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Entry
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- #171400 - MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA; MEN2A
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- OMIM
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<p>
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<span class="h4">#171400</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/171400"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS131100"> <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="#otherFeatures">Other Features</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#cytogenetics">Cytogenetics</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="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<div><a href="https://clinicaltrials.gov/search?cond=MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA" 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="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=19538&Typ=Pat" title="Multiple endocrine neoplasia type 2A" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Multiple endocrine neoplas… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=906&Typ=Pat" title="Multiple endocrine neoplasia type 2" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Multiple endocrine neoplas… </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1257/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=171400[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=247698" title="Multiple endocrine neoplasia type 2A" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Multiple endocrine neoplas…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=653" title="Multiple endocrine neoplasia type 2" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Multiple endocrine neoplas…</a></div>
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</div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/0f5ee85f-e979-4fbd-bc6d-29e06968171a/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0050430" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/171400" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/OMIA001268/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:171400" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 721188000<br />
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<strong>ICD10CM:</strong> E31.22<br />
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<strong>ICD9CM:</strong> 258.02<br />
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<strong>ORPHA:</strong> 247698, 653<br />
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<strong>DO:</strong> 0050430<br />
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">ICD+</a>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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171400
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</span>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA; MEN2A
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</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PHEOCHROMOCYTOMA AND AMYLOID-PRODUCING MEDULLARY THYROID CARCINOMA<br />
|
|
PTC SYNDROME<br />
|
|
SIPPLE SYNDROME
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
THYROID CARCINOMA, FAMILIAL MEDULLARY, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
|
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|
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|
|
|
|
<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/10/158?start=-3&limit=10&highlight=158">
|
|
10q11.21
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Multiple endocrine neoplasia IIA
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/171400"> 171400 </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">
|
|
RET
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/164761"> 164761 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/171400" 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>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/PS131100" 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>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<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/171400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/171400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hirschsprung disease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204739008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204739008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q43.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q43.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019569&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019569</a>, <a href="https://bioportal.bioontology.org/search?q=C3888239&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3888239</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002251</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002251</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Cutaneous lichen amyloidosis <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3805845&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3805845</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0032346" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0032346</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0032346" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0032346</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">
|
|
|
|
- Cushing syndrome <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237735008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237735008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/47270006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">47270006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/E24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E24</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/255.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">255.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0342443&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0342443</a>, <a href="https://bioportal.bioontology.org/search?q=C0010481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010481</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003118" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003118</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003118" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003118</a>]</span><br /> -
|
|
Hypertension <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38341003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38341003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/401-405.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">401-405.99</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/997.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">997.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020538&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020538</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span><br /> -
|
|
C-cell hyperplasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237552009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237552009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E07.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E07.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0342190&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0342190</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011781" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011781</a>]</span><br /> -
|
|
Hyperparathyroidism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/66999008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">66999008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E21.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E21.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/252.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">252.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/252.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">252.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020502&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020502</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000843" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000843</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000843" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000843</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> NEOPLASIA </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Pheochromocytoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/85583005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">85583005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302835009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302835009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0031511&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0031511</a>, <a href="https://bioportal.bioontology.org/search?q=C4551683&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551683</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002666" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002666</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0006748" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006748</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002666" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002666</a>]</span><br /> -
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Medullary thyroid carcinoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1332275004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1332275004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/255032005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">255032005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0238462&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0238462</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002865" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002865</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002865" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002865</a>]</span><br /> -
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Parathyroid adenoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128474007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128474007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0262587&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0262587</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002897" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002897</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002897" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002897</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> LABORATORY ABNORMALITIES </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Increased urinary epinephrine <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868393&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868393</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003639</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003639" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003639</a>]</span><br /> -
|
|
Elevated calcitonin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1868394&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1868394</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003528" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003528</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003528" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003528</a>]</span><br /> -
|
|
Pentagastrin stimulation test <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/252210001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">252210001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0430136&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0430136</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the RET protooncogene (RET, <a href="/entry/164761#0001">164761.0001</a>)<br />
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</span>
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</div>
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</div>
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</div>
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<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
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</div>
|
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</div>
|
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small">
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<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Multiple endocrine neoplasia
|
|
- <a href="/phenotypicSeries/PS131100">PS131100</a>
|
|
- 4 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
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|
|
<a href="/geneMap/10/158?start=-3&limit=10&highlight=158"> 10q11.21 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/171400"> Multiple endocrine neoplasia IIA </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/171400"> 171400 </a>
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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<a href="/entry/164761"> RET </a>
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/164761"> 164761 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/10/158?start=-3&limit=10&highlight=158"> 10q11.21 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/162300"> Multiple endocrine neoplasia IIB </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
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</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/162300"> 162300 </a>
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/164761"> RET </a>
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/164761"> 164761 </a>
|
|
</span>
|
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</td>
|
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</tr>
|
|
|
|
<tr>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<a href="/geneMap/11/561?start=-3&limit=10&highlight=561"> 11q13.1 </a>
|
|
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/131100"> Multiple endocrine neoplasia 1 </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/131100"> 131100 </a>
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613733"> MEN1 </a>
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613733"> 613733 </a>
|
|
</span>
|
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</td>
|
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</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
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<a href="/geneMap/12/181?start=-3&limit=10&highlight=181"> 12p13.1 </a>
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610755"> Multiple endocrine neoplasia, type IV </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/610755"> 610755 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600778"> CDKN1B </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600778"> 600778 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
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|
|
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|
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|
|
<div class="text-right small">
|
|
<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
|
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</div>
|
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</div>
|
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</div>
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</div>
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<div>
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<br />
|
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</div>
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<div>
|
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
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<div id="mimTextFold" class="collapse in ">
|
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<span class="mim-text-font">
|
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<p>A number sign (#) is used with this entry because multiple endocrine neoplasia type IIA (MEN2A) is caused by heterozygous mutation in the RET oncogene (<a href="/entry/164761">164761</a>) on chromosome 10q11.</p>
