 16 close to D16S291. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Approximately 10 to 30% of tuberous sclerosis cases are due to TSC1 mutations, whereas the frequency of TSC2 mutations is consistently higher. TSC1 mutations account for 15 to 30% of familial cases and 10 to 15% of sporadic cases. The frequency of TSC2 mutations in sporadic cases ranges from 75 to 80%. About 15 to 20% of patients have no identifiable mutations, which may be due to mosaicism (Crino et al., 2006; Curatolo et al., 2008). </p><p>In a patient with tuberous sclerosis-2, Kumar et al. (1995) identified a de novo 1-bp deletion in the TSC2 gene (191092.0001). </p><p>In a father and son with tuberous sclerosis-2, Vrtel et al. (1996) identified a truncating mutation in the TSC2 gene (K12X; 191092.0003). The father had a milder phenotype, and was only diagnosed after his son was diagnosed. Flanking markers suggested that the mutated chromosome was of grandmaternal origin. The authors noted that it is possible that the mildly affected father was mosaic (although this was not detected), with the new mutation occurring by chance on the chromosome 16 he received from his mother. Vrtel et al. (1996) stated that the case illustrated the usefulness of mutation analysis in the diagnosis of families with an incomplete phenotype of tuberous sclerosis. </p><p>In 2 unrelated families with tuberous sclerosis-2, Khare et al. (2001) identified a missense mutation in the TSC2 gene (Q1503P; 191092.0011). </p><p>In 6 families with a mild form of tuberous sclerosis, Jansen et al. (2006) identified a heterozygous mutation in the TSC2 gene (R905Q; 191092.0013). The authors identified 2 additional mutations in the same codon, R905W (191092.0014) and R905G (191092.0015), in other families with a more severe phenotype, including cortical tubers, seizures, cognitive impairment, and severe skin lesions. Jansen et al. (2006) noted that the R905W and R905G substitutions resulted in the incorporation of nonpolar amino acids into the sequence, whereas the R905Q substitution introduced a polar amino acid with an amido functional group. Jansen et al. (2006) emphasized that patients with a mild form of tuberous sclerosis may not meet established diagnostic criteria, but can still have detrimental mutations in disease-associated genes. </p><p><strong><em>Modifier of TSC2 Renal Angiomyolipomas</em></strong></p><p>
Because interferon-gamma (IFNG; 147570) is a useful mediator of tumor regression in animal models of kidney tumors and because there is a polymorphism within intron 1 of the IFNG gene for which 1 common allele (allele 2, with 12 CA repeats; 147570.0001) is associated with a higher expression of interferon-gamma in humans, Dabora et al. (2002) examined the relationship between the IFNG genotype and the severity of renal disease in patients with tuberous sclerosis who had TSC2 mutations. Patients were genotyped for the IFNG microsatellite polymorphism, allele 2, and its association with the development of kidney angiomyolipomas (which the authors called KAMLs) was examined. Both chi square analysis and the transmission/disequilibrium test (TDT) suggested an association between allele 2 and the absence of KAMLs in patients with known TSC2 mutations. Among the 127 patients who were more than 5 years old, KAMLs were present in 95 (75%) and absent in 32 (25%). In the group with KAMLs, the frequency of allele 2 was 56%; in the group without KAMLs, the frequency of allele 2 was significantly higher, at 78%. Family-based TDT analysis gave similar results. Subgroup analyses showed that both age and gender may influence the impact of this association. This study suggested that modifier genes play a role in the variable expression of tuberous sclerosis and also suggested a potential therapy for KAMLs in patients with tuberous sclerosis. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Lewis et al. (2004) used validated tools measuring intellectual function, depression, anxiety, and autistic and behavioral disorders to study the relationships between genotype, seizures, mental retardation, and behaviors in a cohort of 92 patients with mutations in the TSC1 or TSC2 genes. TSC2 but not TSC1 mutations were associated with autistic disorder (p = 0.001), infantile spasms (p = 0.001), and higher risk of low IQ (p = 0.0004) even after adjustment for a history of infantile spasms using logistical regression (OR, 3.50; 95% CI, 1.03-11.95). Previously unrecognized anxiety was frequently diagnosed in patients with mutations in either gene. </p><p>Au et al. (2007) performed mutation analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. The authors identified mutations in 72% (199 of 257) of de novo and 77% (53 of 68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in 2 previous large studies. Au et al. (2007) showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. The authors also observed results consistent with 2 similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing metaanalyses of their data and the other 2 large studies in the literature (Dabora et al., 2001; Sancak et al., 2005), Au et al. (2007) found significant correlations for several features that individual studies did not have sufficient power to conclude. Male patients showed more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas. </p><p>Jansen et al. (2008) compared the clinical features of 17 TS patients with mutations in the TSC1 gene and 31 patients with mutations in the TSC2 gene. Patients with TSC2 mutations tended to have an earlier onset of seizures, a higher incidence of infantile spasms, and lower cognition scores compared to those with TSC1 mutations. Patients with TSC2 mutations had more tubers and more tubers per brain proportion than those with TSC1 mutations, but the ranges overlapped. Patients with a mutation deleting or inactivating the GTPase-activating protein domain had more tubers than those with intact GTPase-activating domains. Despite some of these small differences, Jansen et al. (2008) concluded that there was considerable overlap between the groups and that prediction of the phenotype in patients with tuberous sclerosis should not be based on their particular TSC1 or TSC2 mutation. </p><p>Some patients with tuberous sclerosis develop pulmonary lymphangioleiomyomatosis (LAM; 606690), also known as pulmonary lymphangiomyomatosis, which has been reported in 34 to 39% of asymptomatic women and in some men with tuberous sclerosis. In a retrospective review of the chest CT scans of 45 female and 20 male patients with tuberous sclerosis, Muzykewicz et al. (2009) found cysts consistent with LAM in 22 (49%) women and 2 (10%) men. Among the women, changes consistent with LAM were observed in 6 (40%) of 15 with TSC1 mutations, 11 (48%) of 23 with TSC2 mutations, and 5 (71%) of 7 with no mutation identified. While the predominant size of cysts did not differ across these 3 groups, LAM women with TSC2 mutations had a significantly greater number of cysts than did women with TSC1 mutations. Some of the same mutations were identified in patients with LAM and in those without LAM. These findings suggested a higher rate of LAM in patients with TSC1 than previously recognized, as well as a fundamental difference in CT presentation between individuals with TSC1 and TSC2. </p><p>In a retrospective chart review of brain MRI scans of 173 patients with TSC, Chu-Shore et al. (2009) found that 46% of patients had at least 1 cyst-like cortical tuber. The tubers are called cyst-like because they presumably lack the inner endothelial lining seen in true cysts. Patients with TSC2 mutations were more likely to have a cyst-like tuber than patients with TSC1 mutation (p = 0.002) or patients with no mutation identified (p = 0.039). Patients with at least 1 cyst-like cortical tuber were more likely to have a history of infantile spasms (p = 0.00005; relative risk, 2.18), epilepsy (p = 0.0038; relative risk, 1.22), and refractory epilepsy (p = 0.0007; relative risk, 1.47) than patients without a cyst-like cortical tuber. Chu-Shore et al. (2009) concluded that cyst-like cortical tubers are strongly associated with TSC2 gene mutations and a more aggressive seizure phenotype in patients with tuberous sclerosis complex. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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</h4>
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Chu-Shore, C. J., Major, P., Montenegro, M., Thiele, E.
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Dabora, S. L., Jozwiak, S., Franz, D. N., Roberts, P. S., Nieto, A., Chung, J., Choy, Y.-S., Reeve, M. P., Thiele, E., Egelhoff, J. C., Kasprzyk-Obara, J., Domanska-Pakiela, D., Kwiatkowski, D. J.
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Khare, L., Strizheva, G. D., Bailey, J. N., Au, K.-S., Northrup, H., Smith, M., Smalley, S. L., Henske, E. P.
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Kumar, A., Wolpert, C., Kandt, R. S., Segal, J., Pufky, J., Roses, A. D., Pericak-Vance, M. A., Gilbert, J. R.
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Lewis, J. C., Thomas, H. V., Murphy, K. C., Sampson, J. R.