|
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</span>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
|
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<span class="mim-text-font">
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<p>Multiple endocrine neoplasia type IIA is an autosomal dominant syndrome of multiple endocrine neoplasms, including medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid adenomas. MEN2B (<a href="/entry/162300">162300</a>), characterized by MTC with or without pheochromocytoma and with characteristic clinical abnormalities such as ganglioneuromas of the lips, tongue and colon, but without hyperparathyroidism, is also caused by mutation in the RET gene (summary by <a href="#62" class="mim-tip-reference" title="Lore, F., Talidis, F., Di Cairano, G., Renieri, A. <strong>Multiple endocrine neoplasia type 2 syndromes may be associated with renal malformations.</strong> J. Intern. Med. 250: 37-42, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11454140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11454140</a>] [<a href="https://doi.org/10.1046/j.1365-2796.2001.00846.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11454140">Lore et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11454140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of multiple endocrine neoplasia, see MEN1 (<a href="/entry/131100">131100</a>).</p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p><a href="#86" class="mim-tip-reference" title="Schimke, R. N., Hartmann, W. H. <strong>Familial amyloid-producing medullary thyroid carcinoma and pheochromocytoma, a distinct genetic entity.</strong> Ann. Intern. Med. 63: 1027-1039, 1965.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5844561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5844561</a>] [<a href="https://doi.org/10.7326/0003-4819-63-6-1027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5844561">Schimke and Hartmann (1965)</a> described a syndrome of pheochromocytoma and medullary thyroid carcinoma with abundant amyloid stroma. A similar but distinct condition is described under neuromata, mucosal, with endocrine tumors (MEN2B; <a href="/entry/162300">162300</a>). <a href="#100" class="mim-tip-reference" title="Steiner, A. L., Goodman, A. D., Powers, S. R., Jr. <strong>Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasia, type II.</strong> Medicine 47: 371-409, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4386574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4386574</a>] [<a href="https://doi.org/10.1097/00005792-196809000-00001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4386574">Steiner et al. (1968)</a> described a family with 11 cases in successive generations. The pheochromocytomas were bilateral, parathyroid adenoma was present in several, and one patient had Cushing syndrome. <a href="#100" class="mim-tip-reference" title="Steiner, A. L., Goodman, A. D., Powers, S. R., Jr. <strong>Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasia, type II.</strong> Medicine 47: 371-409, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4386574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4386574</a>] [<a href="https://doi.org/10.1097/00005792-196809000-00001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4386574">Steiner et al. (1968)</a> referred to this disorder as 'multiple endocrine neoplasia, type II' to distinguish it from the multiple endocrine adenomatosis described by Wermer (MEN1; <a href="/entry/131100">131100</a>) and called type I by <a href="#100" class="mim-tip-reference" title="Steiner, A. L., Goodman, A. D., Powers, S. R., Jr. <strong>Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasia, type II.</strong> Medicine 47: 371-409, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4386574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4386574</a>] [<a href="https://doi.org/10.1097/00005792-196809000-00001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4386574">Steiner et al. (1968)</a>. <a href="#103" class="mim-tip-reference" title="Urbanski, F. X. <strong>Medullary thyroid carcinoma, parathyroid adenoma, and bilateral pheochromocytoma. An unusual triad of endocrine tumors.</strong> J. Chronic Dis. 20: 627-636, 1967.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6047980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6047980</a>] [<a href="https://doi.org/10.1016/0021-9681(67)90040-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6047980">Urbanski (1967)</a> found parathyroid adenoma to be part of the syndrome also. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5844561+6047980+4386574" 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="#67" class="mim-tip-reference" title="Meyer, J. S., Abdel-Bari, W. <strong>Granules and thyrocalcitonin-like activity in medullary carcinoma of the thyroid gland.</strong> New Eng. J. Med. 278: 523-529, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5637238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5637238</a>] [<a href="https://doi.org/10.1056/NEJM196803072781002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5637238">Meyer and Abdel-Bari (1968)</a> presented observations consistent with the view that medullary carcinoma is a thyrocalcitonin-producing neoplasm of parafollicular cells of the thyroid. Parathyroid hyperplasia or adenomas in some of these patients may be secondary to hypocalcemic effects of thyrocalcitonin. <a href="#47" class="mim-tip-reference" title="Johnston, C. I., Martin, T. J., Riddell, J. <strong>Medullary thyroid carcinoma: a functional peptide secreting tumor.</strong> Australas. Ann. Med. 19: 50-53, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5505521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5505521</a>] [<a href="https://doi.org/10.1111/imj.1970.19.1.50" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5505521">Johnston et al. (1970)</a>, as well as others, have shown calcitonin-secretion by medullary thyroid carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5505521+5637238" 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="#48" class="mim-tip-reference" title="Kaplan, E. L., Arnaud, C. D., Hill, B. J., Peskin, G. W. <strong>Adrenal medullary calcitonin-like factor: a key to multiple endocrine neoplasia, type 2?</strong> Surgery 68: 146-149, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10483461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10483461</a>]" pmid="10483461">Kaplan et al. (1970)</a> showed that the adrenal medulla produces a calcitonin-like material indistinguishable from that of the thyroid by bio- and radioimmunoassay. They suggested that the parafollicular cells of the thyroid are of neural crest origin. The finding that medullary carcinoma of the thyroid arises from parafollicular cells and that, like the cell of origin, it sometimes produces thyrocalcitonin may account for the association of parathyroid hyperplasia and perhaps parathyroid adenoma. <a href="#81" class="mim-tip-reference" title="Poloyan, E., Scanu, A., Straus, F. H., Pickleman, J. R., Poloyan, D. <strong>Familial pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenomas.</strong> JAMA 214: 1443-1447, 1970."None>Poloyan et al. (1970)</a> was impressed with the histologic similarity between the medullary thyroid cancer and pheochromocytoma metastases. <a href="#49" class="mim-tip-reference" title="Keiser, H. R., Beaven, M. A., Doppman, J., Wells, S. A., Jr., Buja, L. M. <strong>Sipple's syndrome: medullary thyroid carcinoma, pheochromocytoma, and parathyroid disease.</strong> Ann. Intern. Med. 78: 561-579, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4632792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4632792</a>] [<a href="https://doi.org/10.7326/0003-4819-78-4-561" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4632792">Keiser et al. (1973)</a> pointed out that histaminase is useful in the identification of metastases of medullary carcinoma. In their opinion parathyroid adenomas are a primary feature of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4632792+10483461" 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="#78" class="mim-tip-reference" title="Pearson, K. D., Wells, S. A., Jr., Keiser, H. R. <strong>Familial medullary carcinoma of the thyroid, adrenal pheochromocytoma and parathyroid hyperplasia. A syndrome of multiple endocrine neoplasia.</strong> Radiology 107: 249-256, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4695886/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4695886</a>] [<a href="https://doi.org/10.1148/107.2.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4695886">Pearson et al. (1973)</a> studied 21 members of a kindred with surgically confirmed multiple endocrine neoplasms. All 21 had medullary carcinoma of the thyroid. Adrenal pheochromocytomas were present in 10 and were bilateral in 6. Three had one or more parathyroid glands showing adenomatous hyperplasia and 10 showed chief cell hyperplasia. The thyroid cancer metastasized to other areas including the liver, lungs, and bone in several of the patients. All patients had elevated peripheral thyrocalcitonin. Peripheral parathyroid hormone was elevated in only 2; however, parathyroid hormone was elevated in the inferior thyroid vein of all patients examined. <a href="#36" class="mim-tip-reference" title="Hamilton, B. P., Landsberg, L., Levine, R. J. <strong>Measurement of urinary epinephrine in screening for pheochromocytoma in multiple endocrine neoplasia type II.</strong> Am. J. Med. 65: 1027-1032, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/742624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">742624</a>] [<a href="https://doi.org/10.1016/0002-9343(78)90757-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="742624">Hamilton et al. (1978)</a> suggested that an increased urinary epinephrine fraction is a sensitive and reliable screening test for pheochromocytoma in MEN II, comparable to the calcitonin radioimmunoassay for medullary carcinoma of the thyroid. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=742624+4695886" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Carney, J. A., Sizemore, G. W., Tyce, G. M. <strong>Bilateral adrenal medullary hyperplasia in multiple endocrine neoplasia, type II. The precursor of bilateral pheochromocytoma.</strong> Mayo Clin. Proc. 50: 3-10, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1110583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1110583</a>]" pmid="1110583">Carney et al. (1975)</a> found bilateral adrenal medullary hyperplasia in an asymptomatic 12-year-old girl. She had bilateral thyroid carcinoma and hyperparathyroidism. The adrenals were explored because of elevated urinary levels of vanillylmandelic acid. Migrating neural crest cells are able to decarboxylate and store precursors of aromatic amines that fluoresce after exposure to formaldehyde vapor. The last is a method for identifying neural crest origin of enterochromaffin, argyrophil cells of the bronchi, islets of Langerhans, and parafollicular cells of the thyroid, among others. These are collectively termed the amine precursor uptake and decarboxylase (APUD) system (<a href="#77" class="mim-tip-reference" title="Pearse, A. G. E. <strong>The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic, and pathologic implications of the concept.</strong> J. Histochem. Cytochem. 17: 303-313, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4143745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4143745</a>] [<a href="https://doi.org/10.1177/17.5.303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4143745">Pearse, 1969</a>). <a href="#102" class="mim-tip-reference" title="Tischler, A. S., Dichter, M. A., Biales, B., DeLellis, R. A., Wolfe, H. <strong>Neural properties of cultured human endocrine tumor cells of proposed neural crest origin.</strong> Science 192: 902-904, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/179139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">179139</a>] [<a href="https://doi.org/10.1126/science.179139" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="179139">Tischler et al. (1976)</a> extended the evidence of neural origin by demonstrating that cultured cells from medullary carcinoma of the thyroid, bronchial carcinoid, and pheochromocytoma display all-or-nothing action potentials of short duration. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1110583+4143745+179139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Easton, D. F., Ponder, M. A., Cummings, T., Gagel, R. F., Hansen, H. H., Reichlin, S., Tashjian, A. H., Jr., Telenius-Berg, M., Ponder, B. A. J., the Cancer Research Campaign Medullary Thyroid Group. <strong>The clinical and screening age-at-onset distribution for the MEN-2 syndrome.</strong> Am. J. Hum. Genet. 44: 208-215, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2563193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2563193</a>]" pmid="2563193">Easton et al. (1989)</a> estimated on the basis of clinical history that 41% of gene carriers are asymptomatic at age 70. Screening by the standard tests for detecting the earliest manifestations of the syndrome increased the penetrance to an estimated 93% by age 31. There was some suggestion of an earlier onset of medullary thyroid cancer in female gene carriers, and of a tendency for pheochromocytoma to cluster in families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2563193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Chen, L., Zhang, J. X., Liu, D. G., Liu, H. G. <strong>A familial case of multiple endocrine neoplasia 2A: from morphology to genetic alterations penetration in three generations of a family.</strong> Diagnostics (Basel) 13: 955, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36900098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36900098</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36900098[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3390/diagnostics13050955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36900098">Chen et al. (2023)</a> reported a 3-generation family with MEN2A. The proband was diagnosed with a left adrenal pheochromocytoma at age 31 years and bilateral multiple medullary thyroid carcinoma (MTC) with lymph node metastasis at age 41 years. At age 28 years, his sister had a left adrenal pheochromocytoma and right follicular thyroid carcinoma (later diagnosed pathologically as MTC when she presented with left thyroid MTC at age 45 years). Their father had been diagnosed with left MTC and left pheochromocytoma at age 42 years. The proband's daughter, aged 18 years, had the RET mutation seen in the rest of the family but was without evidence of disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36900098" 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="#57" class="mim-tip-reference" title="Le Marec, B., Roussey, M., Cornec, A., Calmettes, C., Kerisit, J., Allanic, H. <strong>Cancer de la thyroide a stroma amyloide, syndrome de Sipple, megacolon congenital avec hyperplasie des plexus: une seule et meme affection autosomique dominante a penetrance complete.</strong> J. Genet. Hum. 28: 169-174, 1980."None>Le Marec et al. (1980)</a> reported congenital megacolon with plexus hyperplasia in a family with Sipple syndrome. Megacolon of this type seems to be more usual in MEN III than in MEN II. <a href="#12" class="mim-tip-reference" title="Cameron, D., Spiro, H. M., Landsberg, L. <strong>Zollinger-Ellison syndrome with multiple endocrine adenomatosis type II. (Letter)</strong> New Eng. J. Med. 299: 152-153, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26873</a>] [<a href="https://doi.org/10.1056/NEJM197807202990315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26873">Cameron et al. (1978)</a> described the Zollinger-Ellison syndrome with type II MEA, a first. These families represent an overlap of phenotypic features in the 3 forms of MEN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26873" 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="Gagel, R. F., Levy, M. L., Donovan, D. T., Alford, B. R., Wheeler, T., Tschen, J. A. <strong>Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis.</strong> Ann. Intern. Med. 111: 802-806, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2573304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2573304</a>] [<a href="https://doi.org/10.7326/0003-4819-111-10-802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2573304">Gagel et al. (1989)</a>, <a href="#75" class="mim-tip-reference" title="Nunziata, V., di Giovanni, G., Lettera, A. M., D'Armiento, M., Mancini, M. <strong>Cutaneous lichen amyloidosis associated with multiple endocrine neoplasia type 2A.</strong> Henry Ford Hosp. Med. J. 37: 144-146, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2576949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2576949</a>]" pmid="2576949">Nunziata et al. (1989)</a>, and <a href="#51" class="mim-tip-reference" title="Kousseff, B. G., Espinoza, C., Zamore, G. A. <strong>Sipple syndrome with lichen amyloidosis as a paracrinopathy: pleiotropy, heterogeneity, or a contiguous gene?</strong> J. Am. Acad. Derm. 25: 651-657, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1686438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1686438</a>] [<a href="https://doi.org/10.1016/0190-9622(91)70248-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1686438">Kousseff et al. (1991)</a> observed primary localized cutaneous amyloidosis (PLCA) in association with MEN2A. <a href="#28" class="mim-tip-reference" title="Gagel, R. F., Levy, M. L., Donovan, D. T., Alford, B. R., Wheeler, T., Tschen, J. A. <strong>Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis.</strong> Ann. Intern. Med. 111: 802-806, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2573304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2573304</a>] [<a href="https://doi.org/10.7326/0003-4819-111-10-802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2573304">Gagel et al. (1989)</a> and <a href="#51" class="mim-tip-reference" title="Kousseff, B. G., Espinoza, C., Zamore, G. A. <strong>Sipple syndrome with lichen amyloidosis as a paracrinopathy: pleiotropy, heterogeneity, or a contiguous gene?</strong> J. Am. Acad. Derm. 25: 651-657, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1686438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1686438</a>] [<a href="https://doi.org/10.1016/0190-9622(91)70248-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1686438">Kousseff et al. (1991)</a> referred to it as cutaneous lichen amyloidosis. In a family with 6 affected members in 5 generations, a mother and her daughter had interscapular cutaneous pruritic lesions (<a href="#51" class="mim-tip-reference" title="Kousseff, B. G., Espinoza, C., Zamore, G. A. <strong>Sipple syndrome with lichen amyloidosis as a paracrinopathy: pleiotropy, heterogeneity, or a contiguous gene?</strong> J. Am. Acad. Derm. 25: 651-657, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1686438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1686438</a>] [<a href="https://doi.org/10.1016/0190-9622(91)70248-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1686438">Kousseff et al., 1991</a>). <a href="#52" class="mim-tip-reference" title="Kousseff, B. G. <strong>Sipple syndrome with lichen amyloidosis as a paracrinopathy. (Letter)</strong> Am. J. Med. Genet. 42: 751-753, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1352941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1352941</a>] [<a href="https://doi.org/10.1002/ajmg.1320420526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1352941">Kousseff (1992)</a> provided a pedigree and photographs of the skin lesions. Cutaneous lichen amyloidosis as an apparently independent autosomal dominant trait has also been described (<a href="/entry/105250">105250</a>). The skin deposits of amyloid associated with pruritus in the interscapular region represents a form of 'friction amyloidosis' (<a href="#108" class="mim-tip-reference" title="Wong, C.-K., Lin, C.-S. <strong>Friction amyloidosis.</strong> Int. J. Derm. 27: 302-307, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3391726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3391726</a>] [<a href="https://doi.org/10.1111/j.1365-4362.1988.tb02357.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3391726">Wong and Lin, 1988</a>). It is related to notalgia paresthetica, an inherited neuropathy of the posterior dorsal nerve rami. ('Notalgia' means 'back pain.') The neuropathy hypothesis was supported by the finding of mutations in the RET protooncogene which is expressed in the peripheral and central nervous system. <a href="#15" class="mim-tip-reference" title="Ceccherini, I., Romei, C., Barone, V., Pacini, F., Martino, E., Loviselli, A., Pinchera, A., Romeo, G. <strong>Identification of the cys634-to-tyr mutation of the RET proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A and localized cutaneous lichen amyloidosis.</strong> J. Endocr. Invest. 17: 201-204, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7914213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7914213</a>] [<a href="https://doi.org/10.1007/BF03347719" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7914213">Ceccherini et al. (1994)</a> demonstrated a specific cys634-to-tyr missense mutation (<a href="/entry/164761#0004">164761.0004</a>) in affected members of a pedigree in which MEN2A was combined with localized cutaneous lichen amyloidosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1686438+3391726+2576949+2573304+1352941+7914213" 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="#97" class="mim-tip-reference" title="Skinner, M. A., Safford, S. D., Reeves, J. G., Jackson, M. E., Freemerman, A. J. <strong>Renal aplasia in humans is associated with RET mutations.</strong> Am. J. Hum. Genet. 82: 344-351, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252215[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.10.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252215">Skinner et al. (2008)</a> identified 10 different heterozygous mutations in the RET gene (see, e.g., <a href="/entry/164761#0053">164761.0053</a> and <a href="/entry/164761#0054">164761.0054</a>) in paraffin-embedded tissue from 7 (37%) of 19 stillborn fetuses with bilateral renal agenesis and in 2 (20%) of 10 stillborn fetuses with unilateral renal agenesis. Two fetuses had 2 RET mutations. Parental DNA was not studied. In vitro functional expression studies showed that the mutations resulted in either constitutive RET phosphorylation or absent phosphorylation. <a href="#97" class="mim-tip-reference" title="Skinner, M. A., Safford, S. D., Reeves, J. G., Jackson, M. E., Freemerman, A. J. <strong>Renal aplasia in humans is associated with RET mutations.</strong> Am. J. Hum. Genet. 82: 344-351, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252215[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.10.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252215">Skinner et al. (2008)</a> postulated a loss-of-function effect. The fetuses did not have evidence of Hirschsprung disease (HSCR; <a href="/entry/142623">142623</a>), MEN2A, MEN2B (<a href="/entry/162300">162300</a>), or familial medullary thyroid carcinoma (<a href="/entry/155240">155240</a>). However, <a href="#97" class="mim-tip-reference" title="Skinner, M. A., Safford, S. D., Reeves, J. G., Jackson, M. E., Freemerman, A. J. <strong>Renal aplasia in humans is associated with RET mutations.</strong> Am. J. Hum. Genet. 82: 344-351, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252215[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.10.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18252215">Skinner et al. (2008)</a> noted that these conditions generally present with clinical findings later in childhood; they may have been present in the fetuses and not detected by standard autopsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18252215" 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="#46" class="mim-tip-reference" title="Jeanpierre, C., Mace, G., Parisot, M., Moriniere, V., Pawtowsky, A., Benabou, M., Martinovic, J., Amiel, J., Attie-Bitach, T., Delezoide, A. L., Loget, P., Blanchet, P., and 9 others. <strong>RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects.</strong> J. Med. Genet. 48: 497-504, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21490379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21490379</a>] [<a href="https://doi.org/10.1136/jmg.2010.088526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21490379">Jeanpierre et al. (2011)</a> identified heterozygous variations in the RET gene in 7 (6.6%) of 105 fetuses with severe kidney developmental defects leading to death or termination in utero. Four of the variants were also present in unaffected fathers. In vitro functional studies of most the variants were not performed, but at least 1 was likely a neutral polymorphism. Analysis of 171 additional cases with renal developmental defects showed that the frequency of RET variants was significantly higher in cases compared to controls, suggesting that variants may confer predisposition to a spectrum of renal developmental defects. However, <a href="#46" class="mim-tip-reference" title="Jeanpierre, C., Mace, G., Parisot, M., Moriniere, V., Pawtowsky, A., Benabou, M., Martinovic, J., Amiel, J., Attie-Bitach, T., Delezoide, A. L., Loget, P., Blanchet, P., and 9 others. <strong>RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects.</strong> J. Med. Genet. 48: 497-504, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21490379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21490379</a>] [<a href="https://doi.org/10.1136/jmg.2010.088526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21490379">Jeanpierre et al. (2011)</a> concluded that genetic alteration of RET is not a major mechanism leading to renal agenesis or kidney developmental defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21490379" 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="#37" class="mim-tip-reference" title="Hibi, Y., Ohye, T., Ogawa, K., Shimizu, Y., Shibata, M., Kagawa, C., Mizuno, Y., Kurahashi, H., Iwase, K. <strong>A MEN2A family with two asymptomatic carriers affected by unilateral renal agenesis.</strong> Endocr. J. 61: 19-23, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24152999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24152999</a>] [<a href="https://doi.org/10.1507/endocrj.ej13-0335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24152999">Hibi et al. (2014)</a> reported a family with MEN2A associated with a heterozygous RET mutation (C618R; <a href="/entry/164761#0025">164761.0025</a>). The female proband had MTC and pheochromocytoma, and her brother died of MTC at age 45 years. The proband had 3 asymptomatic sons, all of whom carried the C618R mutation. Two of the sons were found to have unilateral renal agenesis, and 1 also had Hirschsprung disease. <a href="#37" class="mim-tip-reference" title="Hibi, Y., Ohye, T., Ogawa, K., Shimizu, Y., Shibata, M., Kagawa, C., Mizuno, Y., Kurahashi, H., Iwase, K. <strong>A MEN2A family with two asymptomatic carriers affected by unilateral renal agenesis.</strong> Endocr. J. 61: 19-23, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24152999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24152999</a>] [<a href="https://doi.org/10.1507/endocrj.ej13-0335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24152999">Hibi et al. (2014)</a> noted that knockout of Ret in mice results in loss of enteric neurons as well as renal agenesis or severe dysgenesis (<a href="#87" class="mim-tip-reference" title="Schuchardt, A., D'Agati, V., Larsson-Blomberg, L., Costantini, F., Pachnis, V. <strong>Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret.</strong> Nature 367: 380-383, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8114940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8114940</a>] [<a href="https://doi.org/10.1038/367380a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8114940">Schuchardt et al., 1994</a>). The findings in the family reported by <a href="#37" class="mim-tip-reference" title="Hibi, Y., Ohye, T., Ogawa, K., Shimizu, Y., Shibata, M., Kagawa, C., Mizuno, Y., Kurahashi, H., Iwase, K. <strong>A MEN2A family with two asymptomatic carriers affected by unilateral renal agenesis.</strong> Endocr. J. 61: 19-23, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24152999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24152999</a>] [<a href="https://doi.org/10.1507/endocrj.ej13-0335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24152999">Hibi et al. (2014)</a> supported the hypothesis that a constitutively active RET mutation might partially impair RET function and thereby cause loss of function phenotypes, such as renal agenesis or HSCR. However, <a href="#37" class="mim-tip-reference" title="Hibi, Y., Ohye, T., Ogawa, K., Shimizu, Y., Shibata, M., Kagawa, C., Mizuno, Y., Kurahashi, H., Iwase, K. <strong>A MEN2A family with two asymptomatic carriers affected by unilateral renal agenesis.</strong> Endocr. J. 61: 19-23, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24152999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24152999</a>] [<a href="https://doi.org/10.1507/endocrj.ej13-0335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24152999">Hibi et al. (2014)</a> concluded that renal agenesis/dysgenesis is probably extremely rare in patients with RET mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24152999+8114940" 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="#41" class="mim-tip-reference" title="Hwang, D.-Y., Dworschak, G. C., Kohl, S., Saisawat, P., Vivante, A., Hilger, A. C., Reutter, H. M., Soliman, N. A., Bogdanovic, R., Kehinde, E. O., Tasic, V., Hildebrandt, F. <strong>Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract.</strong> Kidney Int. 85: 1429-1433, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24429398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24429398</a>] [<a href="https://doi.org/10.1038/ki.2013.508" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24429398">Hwang et al. (2014)</a> identified 3 different heterozygous RET missense mutations in 3 of 650 different families with various congenital anomalies of the kidney and urinary tract (CAKUT) who were screened for mutations in the coding regions of 12 known dominant renal disease-causing genes. Although clinical details were sparse, the renal phenotype of these patients included renal hypodysplasia, unilateral renal agenesis, vesicoureteral reflux, ureteropelvic junction obstruction, duplex collecting system, and ureterocele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24429398" 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="#20" class="mim-tip-reference" title="Eisenhofer, G., Walther, M. M., Huynh, T.-T., Li, S.-T., Bornstein, S. R., Vortmeyer, A., Mannelli, M., Goldstein, D. S., Linehan, W. M., Lenders, J. W. M., Pacak, K. <strong>Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes.</strong> J. Clin. Endocr. Metab. 86: 1999-2008, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11344198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11344198</a>] [<a href="https://doi.org/10.1210/jcem.86.5.7496" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11344198">Eisenhofer et al. (2001)</a> examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in MEN2 and von Hippel-Lindau syndrome to underlying differences in the expression of tyrosine hydroxylase (TH; <a href="/entry/191290">191290</a>), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT; <a href="/entry/171190">171190</a>), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN2 patients and 30 von Hippel-Lindau patients with adrenal pheochromocytomas. MEN2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than von Hippel-Lindau patients. MEN2 patients all had elevated plasma concentrations of the epinephrine metabolite metanephrine, whereas von Hippel-Lindau patients showed specific increases in the norepinephrine metabolite normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from von Hippel-Lindau than from MEN2 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11344198" 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>In affected members of 7 families, <a href="#106" class="mim-tip-reference" title="Van Dyke, D. L., Jackson, C. E., Babu, V. R. <strong>Localization of autosomal dominant multiple endocrine neoplasia 2 syndrome (MEN2) to 20p12.2. (Abstract)</strong> Cytogenet. Cell Genet. 