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Liang, N., Zhang, C., Dill, P., Panasyuk, G., Pion, D., Koka, V., Gallazzini, M., Olson, E. N., Lam, H., Henske, E. P., Dong, Z., Apte, U., Pallet, N., Johnson, R. L., Terzi, F., Kwiatkowski, D. J., Scoazec, J.-Y., Martignoni, G., Pende, M.
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Martin, N., Zugge, K., Brandt, R., Friebel, D., Janssen, B., Zimmerhackl, L. B.
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McMaster, M. L., Goldstein, A. M., Parry, D. M.
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Muzykewicz, D. A., Sharma, A., Muse, V., Numis, A. L., Rajagopal, J., Thiele, E. A.
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Pericak-Vance, M. A., Gardner, R. J. M., Steingold, S., Wall, S. L., Carter, S., DiMario, F. J., Vance, J. M., Reeders, S., Roses, A. D., Kandt, R. S.
<strong>Confirmation of linkage of tuberous sclerosis to chromosome 16p. (Abstract)</strong>
Am. J. Hum. Genet. 51 (suppl.): A198, 1992.
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<p class="mim-text-font">
Povey, S., Burley, M. W., Attwood, J., Benham, F., Hunt, D., Jeremiah, S. J., Franklin, D., Gillett, G., Malas, S., Robson, E. B., Tippett, P., Edwards, J. H., Kwiatkowski, D. J., Super, M., Mueller, R., Fryer, A., Clarke, A., Webb, D., Osborne, J.
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Sancak, O., Nellist, M., Goedbloed, M., Elfferich, P., Wouters, C., Maat-Kievit, A., Zonnenberg, B., Verhoef, S., Halley, D., van den Ouweland, A.
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<p class="mim-text-font">
Short, M. P., Haines, J. L., Bove, C., Henske, E. P., Guillemette, W., Sitsma, M., Amos, J., Andermann, E., Gusella, J. F., Kwiatkowski, D. J.
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Smith, M., Handa, K., Sokolov, G., Postle, S., Flodman, P., Spence, M. A.
<strong>Further evidence for a tuberous sclerosis gene locus on chromosome 16p13. (Abstract)</strong>
Am. J. Hum. Genet. 51 (suppl.): A201, 1992.
</p>
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<li>
<p class="mim-text-font">
Verhoef, S., Bakker, L., Tempelaars, A. M. P., Hesseling-Janssen, A. L. W., Mazurczak, T., Jozwiak, S., Fois, A., Bartalini, G., Zonnenberg, B. A., van Essen, A. J., Lindhout, D., Halley, D. J. J., van den Ouweland, A. M. W.
<strong>High rate of mosaicism in tuberous sclerosis complex.</strong>
Am. J. Hum. Genet. 64: 1632-1637, 1999.
[PubMed: 10330349]
[Full Text: https://doi.org/10.1086/302412]
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<li>
<p class="mim-text-font">
Verhoef, S., Vrtel, R., van Essen, T., Bakker, L., Sikkens, E., Halley, D., Lindhout, D., van den Ouweland, A.
<strong>Somatic mosaicism and clinical variation in tuberous sclerosis complex.</strong>
Lancet 345: 202 only, 1995.
[PubMed: 7823706]
[Full Text: https://doi.org/10.1016/s0140-6736(95)90213-9]
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<li>
<p class="mim-text-font">
Vrtel, R., Verhoef, S., Bouman, K., Maheshwar, M. M., Nellist, M., van Essen, A. J., Bakker, P. L. G., Hermans, C. J., Bink-Boelkens, M. T. E., van Elburg, R. M., Hoff, M., Lindhout, D., Sampson, J., Halley, D. J. J., van den Ouweland, A. M. W.
<strong>Identification of a nonsense mutation at the 5-prime end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex.</strong>
J. Med. Genet. 33: 47-51, 1996.
[PubMed: 8825048]
[Full Text: https://doi.org/10.1136/jmg.33.1.47]
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Paul J. Converse - updated : 02/12/2015<br>Cassandra L. Kniffin - updated : 8/9/2011
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