32: 324 only, 1982."None>Van Dyke et al. (1982)</a> found a small deletion of chromosome 20p12.2 segregating with MEN II. <a href="#105" class="mim-tip-reference" title="Van Dyke, D. L., Jackson, C. E., Babu, V. R. <strong>Multiple endocrine neoplasia type 2 (MEN-2): an autosomal dominant syndrome with a possible chromosome 20 deletion. (Abstract)</strong> Am. J. Hum. Genet. 33: 69A only, 1981."None>Van Dyke et al. (1981)</a> demonstrated the 20p deletion in 16 cases of MEN II in 7 families, and in 1 case of MEN III. <a href="#38" class="mim-tip-reference" title="Hsu, T. C., Pathak, S., Samaan, N., Hickey, R. C. <strong>Chromosome instability in patients with medullary carcinoma of the thyroid.</strong> JAMA 246: 2046-2048, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6116812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6116812</a>]" pmid="6116812">Hsu et al. (1981)</a> found a higher frequency of metaphases with chromosome and chromatid abnormalities (average, 11.0%) in cases of Sipple syndrome than in controls (average, 3.8%). In one pair of sibs, they failed to find the same deletion in chromosome 20. <a href="#44" class="mim-tip-reference" title="Jackson, C. E. <strong>Personal Communication.</strong> Detroit, Mich. 4/14/1982."None>Jackson (1982)</a> stated that his group had correctly identified 18 persons in blinded studies. A small deletion was found in 18 members of 8 families with Sipple syndrome and also in 2 unrelated patients with MEN III. See <a href="#3" class="mim-tip-reference" title="Babu, V. R., Jackson, C. E., Van Dyke, D. L. <strong>Chromosome 20 deletion in multiple endocrine neoplasia syndrome types 2A and 2B. (Abstract)</strong> Clin. Res. 30: 489A only, 1982."None>Babu et al. (1982)</a>. Although, as they pointed out, their experience is not proof of the absence of deletion, <a href="#35" class="mim-tip-reference" title="Gustavson, K.-H., Jansson, R., Oberg, K. <strong>Chromosomal breakage in multiple endocrine adenomatosis (types I and II).</strong> Clin. Genet. 23: 143-149, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6132690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6132690</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1983.tb01863.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6132690">Gustavson et al. (1983)</a> could not demonstrate such by high resolution banding in either MEN I or MEN II. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6116812+6132690" 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>High resolution cytogenetics in 5 persons studied by <a href="#21" class="mim-tip-reference" title="Emmertsen, K., Lamm, L. U., Rasmussen, K. Z., Elbrond, O., Hansen, H. H., Henningsen, K., Jorgensen, J., Petersen, G. B. <strong>Linkage and chromosome study of multiple endocrine neoplasia IIa.</strong> Cancer Genet. Cytogenet. 9: 251-259, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6134579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6134579</a>] [<a href="https://doi.org/10.1016/0165-4608(83)90009-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6134579">Emmertsen et al. (1983)</a> showed no deletion in band 20p12.2. In both MEN2A and MEN2B, <a href="#5" class="mim-tip-reference" title="Babu, V. R., Van Dyke, D. L., Jackson, C. E. <strong>Chromosome 20 deletion in human multiple endocrine neoplasia types 2A and 2B: a double-blind study.</strong> Proc. Nat. Acad. Sci. 81: 2525-2528, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6585814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6585814</a>] [<a href="https://doi.org/10.1073/pnas.81.8.2525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6585814">Babu et al. (1984)</a> reported the finding of an interstitial deletion in band 20p12.2. In a double-blind study, 2 of 13 controls were thought to have the deletion; all 9 blood samples from 8 affected members of 4 MEN2A families were found to have the deletion; from 3 MEN2B families, 5 blood samples from 4 affected members showed the deletion, whereas 3 did not. The authors suggested that these 2 entities are genetically closely related; that the dominant expression of the mutation at 20p12.2 is hyperplasia of thyroid C cells and adrenal medullary cells; that in accordance with Knudson's 2-mutation-event theory and in analogy to retinoblastoma, thyroid cancer and pheochromocytoma are recessive manifestations. <a href="#111" class="mim-tip-reference" title="Zatterale, A., Stabile, M., Nunziata, V., Di Giovanni, G., Vecchione, R., Ventruto, V. <strong>Multiple endocrine neoplasia type 2 (Sipple's syndrome): clinical and cytogenetic analysis of a kindred.</strong> J. Med. Genet. 21: 108-111, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6143828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6143828</a>] [<a href="https://doi.org/10.1136/jmg.21.2.108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6143828">Zatterale et al. (1984)</a> could not detect a 20p12.2 deletion in prometaphase banding studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6134579+6585814+6143828" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Babu, V. R., Van Dyke, D. L., Flejter, W. L., Jackson, C. E. <strong>Chromosome 20 deletion in multiple endocrine neoplasia type 2: expanded double-blind studies.</strong> Am. J. Med. Genet. 27: 739-748, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2888311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2888311</a>] [<a href="https://doi.org/10.1002/ajmg.1320270336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2888311">Babu et al. (1987)</a> reported on an expanded double-blind study of chromosome 20 deletion in MEN2A and MEN2B. A deletion in 20p12.2 was found in 15 of 21 MEN2A patients and in 4 of 8 MEN2B patients. These findings await explanation since the locus for these disorders maps elsewhere. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2888311" 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="#43" class="mim-tip-reference" title="Jackson, C. E., Conneally, P. M., Sizemore, G. W., Tashjian, A. H., Jr. <strong>Possible linear order of genes for endocrine neoplasia type 2, the P red cell antigen and HL-A on chromosome 6.</strong> Birth Defects Orig. Art. Ser. 12(1): 159-164, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/990440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">990440</a>]" pmid="990440">Jackson et al. (1976)</a> found a suggestion of linkage to P blood group (<a href="/entry/111400">111400</a>) but not to HLA. <a href="#89" class="mim-tip-reference" title="Simpson, N. E., Falk, J., Forster-Gibson, C. J., Goodall, J., Sears, E., Partington, M. W., Ghent, W. <strong>Possible linkage between the loci for multiple endocrine neoplasias type II (MEN2) and HLA. (Abstract)</strong> Cytogenet. Cell Genet. 25: 204 only, 1979."None>Simpson et al. (1979)</a> found 23.1% recombination between MEN II and HLA, but this linkage was rendered highly unlikely by further studies by <a href="#90" class="mim-tip-reference" title="Simpson, N. E., Falk, J. <strong>Exclusion of linkage between the loci for multiple endocrine neoplasia type-2 (MEN-2) and HLA.</strong> Hum. Genet. 60: 157 only, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7076256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7076256</a>] [<a href="https://doi.org/10.1007/BF00569703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7076256">Simpson and Falk (1982)</a>. <a href="#42" class="mim-tip-reference" title="Jackson, C. E., Block, M. A., Greenawalt, K. A., Tashjian, A. H., Jr. <strong>The two-mutational-event theory in medullary thyroid cancer.</strong> Am. J. Hum. Genet. 31: 704-710, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/517520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">517520</a>]" pmid="517520">Jackson et al. (1979)</a> concluded that medullary thyroid cancer fits a 2-mutation theory. They suggested that C-cell hyperplasia is the gene-determined first mutational event and cancer the second. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7076256+517520+990440" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Emmertsen, K., Lamm, L. U., Rasmussen, K. Z., Elbrond, O., Hansen, H. H., Henningsen, K., Jorgensen, J., Petersen, G. B. <strong>Linkage and chromosome study of multiple endocrine neoplasia IIa.</strong> Cancer Genet. Cytogenet. 9: 251-259, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6134579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6134579</a>] [<a href="https://doi.org/10.1016/0165-4608(83)90009-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6134579">Emmertsen et al. (1983)</a> found no significantly positive lod scores between MEN II and 25 different genetic markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6134579" 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="#91" class="mim-tip-reference" title="Simpson, N. E., Goodfellow, P. J., Riddell, D. C., Hamerton, J. L., Holden, J. J. A., White, B. N. <strong>Assignment of the calcitonin gene to chromosome 11 and probable exclusion of linkage between the gene and the locus for multiple endocrine neoplasia type 2. (Abstract)</strong> Am. J. Hum. Genet. 36: 153S only, 1984."None>Simpson et al. (1984)</a> assigned the calcitonin gene to chromosome 11 by use of a cDNA clone isolated from medullary thyroid carcinoma and a somatic cell hybrid panel. With a TaqI RFLP detected by this probe, they studied linkage of the calcitonin locus and MEN2; negative lod scores were found at all recombination values. <a href="#32" class="mim-tip-reference" title="Goodfellow, P. J., White, B. N., Holden, J. J. A., Duncan, A. M. V., Wang, H.-S., Greenberg, C. R., Sears, E. V. P., Ghent, W. R., Simpson, N. E. <strong>Linkage studies in multiple endocrine neoplasia type-2 using chromosome 20 markers. (Abstract)</strong> Am. J. Hum. Genet. 36: 138S only, 1984."None>Goodfellow et al. (1984)</a> studied linkage between MEN2 and DNA probes assigned to 20p12.2 by in situ hybridization. Negative lod scores were obtained.</p><p>In 2 large MEN2A pedigrees, <a href="#31" class="mim-tip-reference" title="Goodfellow, P. J., White, B. N., Holden, J. J. A., Duncan, A. M. V., Sears, E. V. P., Wang, H.-S., Berlin, L., Kidd, K. K., Simpson, N. E. <strong>Linkage analysis of a DNA marker localized to 20p12 and multiple endocrine neoplasia type 2A.</strong> Am. J. Hum. Genet. 37: 890-897, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2864854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2864854</a>]" pmid="2864854">Goodfellow et al. (1985)</a> studied linkage with 2 RFLPs found in an anonymous DNA segment D20S5, which had been isolated from a chromosome 19/20 flow-sorted library and shown by in situ hybridization to be located at 20p12. Linkage was excluded at theta equal to or less than 0.13. In studies of a single large kindred, <a href="#53" class="mim-tip-reference" title="Kruger, S. D., Gertner, J. M., Sparkes, R. S., Haedt, L. E., Crist, M., Sparkes, M. C., Genel, M., Kidd, K. K. <strong>Linkage analyses of multiple endocrine neoplasia, type 2 (MEN-2) with 23 classical genetic polymorphisms.</strong> Hum. Hered. 36: 6-11, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2868987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2868987</a>] [<a href="https://doi.org/10.1159/000153592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2868987">Kruger et al. (1986)</a> excluded close linkage with several markers and found no statistically significant linkage with any marker. Low positive lod scores were obtained with GC (<a href="/entry/139200">139200</a>), GPT (<a href="/entry/138200">138200</a>) and HP (<a href="/entry/140100">140100</a>). <a href="#80" class="mim-tip-reference" title="Perrier, P., Thomas, J. L., Bonaiti-Pellie, C., Gay, G., Leclere, J., Streiff, F. <strong>Lack of linkage between HLA and multiple endocrine neoplasia type 2 in a French family.</strong> Tissue Antigens 29: 13-17, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2884753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2884753</a>] [<a href="https://doi.org/10.1111/j.1399-0039.1987.tb01543.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2884753">Perrier et al. (1987)</a> found no linkage of MEN2 and HLA. By multipoint linkage analysis, <a href="#22" class="mim-tip-reference" title="Farrer, L. A., Goodfellow, P. J., Lamarche, C. M., Franjkovic, I., Myers, S., White, B. N., Holden, J. J. A., Kidd, J. R., Simpson, N. E., Kidd, K. K. <strong>An efficient strategy for gene mapping using multipoint linkage analysis: exclusion of the multiple endocrine neoplasia 2A (MEN2A) locus from chromosome 13.</strong> Am. J. Hum. Genet. 40: 329-337, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2883889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2883889</a>]" pmid="2883889">Farrer et al. (1987)</a> excluded a large portion of chromosome 13 as the site of the MEN2A locus. <a href="#22" class="mim-tip-reference" title="Farrer, L. A., Goodfellow, P. J., Lamarche, C. M., Franjkovic, I., Myers, S., White, B. N., Holden, J. J. A., Kidd, J. R., Simpson, N. E., Kidd, K. K. <strong>An efficient strategy for gene mapping using multipoint linkage analysis: exclusion of the multiple endocrine neoplasia 2A (MEN2A) locus from chromosome 13.</strong> Am. J. Hum. Genet. 40: 329-337, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2883889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2883889</a>]" pmid="2883889">Farrer et al. (1987)</a> could find no linkage of MEN2A to 3 DNA markers that mapped to chromosome 20. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2868987+2884753+2864854+2883889" 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="#92" class="mim-tip-reference" title="Simpson, N. E., Kidd, K. K., Goodfellow, P. J., McDermid, H., Myers, S., Kidd, J. R., Jackson, C. E., Duncan, A. M. V., Farrer, L. A., Brasch, K., Castiglione, C., Genel, M., Gertner, J., Greenberg, C. R., Gusella, J. F., Holden, J. J. A., White, B. N. <strong>Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage.</strong> Nature 328: 528-530, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2886918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2886918</a>] [<a href="https://doi.org/10.1038/328528a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2886918">Simpson et al. (1987)</a> performed linkage studies in 5 families, each with at least 1 member found to have a deletion at 20p12.2. In these families, the MEN2 locus was found to be linked to a DNA marker on chromosome 10, D10S5, which by in situ hybridization maps to 10q21.1. The maximal lod score was 3.58 for a recombination fraction of 0.19. With 2 RFLPs recognized by an RBP3 probe (<a href="/entry/180290">180290</a>), <a href="#92" class="mim-tip-reference" title="Simpson, N. E., Kidd, K. K., Goodfellow, P. J., McDermid, H., Myers, S., Kidd, J. R., Jackson, C. E., Duncan, A. M. V., Farrer, L. A., Brasch, K., Castiglione, C., Genel, M., Gertner, J., Greenberg, C. R., Gusella, J. F., Holden, J. J. A., White, B. N. <strong>Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage.</strong> Nature 328: 528-530, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2886918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2886918</a>] [<a href="https://doi.org/10.1038/328528a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2886918">Simpson et al. (1987)</a> found a maximal lod score of 8.0 at theta = 0.11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2886918" 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 studies of 5 Japanese families, <a href="#110" class="mim-tip-reference" title="Yamamoto, M., Takai, S., Miki, T., Motomura, K., Okazaki, M., Nishisho, I., Tateishi, H., Miyauchi, A., Honjo, T., Pakstis, A. J., Mori, T. <strong>Close linkage of MEN2A with RBP3 locus in Japanese kindreds.</strong> Hum. Genet. 82: 287-288, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2567278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2567278</a>] [<a href="https://doi.org/10.1007/BF00291173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2567278">Yamamoto et al. (1989)</a> found that MEN2A is closely linked to RBP3; the maximum lod score was 5.19 at a recombination fraction of 0.00. In 2 kindreds, <a href="#63" class="mim-tip-reference" title="Mathew, C. G. P., Chin, K. S., Easton, D. F., Thorpe, K., Carter, C., Liou, G. I., Fong, S.-L., Bridges, C. D. B., Haak, H., Nieuwenhuijzen Kruseman, A. C., Schifter, S., Hansen, H. H., Telenius, H., Telenius-Berg, M., Ponder, B. A. J. <strong>A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10.</strong> Nature 328: 527-528, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2886917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2886917</a>] [<a href="https://doi.org/10.1038/328527a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2886917">Mathew et al. (1987)</a> found a maximal lod score of 3.88 at theta = 0.04 for linkage with RBP3, which has been positioned at 10p11.2-q11.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2886917+2567278" 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="#98" class="mim-tip-reference" title="Sobol, H., Narod, S. A., Lenoir, G. M. <strong>Linkage of medullary thyroid carcinoma with and without pheochromocytoma. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A34 only, 1989."None>Sobol et al. (1989)</a> reported on linkage studies in 35 families with medullary carcinoma of the thyroid with or without pheochromocytoma. Their results suggested that a susceptibility gene for hereditary medullary carcinoma of the thyroid may be located at the same locus on chromosome 10 as that of MEN2A. <a href="#73" class="mim-tip-reference" title="Narod, S. A., Sobol, H., Nakamura, Y., Calmettes, C., Baulieu, J.-L., Bigorgne, J.-C., Chabrier, G., Couette, J., de Gennes, J.-L., Duprey, J., Gardet, P., Guillausseau, P.-J., and 11 others. <strong>Linkage analysis of hereditary thyroid carcinoma with and without pheochromocytoma.</strong> Hum. Genet. 83: 353-358, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2572534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2572534</a>] [<a href="https://doi.org/10.1007/BF00291380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2572534">Narod et al. (1989)</a> did linkage studies in 18 families, 9 with MEN2A and 9 with medullary carcinoma of the thyroid without pheochromocytoma, with probes specific for the pericentromeric region of chromosome 10 and concluded that the mutations for the 2 presentations are closely situated. Genetic heterogeneity of the susceptibility locus was not seen among these 18 families. The genetic mutation for medullary carcinoma was in disequilibrium with alleles at 2 closely linked markers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2572534" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a panel of markers from the pericentric region of chromosome 10, <a href="#54" class="mim-tip-reference" title="Lairmore, T. C., Howe, J. R., Korte, J. A., Dilley, W. G., Aine, L., Aine, E., Wells, S. A., Jr., Donis-Keller, H. <strong>Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A.</strong> Genomics 9: 181-192, 1991. Note: Erratum: Genomics 10: 514 only, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1672289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1672289</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90237-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1672289">Lairmore et al. (1991)</a> performed linkage studies in 2 large families with medullary thyroid carcinoma (MTC1) and 6 families with MEN2B. The maximum lod score between MTC1 and marker D10Z1 was 5.88 with 0% recombination. MEN2B showed similarly tight linkage to D10Z1, with a maximum lod score of 3.58 at 0% recombination. The multipoint lod score for MEN2B at D10Z1 was 4.08. Linkage studies in a single large MEN2A kindred showed tight linkage to D10Z1 in this condition as well, with a maximum multipoint lod score of 7.04 at a recombination fraction of 0. The highest lod score obtained was between MEN2A and the haplotyped locus RBP3 with a lod score of 11.33 at a recombination fraction of 0. Linkage data between MEN2A and 3 additional markers on 10q, as well as between MEN2A and the FNRB locus (<a href="/entry/135630">135630</a>) on 10p11.2, were also presented. <a href="#54" class="mim-tip-reference" title="Lairmore, T. C., Howe, J. R., Korte, J. A., Dilley, W. G., Aine, L., Aine, E., Wells, S. A., Jr., Donis-Keller, H. <strong>Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A.</strong> Genomics 9: 181-192, 1991. Note: Erratum: Genomics 10: 514 only, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1672289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1672289</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90237-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1672289">Lairmore et al. (1991)</a> found no evidence for genetic heterogeneity among families with MEN2A, MEN2B, and MTC. In 2 families with medullary thyroid carcinoma with parathyroid tumors alone, <a href="#14" class="mim-tip-reference" title="Carson, N. L., Wu, J., Jackson, C. E., Kidd, K. K., Simpson, N. E. <strong>The mutation for medullary thyroid carcinoma with parathyroid tumors (MTC with PTs) is closely linked to the centromeric region of chromosome 10.</strong> Am. J. Hum. Genet. 47: 946-951, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1978560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1978560</a>]" pmid="1978560">Carson et al. (1990)</a> demonstrated that the disorder was closely linked to 2 markers in the vicinity of the centromere of chromosome 10, namely, RBP3 and D10Z1. Using a centromeric marker at the D10Z1 locus in 30 families with MEN2A, <a href="#74" class="mim-tip-reference" title="Narod, S. A., Sobol, H., Schuffenecker, I., Lavoue, M.-F., Lenoir, G. M. <strong>The gene for MEN 2A is tightly linked to the centromere of chromosome 10.</strong> Hum. Genet. 86: 529-530, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673115</a>] [<a href="https://doi.org/10.1007/BF00194649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1673115">Narod et al. (1991)</a> demonstrated tight linkage with the centromere. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1672289+1978560+1673115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Brooks-Wilson, A. R., Smailus, D. E., Goodfellow, P. J. <strong>A cluster of CpG islands at D10S94, near the locus responsible for multiple endocrine neoplasia type 2A (MEN2A).</strong> Genomics 13: 339-343, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1351867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1351867</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90250-v" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1351867">Brooks-Wilson et al. (1992)</a> characterized a dense cluster of CpG islands at D10S94 in proximal 10q11.2. No recombinants between D10S94 and MEN2A had been identified. They generated a 570-kb restriction map by pulsed field gel electrophoresis. Six CpG islands were clustered within a 180-kb region. They suggested that these CpG islands may represent the 5-prime ends of candidate genes for MEN2A, MEN2B, and/or MTC1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1351867" 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="#66" class="mim-tip-reference" title="McDonald, H., Smailus, D., Jenkins, H., Adams, K., Simpson, N. E., Goodfellow, P. J. <strong>Identification and characterization of a gene at D10S94 in the MEN2A region.</strong> Genomics 13: 344-348, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1351868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1351868</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90251-m" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1351868">McDonald et al. (1992)</a> further identified an MEN2A candidate gene by use of an evolutionarily conserved sequence from D10S94. The gene spanned 11 kb and had an unmethylated CpG island at its 5-prime end. It encoded a putative 415-amino acid polypeptide similar in sequence to nucleolin (<a href="/entry/164035">164035</a>), an abundant nucleolar protein. In a patient with MEN2A, they found no difference in the candidate gene, termed mcs94-1, from the MEN2A chromosome or its wildtype homolog. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1351868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By genetic linkage analysis, <a href="#30" class="mim-tip-reference" title="Gardner, E., Papi, L., Easton, D. F., Cummings, T., Jackson, C. E., Kaplan, M., Love, D. R., Mole, S. E., Moore, J. K., Mulligan, L. M., Norum, R. A., Ponder, M. A., Reichlin, S., Stall, G., Telenius, H., Telenius-Berg, M., Tunnacliffe, A., Ponder, B. A. J. <strong>Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2.</strong> Hum. Molec. Genet. 2: 241-246, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8098977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8098977</a>] [<a href="https://doi.org/10.1093/hmg/2.3.241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8098977">Gardner et al. (1993)</a> demonstrated that the MEN2A gene is located in a small region of 10q11.2 flanked by D10S141 proximally and D10S94 distally, these 2 markers being separated by a sex-average genetic distance of 0.55 cM. <a href="#68" class="mim-tip-reference" title="Mole, S. E., Mulligan, L. M., Healey, C. S., Ponder, B. A. J., Tunnacliffe, A. <strong>Localisation of the gene for multiple endocrine neoplasia type 2A to a 480 kb region in chromosome band 10q11.2.</strong> Hum. Molec. Genet. 2: 247-252, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8098978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8098978</a>] [<a href="https://doi.org/10.1093/hmg/2.3.247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8098978">Mole et al. (1993)</a> constructed a YAC contig spanning 1.1 Mb of band 10q11.2 which must include MEN2A because it encompassed 3 markers, D10S141, RET, and D10S94. A 480-kb region separated D10S141 and D10S94. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8098978+8098977" 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="#45" class="mim-tip-reference" title="Janson, M., Larsson, C., Werelius, B., Jones, C., Glaser, T., Nakamura, Y., Jones, C. P., Nordenskjold, M. <strong>Detailed physical map of human chromosomal region 11q12-13 shows high meiotic recombination rate around the MEN1 locus.</strong> Proc. Nat. Acad. Sci. 88: 10609-10613, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1683706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1683706</a>] [<a href="https://doi.org/10.1073/pnas.88.23.10609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1683706">Janson et al. (1991)</a> constructed a physical map of the MEN2 region by combining data from pulsed field gel electrophoresis (PFGE) with those generated from a panel of radiation-reduced somatic cell hybrids. Comparison of the physical map with the linkage map showed a recombination rate higher than expected: thus, for the closest pair of linked markers on the centromeric side of MEN2, 1 centimorgan corresponded to approximately 300 kb, and for markers on the telomeric side, 1 centimorgan corresponded to approximately 350 to 600 kb. There is evidence from other sources that the 11q12-q13 region is unusual in having a high G-C content, suggesting a high concentration of genes and other characteristics including increased meiotic recombination usually associated with telomeric regions (<a href="#84" class="mim-tip-reference" title="Saccone, S., De Sario, A., Della Valle, G., Bernardi, G. <strong>The highest gene concentrations in the human genome are in telomeric bands of metaphase chromosomes.</strong> Proc. Nat. Acad. Sci. 89: 4913-4917, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1594593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1594593</a>] [<a href="https://doi.org/10.1073/pnas.89.11.4913" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1594593">Saccone et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1594593+1683706" 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="#63" class="mim-tip-reference" title="Mathew, C. G. P., Chin, K. S., Easton, D. F., Thorpe, K., Carter, C., Liou, G. I., Fong, S.-L., Bridges, C. D. B., Haak, H., Nieuwenhuijzen Kruseman, A. C., Schifter, S., Hansen, H. H., Telenius, H., Telenius-Berg, M., Ponder, B. A. J. <strong>A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10.</strong> Nature 328: 527-528, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2886917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2886917</a>] [<a href="https://doi.org/10.1038/328527a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2886917">Mathew et al. (1987)</a> found deletion of a hypervariable region of DNA on 1p in 7 of 14 tumors (pheochromocytomas and medullary carcinomas) developing in patients with MEN2. In 1 of 2 families examined, the deleted chromosome was that inherited from the affected parent. Thus, the site of deletion presumably does not represent the location of the inherited gene. The deleted region was distal to the breakpoint commonly detected in neuroblastomas (<a href="/entry/256700">256700</a>), which share with the tumors of MEN2 embryologic origin from neuroectoderm. The most frequent breakpoint involved in neuroblastomas is 1p32, whereas the genes deleted in the tumors studied by <a href="#63" class="mim-tip-reference" title="Mathew, C. G. P., Chin, K. S., Easton, D. F., Thorpe, K., Carter, C., Liou, G. I., Fong, S.-L., Bridges, C. D. B., Haak, H., Nieuwenhuijzen Kruseman, A. C., Schifter, S., Hansen, H. H., Telenius, H., Telenius-Berg, M., Ponder, B. A. J. <strong>A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10.</strong> Nature 328: 527-528, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2886917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2886917</a>] [<a href="https://doi.org/10.1038/328527a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2886917">Mathew et al. (1987)</a> were located at 1p35-p33. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2886917" 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 an analysis of tumor DNA from 42 patients with MEN2A, <a href="#55" class="mim-tip-reference" title="Landsvater, R. M., Mathew, C. G. P., Smith, B. A., Marcus, E. M., te Meerman, G. J., Lips, C. J. M., Geerdink, R. A., Nakamura, Y., Ponder, B. A. J., Buys, C. H. C. M. <strong>Development of multiple endocrine neoplasia type 2A does not involve substantial deletions of chromosome 10.</strong> Genomics 4: 246-250, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2565874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2565874</a>] [<a href="https://doi.org/10.1016/0888-7543(89)90327-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2565874">Landsvater et al. (1989)</a> showed that markers on chromosome 10 were lost in only 1 tumor, a result that contrasts with studies in other tumors for which both familial and sporadic cases are known. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2565874" 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>That MEN2A is genetically heterogeneous is suggested by the linkage in some families to markers at the 10q11.2 region and the lack of linkage in other families. The basis of the above subclassification, whether different mutations in one gene or mutations in adjacent genes in the 10q11.2 region, is not clear (<a href="#94" class="mim-tip-reference" title="Simpson, N. E. <strong>Personal Communication.</strong> Kingston, Ontario, Canada 1/14/1992."None>Simpson, 1992</a>). The subclasses do seem to 'breed true' in different families.</p><p>In a panel of 34 families with MEN2A, <a href="#72" class="mim-tip-reference" title="Narod, S. A., Lavoue, M.-F., Morgan, K., Calmettes, C., Sobol, H., Goodfellow, P. J., Lenoir, G. M. <strong>Genetic analysis of 24 French families with multiple endocrine neoplasia type 2A.</strong> Am. J. Hum. Genet. 51: 469-477, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353939</a>]" pmid="1353939">Narod et al. (1992)</a> found no evidence of genetic heterogeneity. No recombination was observed between MEN2A and any of 4 DNA marker loci. <a href="#72" class="mim-tip-reference" title="Narod, S. A., Lavoue, M.-F., Morgan, K., Calmettes, C., Sobol, H., Goodfellow, P. J., Lenoir, G. M. <strong>Genetic analysis of 24 French families with multiple endocrine neoplasia type 2A.</strong> Am. J. Hum. Genet. 51: 469-477, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353939</a>]" pmid="1353939">Narod et al. (1992)</a> constructed haplotypes for 11 polymorphisms in the MEN2A region for mutation-bearing chromosomes in 24 French families and for 100 spouse controls. One haplotype was present in 4 MEN2A families but was not observed in any control (P = less than 0.01). Two additional families shared a core segment of this haplotype near the MEN2A gene. <a href="#72" class="mim-tip-reference" title="Narod, S. A., Lavoue, M.-F., Morgan, K., Calmettes, C., Sobol, H., Goodfellow, P. J., Lenoir, G. M. <strong>Genetic analysis of 24 French families with multiple endocrine neoplasia type 2A.</strong> Am. J. Hum. Genet. 51: 469-477, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1353939/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1353939</a>]" pmid="1353939">Narod et al. (1992)</a> suggested that these 6 families had a common affected ancestor. Because the incidence of pheochromocytoma among carriers varied from 0.0 to 74% in these 6 families, they suggested that additional factors modify the expression of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1353939" 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>Curiously, the most consistent molecular genetic abnormality that has been found in pheochromocytomas and medullary thyroid cancers, either sporadic or part of MEN2, is loss of heterozygosity (LOH) on 1p. Using RFLP analysis, <a href="#69" class="mim-tip-reference" title="Moley, J. F., Brother, M. B., Fong, C. T., White, P. S., Baylin, S. B., Nelkin, B., Wells, S. A., Brodeur, G. M. <strong>Consistent association of 1p loss of heterozygosity with pheochromocytomas from patients with multiple endocrine neoplasia type 2 syndromes.</strong> Cancer Res. 52: 770-774, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1346584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1346584</a>]" pmid="1346584">Moley et al. (1992)</a> identified loss of all or a portion of 1p in 12 of 18 pheochromocytomas. LOH of 1p was found in all 9 pheochromocytomas in MEN2A and MEN2B patients, compared with only 2 of 7 sporadic pheochromocytomas. They also found 1p LOH in the pheochromocytoma of 1 of 2 von Hippel-Lindau patients (<a href="/entry/193300">193300</a>). LOH on 1p was noted in only 3 of 24 informative medullary thyroid carcinomas, and these were from patients with MEN2A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1346584" 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="#71" class="mim-tip-reference" title="Mulligan, L. M., Kwok, J. B. J., Healey, C. S., Elsdon, M. J., Eng, C., Gardner, E., Love, D. R., Mole, S. E., Moore, J. K., Papi, L., Ponder, M. A., Telenius, H., Tunnacliffe, A., Ponder, B. A. J. <strong>Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.</strong> Nature 363: 458-460, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8099202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8099202</a>] [<a href="https://doi.org/10.1038/363458a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8099202">Mulligan et al. (1993)</a> identified missense mutations in the RET protooncogene in 20 of 23 apparently distinct MEN2A families, but not in 23 normal controls. Of these 20 mutations, 19 affected the same conserved cysteine residue at the boundary of the RET extracellular and intracellular domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8099202" 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="#83" class="mim-tip-reference" title="Quadro, L., Fattoruso, O., Cosma, M. P., Verga, U., Porcellini, A., Libroia, A., Colantuoni, V. <strong>Loss of heterozygosity at the RET protooncogene locus in a case of multiple endocrine neoplasia type 2A.</strong> J. Clin. Endocr. Metab. 86: 239-244, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11232007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11232007</a>] [<a href="https://doi.org/10.1210/jcem.86.1.7144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11232007">Quadro et al. (2001)</a> reported a patient affected by MEN2A bearing a heterozygous cys634-to-arg (<a href="/entry/164761#0011">164761.0011</a>) germline mutation in exon 11 and an additional somatic mutation (<a href="/entry/164761#0012">164761.0012</a>) of the RET protooncogene. A large intragenic deletion spanning exon 4 to exon 16 affected the normal allele and was detected by quantitative PCR, Southern blot analysis, and screening of several polymorphic markers. This deletion causes RET loss of heterozygosity exclusively in the metastasis and not in the primary tumor, thus suggesting a role for this second mutational event in tumor progression. No additional mutations were found in the other exons analyzed. The authors concluded that this unusual genetic profile may be related to the clinical course and very poor outcome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11232007" 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="#39" class="mim-tip-reference" title="Huang, S. C., Koch, C. A., Vortmeyer, A. O., Pack, S. D., Lichtenauer, U. D., Mannan, P., Lubensky, I. A., Chrousos, G. P., Gagel, R. F., Pacak, K., Zhuang, Z. <strong>Duplication of the mutant RET allele in trisomy 10 or loss of the wild-type allele in multiple endocrine neoplasia type 2-associated pheochromocytomas.</strong> Cancer Res. 60: 6223-6226, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11103773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11103773</a>]" pmid="11103773">Huang et al. (2000)</a> and <a href="#50" class="mim-tip-reference" title="Koch, C. A., Huang, S. C., Moley, J. F., Azumi, N., Chrousos, G. P., Gagel, R. F., Zhuang, Z., Pacak, K., Vortmeyer, A. O. <strong>Allelic imbalance of the mutant and wild-type RET allele in MEN 2A-associated medullary thyroid carcinoma.</strong> Oncogene 20: 7809-7811, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11753660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11753660</a>] [<a href="https://doi.org/10.1038/sj.onc.1204991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11753660">Koch et al. (2001)</a> identified 2 second-hit mechanisms involved in the development of MEN2-associated tumors: trisomy 10 with duplication of the mutant RET allele and loss of the wildtype RET allele. However, some of the MEN2-associated tumors investigated did not demonstrate either mechanism. <a href="#40" class="mim-tip-reference" title="Huang, S. C., Torres-Cruz, J., Pack, S. D., Koch, C. A., Vortmeyer, A. O., Mannan, P., Lubensky, I. A., Gagel, R. F., Zhuang, Z. <strong>Amplification and overexpression of mutant RET in multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma.</strong> J. Clin. Endocr. Metab. 88: 459-463, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519890</a>] [<a href="https://doi.org/10.1210/jc.2002-021254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12519890">Huang et al. (2003)</a> studied the TT cell line, derived from MEN2-associated medullary thyroid carcinoma with a RET germline mutation in codon 634, for alternative mechanisms of tumorigenesis. Although they observed a 2-to-1 ratio between mutant and wildtype RET at the genomic DNA level in this cell line, FISH analysis revealed neither trisomy 10 nor loss of the normal chromosome 10. Instead, a tandem duplication event was responsible for amplification of mutant RET. In further studies <a href="#40" class="mim-tip-reference" title="Huang, S. C., Torres-Cruz, J., Pack, S. D., Koch, C. A., Vortmeyer, A. O., Mannan, P., Lubensky, I. A., Gagel, R. F., Zhuang, Z. <strong>Amplification and overexpression of mutant RET in multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma.</strong> J. Clin. Endocr. Metab. 88: 459-463, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12519890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12519890</a>] [<a href="https://doi.org/10.1210/jc.2002-021254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12519890">Huang et al. (2003)</a> demonstrated for the first time that the genomic chromosome 10 abnormalities in this cell line cause an increased production of mutant RET mRNA. The authors concluded that these findings provided evidence for a third second-hit mechanism resulting in overrepresentation and overexpression of mutant RET in MEN2-associated tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12519890+11753660+11103773" 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="Abu-Amero, K. K., Alzahrani, A. S., Zou, M., Shi, Y. <strong>Association of mitochondrial DNA transversion mutations with familial medullary thyroid carcinoma/multiple endocrine neoplasia type 2 syndrome.</strong> Oncogene 25: 677-684, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16205644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16205644</a>] [<a href="https://doi.org/10.1038/sj.onc.1209094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16205644">Abu-Amero et al. (2006)</a> identified nonsynonymous germline mitochondrial DNA (mtDNA) mutations in both normal and tumor tissue from 20 (76.9%) of 26 cases of medullary thyroid carcinoma, including 9 (69.2%) of 13 sporadic cases and 11 (84.6%) of 13 familial cases; 10 of 13 familial cases were patients with MEN2. The familial cases tended to have transversion mtDNA mutations rather than transition mutations. All 13 familial cases also had germline RET mutations. <a href="#1" class="mim-tip-reference" title="Abu-Amero, K. K., Alzahrani, A. S., Zou, M., Shi, Y. <strong>Association of mitochondrial DNA transversion mutations with familial medullary thyroid carcinoma/multiple endocrine neoplasia type 2 syndrome.</strong> Oncogene 25: 677-684, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16205644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16205644</a>] [<a href="https://doi.org/10.1038/sj.onc.1209094" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16205644">Abu-Amero et al. (2006)</a> suggested that mtDNA mutations may be involved in medullary thyroid carcinoma tumorigenesis and/or progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16205644" 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 3-generation family with MEN2A, <a href="#17" class="mim-tip-reference" title="Chen, L., Zhang, J. X., Liu, D. G., Liu, H. G. <strong>A familial case of multiple endocrine neoplasia 2A: from morphology to genetic alterations penetration in three generations of a family.</strong> Diagnostics (Basel) 13: 955, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36900098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36900098</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36900098[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.3390/diagnostics13050955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36900098">Chen et al. (2023)</a> identified a C634G mutation in the RET gene (<a href="/entry/164761#0003">164761.0003</a>) in 4 family members. Three of them had been diagnosed with pheochromocytoma and medullary thyroid cancer, while the youngest, aged 18 years, had no evidence of disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36900098" 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>In the Netherlands, <a href="#107" class="mim-tip-reference" title="Vasen, H. F. A., Nieuwenhuijzen Kruseman, A. C., Berkel, H., Beukers, E. K. M., Delprat, C. C., Van Doorn, R. G., Geerdink, R. A., Haak, H. R., Hackeng, W. H. L., Koppeschaar, H. P. F., Krenning, E. P., Lamberts, S. W. J., Lekkerkerker, F. J. F., Michels, R. P. J., Moers, A. M. J., Pieters, G. F. F. M., Wiersinga, W. M., Lips, C. J. M. <strong>Multiple endocrine neoplasia syndrome type 2: the value of screening and central registration: a study of 15 kindreds in The Netherlands.</strong> Am. J. Med. 83: 847-852, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2890300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2890300</a>] [<a href="https://doi.org/10.1016/0002-9343(87)90641-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2890300">Vasen et al. (1987)</a> demonstrated the usefulness of screening and a central registry for the long-term follow-up of cases. In an 18-year study of a large kindred, <a href="#29" class="mim-tip-reference" title="Gagel, R. F., Tashjian, A. H., Jr., Cummings, T., Papathanasopoulos, N., Kaplan, M. M., DeLellis, R. A., Wolfe, H. J., Reichlin, S. <strong>The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a: an 18-year experience.</strong> New Eng. J. Med. 318: 478-484, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2893259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2893259</a>] [<a href="https://doi.org/10.1056/NEJM198802253180804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2893259">Gagel et al. (1988)</a> found that prospective screening and early treatment of manifestations of multiple endocrine neoplasia can prevent metastasis of medullary thyroid carcinoma and the morbidity and mortality of pheochromocytoma. Medullary carcinoma of the thyroid is the most consistent single manifestation of this disorder and occurs in almost all cases by age 40. Before age 40 in particular, it is necessary to use a provocative test of the combined calcitonin secretagogues enterogastrone and calcium in order to detect the disorder since the basal levels are not elevated (<a href="#7" class="mim-tip-reference" title="Baylin, S. B. <strong>Personal Communication.</strong> Baltimore, Md. 4/22/1989."None>Baylin, 1989</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2893259+2890300" 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>As part of a French national program, <a href="#98" class="mim-tip-reference" title="Sobol, H., Narod, S. A., Lenoir, G. M. <strong>Linkage of medullary thyroid carcinoma with and without pheochromocytoma. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A34 only, 1989."None>Sobol et al. (1989)</a> used DNA probes in a genetic linkage study of 130 members of 11 families of European and North African origin who were ascertained through members with MEN2A. No recombination was found between the mutation causing MEN2A and 2 of 3 markers used. All 11 families were informative for at least 1 of the markers and linkage information was adequate to permit genetic counseling in 8 families. <a href="#98" class="mim-tip-reference" title="Sobol, H., Narod, S. A., Lenoir, G. M. <strong>Linkage of medullary thyroid carcinoma with and without pheochromocytoma. (Abstract)</strong> Am. J. Hum. Genet. 45 (suppl.): A34 only, 1989."None>Sobol et al. (1989)</a> concluded that RFLP analysis is more useful in predicting the carrier state than conventional endocrine challenge, especially in younger persons, but accuracy is maximal when both methods are used.</p><p><a href="#64" class="mim-tip-reference" title="Mathew, C. G. P., Easton, D. F., Nakamura, Y., Ponder, B. A. J., the MEN 2A International Collaborative Group. <strong>Presymptomatic screening for multiple endocrine neoplasia type 2A with linked DNA markers.</strong> Lancet 337: 7-11, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670689</a>] [<a href="https://doi.org/10.1016/0140-6736(91)93329-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1670689">Mathew et al. (1991)</a>, including 23 members of the MEN2A International Collaborative Group, described 4 markers from the pericentric region of chromosome 10 that are tightly linked to MEN2A and are useful for testing for carrier status in individuals genetically at risk but showing a negative biochemical screening test for thyroid C-cell hyperplasia. The tests were also accurate for prenatal diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1670689" 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="Calmettes, C., Ponder, B. A. J., Fischer, J. A., Raue, F. <strong>Early diagnosis of the multiple endocrine neoplasia type 2 syndrome: consensus statement.</strong> Europ. J. Clin. Invest. 22: 755-760, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1362156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1362156</a>] [<a href="https://doi.org/10.1111/j.1365-2362.1992.tb01441.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1362156">Calmettes et al. (1992)</a> reported the consensus on biochemical and genetic screening formulated by the European Community Concerted Action on the subject of medullary thyroid carcinoma. For biochemical screening, measurement of the basal and pentagastrin- and/or calcium-stimulated serum levels of calcitonin by radioimmunoassay was considered essential starting at the age of 3 and continuing annually until the age of 35. Furthermore, annual screening for pheochromocytoma by measurement of urinary excretion of catecholamines and for hyperparathyroidism by serum calcium determination was considered indicated. Biochemical screening can be reserved for gene carriers in some families; genetic screening using genetic markers can be done with 95% accuracy in informative families whenever DNA is available from at least 2 family members proven to be affected. Total thyroidectomy at an early stage usually cures the patient with medullary thyroid carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1362156" 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>On the basis of studies in a very large kindred, <a href="#56" class="mim-tip-reference" title="Landsvater, R. M., Rombouts, A. G. M., te Meerman, G. J., Schillhorn-van Veen, J. M. J., Berends, M. J. H., Geerdink, R. A., Struyvenberg, A., Buys, C. H. C. M., Lips, C. J. M. <strong>The clinical implications of a positive calcitonin test for C-cell hyperplasia in genetically unaffected members of an MEN2A kindred.</strong> Am. J. Hum. Genet. 52: 335-342, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094268/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094268</a>]" pmid="8094268">Landsvater et al. (1993)</a> found 7 individuals with abnormal calcitonin test results. Five of these people were thyroidectomized, and C-cell hyperplasia was diagnosed. Four were the offspring of a mother at risk for the development of MEN2A who showed, however, normal calcitonin test results throughout the years, whereas the father, who was not at risk, had abnormal test results over a period of 10 years, without evidence of progressive elevation. None of the 7 individuals developed other manifestations of MEN2A. DNA analysis using markers linked to the MEN2A gene demonstrated, with more than 99% likelihood, that none of the persons who could be genotyped was a gene carrier. Thus, C-cell hyperplasia due to some mechanism other than the presence of the MEN2A gene may occur in MEN2A kindreds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8094268" 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="#88" class="mim-tip-reference" title="Schuffenecker, I., Ginet, N., Goldgar, D., Eng, C., Chambe, B., Boneu, A., Houdent, C., Pallo, D., Schlumberger, M., Thivolet, C., Lenoir, G. M., Le Groupe d'Etude des Tumeurs a Calcitonine. <strong>Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. (Letter)</strong> Am. J. Hum. Genet. 60: 233-237, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981969</a>]" pmid="8981969">Schuffenecker et al. (1997)</a> reported that 5.6% to 9% of cases of MEN2A/MTC are de novo cases with no family history. They reported further that new mutations in the RET oncogene in these cases were demonstrated exclusively on the paternal allele. Retrospective analysis on 274 MEN2A cases revealed that in 40.2% of patients pheochromocytoma occurred 2 to 11 years subsequent to MTC. <a href="#88" class="mim-tip-reference" title="Schuffenecker, I., Ginet, N., Goldgar, D., Eng, C., Chambe, B., Boneu, A., Houdent, C., Pallo, D., Schlumberger, M., Thivolet, C., Lenoir, G. M., Le Groupe d'Etude des Tumeurs a Calcitonine. <strong>Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. (Letter)</strong> Am. J. Hum. Genet. 60: 233-237, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8981969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8981969</a>]" pmid="8981969">Schuffenecker et al. (1997)</a> concluded that all apparently sporadic MTC patients should be examined for de novo RET mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8981969" 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>Sporadic medullary thyroid carcinoma has usually been found to result from a mutational event occurring at the single-cell level, indicating that they are monoclonal. By clonality assay of medullary carcinoma of the thyroid in MEN type 2, <a href="#24" class="mim-tip-reference" title="Ferraris, A. M., Mangerini, R., Gaetani, G. F., Romei, C., Pinchera, A., Pacini, F. <strong>Polyclonal origin of medullary carcinoma of the thyroid in multiple endocrine neoplasia type 2.</strong> Hum. Genet. 99: 202-205, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9048921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9048921</a>] [<a href="https://doi.org/10.1007/s004390050339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9048921">Ferraris et al. (1997)</a> showed the carcinomas they studied to be polyclonal in most instances. They used a polymorphic trinucleotide repeat of the X-linked human androgen receptor gene (<a href="/entry/313700">313700</a>) to demonstrate that 10 out of 11 MTCs expressed a polyclonal pattern of X inactivation; furthermore, a significant percentage of cases clinically defined as sporadic showed a polyclonal pattern. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9048921" 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="Brandi, M. L., Gagel, R. F., Angeli, A., Bilezikian, J. P., Beck-Peccoz, P., Bordi, C., Conte-Devolx, B., Falchetti, A., Gheri, R. G., Libroia, A., Lips, C. J. M., Lombardi, G., and 12 others. <strong>Guidelines for diagnosis and therapy of MEN type 1 and type 2.</strong> J. Clin. Endocr. Metab. 86: 5658-5671, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11739416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11739416</a>] [<a href="https://doi.org/10.1210/jcem.86.12.8070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11739416">Brandi et al. (2001)</a> authored a consensus statement covering the diagnosis and management of MEN1 (<a href="/entry/131100">131100</a>) and MEN2, including important contrasts between them. The most common tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial MTC. They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11739416" 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="#33" class="mim-tip-reference" title="Gourgiotis, L., Sarlis, N. J., Reynolds, J. C., Vanwaes, C., Merino, M. J., Pacak, K. <strong>Localization of medullary thyroid carcinoma metastasis in a multiple endocrine neoplasia type 2A patient by 6-[18F]-fluorodopamine positron emission tomography.</strong> J. Clin. Endocr. Metab. 88: 637-641, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12574193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12574193</a>] [<a href="https://doi.org/10.1210/jc.2002-021354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12574193">Gourgiotis et al. (2003)</a> reported the case of a 42-year-old woman with MEN2A in whom biopsy-proven recurrent MTC was detected by 6-[18F]fluorodopamine PET scanning. The study showed a focus of radionuclide accumulation corresponding to the parapharyngeal mass. After resection of the latter, pathology confirmed metastatic MTC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12574193" 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>Medullary thyroid carcinoma is the most common cause of death in patients with MEN2A. <a href="#96" class="mim-tip-reference" title="Skinner, M. A., Moley, J. A., Dilley, W. G., Owzar, K., DeBenedetti, M. K., Wells, S. A., Jr. <strong>Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A.</strong> New Eng. J. Med. 353: 1105-1113, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16162881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16162881</a>] [<a href="https://doi.org/10.1056/NEJMoa043999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16162881">Skinner et al. (2005)</a> sought to determine whether total thyroidectomy in asymptomatic young members of kindreds with this genetic disorder who had a mutated allele in the RET protooncogene (<a href="/entry/164761">164761</a>) could prevent or cure medullary thyroid carcinoma. In a total of 50 patients of 19 years of age or younger who were consecutively identified through a genetic screening program as carriers of a RET mutations characteristic of MEN2A underwent total thyroidectomy. Five to 10 years after surgery, each patient was evaluated by physical examination and by determination of plasma calcitonin levels after stimulation with provocative agents, mainly combined calcium and pentagastrin. In 44 of the 50 patients, basal and stimulated plasma calcitonin levels were at or below the limits of detection of the assay. The data suggested that there was a lower incidence of persistent or recurrent disease in children who underwent total thyroidectomy before 8 years of age and in children in whom there were no metastases to cervical lymph nodes. <a href="#96" class="mim-tip-reference" title="Skinner, M. A., Moley, J. A., Dilley, W. G., Owzar, K., DeBenedetti, M. K., Wells, S. A., Jr. <strong>Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A.</strong> New Eng. J. Med. 353: 1105-1113, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16162881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16162881</a>] [<a href="https://doi.org/10.1056/NEJMoa043999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16162881">Skinner et al. (2005)</a> concluded that a longer period of evaluation would be necessary to confirm that the subjects are cured. <a href="#70" class="mim-tip-reference" title="Moore, F. D., Dluhy, R. G. <strong>Prophylactic thyroidectomy in MEN-2A: a stitch in time? (Editorial)</strong> New Eng. J. Med. 353: 1162-1164, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16162888/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16162888</a>] [<a href="https://doi.org/10.1056/NEJMe058182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16162888">Moore and Dluhy (2005)</a> reviewed considerations that led to several conclusions. First, this complex pediatric endocrine surgery should be conducted at centers with expert teams of surgeons, endocrinologists, anesthesiologists, geneticists, and pediatricians. An integral member of such a team at most centers should be a genetic counselor who constructs family pedigrees, arranges for screening of persons at risk, and provides information and emotional support to the patient and the family. Second, surgery should occur at the earliest stage at which the team can perform it safely. In the absence of completely definitive data linking genotype to phenotype, the age at which surgery is safe is likely to be 3 years or younger. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16162888+16162881" 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>See <a href="/entry/171300">171300</a> for a review of the original description of classic pheochromocytoma (<a href="#26" class="mim-tip-reference" title="Frankel, F. <strong>Ein Fall von doppelseitigem, vollig latent verlaufenen Nebennierentumor und gleichzeitiger Nephritis mit Veranderungen am Circulationsapparat und Retinitis.</strong> Arch. Path. Anat. Physiol. Klin. Med. 103: 244-263, 1886."None>Frankel, 1886</a>) and follow-up of the patient's living relatives, which revealed the presence of MEN2A in the family.</p>
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<a href="#Anderson1971" class="mim-tip-reference" title="Anderson, T. E., Spackman, T. J., Schwartz, S. S. <strong>Roentgen findings in intestinal ganglioneuromatosis: its association with medullary thyroid carcinoma and pheochromocytoma.</strong> Radiology 101: 93-96, 1971.">Anderson et al. (1971)</a>; <a href="#Baylin1978" class="mim-tip-reference" title="Baylin, S. B., Hsu, S. H., Gann, D. S., Smallridge, R. C., Wells, S. A., Jr. <strong>Inherited medullary thyroid carcinoma: a final monoclonal mutation in one of multiple clones of susceptible cells.</strong> Science 199: 429-431, 1978.">Baylin et al. (1978)</a>; <a href="#Block1967" class="mim-tip-reference" title="Block, M. A., Horn, R. C., Jr., Miller, J. M., Barrett, J. L., Brush, B. E. <strong>Familial medullary carcinoma of the thyroid.</strong> Ann. Surg. 166: 403-412, 1967.">Block et al. (1967)</a>; <a href="#Cerny1982" class="mim-tip-reference" title="Cerny, J. C., Jackson, C. E., Talpos, G. B., Yott, J. B., Lee, M. W. <strong>Pheochromocytoma in multiple endocrine neoplasia type II: an example of the two-hit theory of neoplasia.</strong> Surgery 92: 849-852, 1982.">Cerny et al. (1982)</a>; <a href="#Cushman1962" class="mim-tip-reference" title="Cushman, P., Jr. <strong>Familial endocrine tumors: report of two unrelated kindreds affected with pheochromocytomas, one also with multiple thyroid carcinomas.</strong> Am. J. Med. 32: 352-360, 1962.">Cushman (1962)</a>; <a href="#Farrer1987" class="mim-tip-reference" title="Farrer, L. A., Goodfellow, P. J., White, B. N., Holden, J. J. A., Kidd, J. R., Simpson, N. E., Kidd, K. K. <strong>Linkage analysis of multiple endocrine neoplasia type 2A (MEN-2A) and three DNA markers on chromosome 20: evidence against synteny.</strong> Cancer Genet. Cytogenet. 27: 327-334, 1987.">Farrer et al. (1987)</a>; <a href="#Francke1985" class="mim-tip-reference" title="Francke, U. <strong>Personal Communication.</strong> New Haven, Conn. 1985.">Francke
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(1985)</a>; <a href="#Gagel1982" class="mim-tip-reference" title="Gagel, R. F., Jackson, C. E., Block, M. A., Feldman, Z. T., Reichlin, S., Hamilton, B. P., Tashjian, A. H., Jr. <strong>Age-related probability of development of hereditary medullary thyroid carcinoma.</strong> J. Pediat. 101: 941-946, 1982.">Gagel et al. (1982)</a>; <a href="#Graze1978" class="mim-tip-reference" title="Graze, K. <strong>Natural history of a familial medullary thyroid carcinoma.</strong> New Eng. J. Med. 299: 980-985, 1978.">Graze (1978)</a>; <a href="#Li1974" class="mim-tip-reference" title="Li, F. P., Melvin, K. E. W., Tashjian, A. H., Jr., Levine, P. H., Fraumeni, J. F., Jr. <strong>Familial medullary thyroid carcinoma and pheochromocytoma: epidemiologic investigations.</strong> J. Nat. Cancer Inst. 52: 285-287, 1974.">Li et al. (1974)</a>; <a href="#Lima1971" class="mim-tip-reference" title="Lima, J. B., Smith, P. D. <strong>Sipple's syndrome (pheochromocytoma and thyroid carcinoma) with bilateral breast carcinoma.</strong> Am. J. Surg. 121: 732-735, 1971.">Lima and
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Smith (1971)</a>; <a href="#Lips1978" class="mim-tip-reference" title="Lips, C. J. M., Minder, W. H., Leo, J. R., Alleman, A., Hackeng, W. H. L. <strong>Evidence of multicentric origin of the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome) in a large family in the Netherlands: diagnostic and therapeutic implications.</strong> Am. J. Med. 64: 569-578, 1978.">Lips et al. (1978)</a>; <a href="#Lips1981" class="mim-tip-reference" title="Lips, C. J. M., Van der Sluys Veer, J., Struyvenberg, A., Alleman, A., Leo, J. R., Wittebol, P., Minder, W. H., Kooiker, C. J., Geerdink, R. A., Van Waes, P. F. G. M., Hackeng, W. H. L. <strong>Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome).</strong> Am. J. Med. 70: 1051-1060, 1981.">Lips et al. (1981)</a>; <a href="#Mathew1987" class="mim-tip-reference" title="Mathew, C. G. P., Smith, B. A., Thorpe, K., Wong, Z., Royle, N. J., Jeffreys, A. J., Ponder, B. A. J. <strong>Deletion of genes on chromosome 1 in endocrine neoplasia.</strong> Nature 328: 524-526, 1987.">Mathew et al.
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(1987)</a>; <a href="#O'Dorisio1982" class="mim-tip-reference" title="O'Dorisio, T. M., Falko, J. M., Cataland, S., Almoney, R. W., George, J. M., Mazzaferri, E. L., Reynolds, J. C. <strong>Gastrin responses to a test meal in patients with familial medullary thyroid carcinoma.</strong> J. Clin. Endocr. Metab. 54: 798-802, 1982.">O'Dorisio et al. (1982)</a>; <a href="#Pearson1985" class="mim-tip-reference" title="Pearson, P. L. <strong>Personal Communication.</strong> Leiden, The Netherlands 1985.">Pearson (1985)</a>; <a href="#Ponder1993" class="mim-tip-reference" title="Ponder, B. A. J. <strong>Personal Communication.</strong> Cambridge, England 5/30/1993.">Ponder (1993)</a>; <a href="#Sarosi1968" class="mim-tip-reference" title="Sarosi, G., Doe, R. P. <strong>Familial occurrence of parathyroid adenomas, pheochromocytoma, and medullary carcinoma of the thyroid with amyloid stroma (Sipple's syndrome).</strong> Ann. Intern. Med. 68: 1305-1309, 1968.">Sarosi and Doe (1968)</a>; <a href="#Simpson1987" class="mim-tip-reference" title="Simpson, N. E., Kidd, K. K., Goodfellow, P. J., McDermid, H., Myers, S., Kidd, J. R., Jackson, C. E., Duncan, A. M. V., Farrer, L. A., Brasch, K., Castiglione, C., Genel, M., Gertner, J., Greenberg, C. R., Gusella, J. F., Holden, J. J. A., White, B. N. <strong>Linkage of multiple endocrine neoplasia type 2A (MEN2A) and a new DNA marker (D10S5) at 10q21.1. (Abstract)</strong> Cytogenet. Cell Genet. 46: 693 only, 1987.">Simpson et al. (1987)</a>; <a href="#Sipple1961" class="mim-tip-reference" title="Sipple, J. H. <strong>The association of pheochromocytoma with carcinoma of the thyroid gland.</strong> Am. J. Med. 31: 163-166, 1961.">Sipple (1961)</a>; <a href="#Sobol1989" class="mim-tip-reference" title="Sobol, H., Narod, S. A., Nakamura, Y., Boneu, A., Calmettes, C., Chadenas, D., Charpentier, G., Chatal, J. F., Delepine, N., Delisle, M. J. <strong>Screening for multiple endocrine neoplasia type 2a with DNA-polymorphism analysis.</strong> New Eng. J. Med. 321: 996-1001, 1989.">Sobol et
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al. (1989)</a>; <a href="#Tashjian1968" class="mim-tip-reference" title="Tashjian, A. H., Jr., Melvin, K. E. W. <strong>Medullary carcinoma of the thyroid: thyrocalcitonin in plasma and tumor.</strong> New Eng. J. Med. 279: 279-283, 1968.">Tashjian and Melvin (1968)</a>; <a href="#Valk1981" class="mim-tip-reference" title="Valk, T. W., Frager, M. S., Gross, M. D., Sisson, J. C., Wieland, D. M., Swanson, D. P., Mangner, T. J., Beierwaltes, W. H. <strong>Spectrum of pheochromocytoma in multiple endocrine neoplasia: a scintigraphic portrayal using (131)I-metaiodobenzylguanidine.</strong> Ann. Intern. Med. 94: 762-767, 1981.">Valk et al. (1981)</a>; <a href="#Wood1979" class="mim-tip-reference" title="Wood, D. <strong>Multiple endocrine neoplasia II at Hartford Hospital.</strong> Hartford Hosp. Bull. 32: 121-134, 1979.">Wood
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Abu-Amero, K. K., Alzahrani, A. S., Zou, M., Shi, Y.
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<strong>Association of mitochondrial DNA transversion mutations with familial medullary thyroid carcinoma/multiple endocrine neoplasia type 2 syndrome.</strong>
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Oncogene 25: 677-684, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16205644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16205644</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16205644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.onc.1209094" target="_blank">Full Text</a>]
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Anderson, T. E., Spackman, T. J., Schwartz, S. S.
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<strong>Roentgen findings in intestinal ganglioneuromatosis: its association with medullary thyroid carcinoma and pheochromocytoma.</strong>
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Radiology 101: 93-96, 1971.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5111989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5111989</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5111989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1148/101.1.93" target="_blank">Full Text</a>]
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Babu, V. R., Jackson, C. E., Van Dyke, D. L.
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<strong>Chromosome 20 deletion in multiple endocrine neoplasia syndrome types 2A and 2B. (Abstract)</strong>
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Clin. Res. 30: 489A only, 1982.
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[<a href="https://doi.org/10.1210/jcem.86.12.8070" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1365-2362.1992.tb01441.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197807202990315" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2002-021254" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa043999" target="_blank">Full Text</a>]
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<div class="">
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18252215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18252215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18252215[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=18252215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2007.10.008" target="_blank">Full Text</a>]
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<a id="Sobol1989" class="mim-anchor"></a>
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<a id="Sobol1989" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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[<a href="https://doi.org/10.1056/NEJM198910123211502" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4386574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4386574</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4386574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1097/00005792-196809000-00001" target="_blank">Full Text</a>]
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<a id="Tashjian1968" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5660301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5660301</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5660301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM196808082790602" target="_blank">Full Text</a>]
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<a id="Tischler1976" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/179139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">179139</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=179139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.179139" target="_blank">Full Text</a>]
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<a id="Urbanski1967" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6047980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6047980</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6047980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0021-9681(67)90040-9" target="_blank">Full Text</a>]
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<a id="104" class="mim-anchor"></a>
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<a id="Valk1981" class="mim-anchor"></a>
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<div class="">
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Valk, T. W., Frager, M. S., Gross, M. D., Sisson, J. C., Wieland, D. M., Swanson, D. P., Mangner, T. J., Beierwaltes, W. H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7235418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7235418</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7235418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.7326/0003-4819-94-6-762" target="_blank">Full Text</a>]
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<a id="Van Dyke1981" class="mim-anchor"></a>
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Van Dyke, D. L., Jackson, C. E., Babu, V. R.
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<strong>Multiple endocrine neoplasia type 2 (MEN-2): an autosomal dominant syndrome with a possible chromosome 20 deletion. (Abstract)</strong>
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<a id="106" class="mim-anchor"></a>
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<a id="Van Dyke1982" class="mim-anchor"></a>
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Van Dyke, D. L., Jackson, C. E., Babu, V. R.
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<a id="107" class="mim-anchor"></a>
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<a id="Vasen1987" class="mim-anchor"></a>
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Vasen, H. F. A., Nieuwenhuijzen Kruseman, A. C., Berkel, H., Beukers, E. K. M., Delprat, C. C., Van Doorn, R. G., Geerdink, R. A., Haak, H. R., Hackeng, W. H. L., Koppeschaar, H. P. F., Krenning, E. P., Lamberts, S. W. J., Lekkerkerker, F. J. F., Michels, R. P. J., Moers, A. M. J., Pieters, G. F. F. M., Wiersinga, W. M., Lips, C. J. M.
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<strong>Multiple endocrine neoplasia syndrome type 2: the value of screening and central registration: a study of 15 kindreds in The Netherlands.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2890300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2890300</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2890300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0002-9343(87)90641-3" target="_blank">Full Text</a>]
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<a id="108" class="mim-anchor"></a>
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<a id="Wong1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wong, C.-K., Lin, C.-S.
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<strong>Friction amyloidosis.</strong>
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Int. J. Derm. 27: 302-307, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3391726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3391726</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3391726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-4362.1988.tb02357.x" target="_blank">Full Text</a>]
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<a id="Wood1979" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wood, D.
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<strong>Multiple endocrine neoplasia II at Hartford Hospital.</strong>
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Hartford Hosp. Bull. 32: 121-134, 1979.
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Yamamoto, M., Takai, S., Miki, T., Motomura, K., Okazaki, M., Nishisho, I., Tateishi, H., Miyauchi, A., Honjo, T., Pakstis, A. J., Mori, T.
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<strong>Close linkage of MEN2A with RBP3 locus in Japanese kindreds.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2567278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2567278</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2567278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00291173" target="_blank">Full Text</a>]
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<a id="111" class="mim-anchor"></a>
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Zatterale, A., Stabile, M., Nunziata, V., Di Giovanni, G., Vecchione, R., Ventruto, V.
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<strong>Multiple endocrine neoplasia type 2 (Sipple's syndrome): clinical and cytogenetic analysis of a kindred.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6143828/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6143828</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6143828" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.21.2.108" target="_blank">Full Text</a>]
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<br />
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 4/3/2014
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 2/12/2007<br>Cassandra L. Kniffin - updated : 5/2/2006<br>Victor A. McKusick - updated : 10/17/2005<br>John A. Phillips, III - updated : 9/11/2003<br>John A. Phillips, III - updated : 8/28/2003<br>Victor A. McKusick - updated : 9/26/2002<br>John A. Phillips, III - updated : 5/22/2002<br>John A. Phillips, III - updated : 7/11/2001<br>Victor A. McKusick - updated : 2/13/1997<br>Moyra Smith - updated : 1/27/1997
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Creation Date:
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Victor A. McKusick : 6/2/1986
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carol : 11/18/2024<br>carol : 01/11/2022<br>mcolton : 08/12/2014<br>carol : 4/8/2014<br>ckniffin : 4/3/2014<br>carol : 9/19/2013<br>carol : 7/8/2013<br>terry : 5/25/2012<br>wwang : 7/6/2010<br>terry : 6/3/2009<br>carol : 1/31/2008<br>alopez : 10/26/2007<br>carol : 5/3/2007<br>wwang : 2/12/2007<br>carol : 2/12/2007<br>wwang : 5/4/2006<br>ckniffin : 5/2/2006<br>ckniffin : 1/6/2006<br>alopez : 10/24/2005<br>terry : 10/17/2005<br>terry : 6/25/2004<br>alopez : 9/11/2003<br>alopez : 8/28/2003<br>alopez : 1/8/2003<br>carol : 9/30/2002<br>tkritzer : 9/26/2002<br>tkritzer : 9/26/2002<br>alopez : 5/22/2002<br>alopez : 7/11/2001<br>alopez : 3/13/2001<br>terry : 5/5/1999<br>mark : 7/16/1997<br>alopez : 7/10/1997<br>alopez : 7/10/1997<br>alopez : 7/10/1997<br>alopez : 6/2/1997<br>mark : 2/13/1997<br>mark : 2/13/1997<br>terry : 2/12/1997<br>terry : 1/27/1997<br>mark : 1/24/1997<br>mark : 8/18/1995<br>pfoster : 7/10/1995<br>carol : 9/23/1994<br>davew : 8/18/1994<br>mimadm : 5/5/1994<br>warfield : 4/12/1994
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<h3>
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<span class="mim-font">
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<strong>#</strong> 171400
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</h3>
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<h3>
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<span class="mim-font">
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MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA; MEN2A
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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PHEOCHROMOCYTOMA AND AMYLOID-PRODUCING MEDULLARY THYROID CARCINOMA<br />
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PTC SYNDROME<br />
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SIPPLE SYNDROME
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<span class="mim-font">
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Other entities represented in this entry:
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<span class="h3 mim-font">
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THYROID CARCINOMA, FAMILIAL MEDULLARY, INCLUDED
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<strong>SNOMEDCT:</strong> 721188000;
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<strong>ICD10CM:</strong> E31.22;
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<strong>ICD9CM:</strong> 258.02;
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<strong>ORPHA:</strong> 247698, 653;
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<strong>DO:</strong> 0050430;
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<strong>Phenotype-Gene Relationships</strong>
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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">
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10q11.21
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<span class="mim-font">
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Multiple endocrine neoplasia IIA
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<span class="mim-font">
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171400
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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RET
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<td>
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<span class="mim-font">
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164761
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</table>
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<span class="mim-font">
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because multiple endocrine neoplasia type IIA (MEN2A) is caused by heterozygous mutation in the RET oncogene (164761) on chromosome 10q11.</p>
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<span class="mim-font">
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<strong>Description</strong>
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<p>Multiple endocrine neoplasia type IIA is an autosomal dominant syndrome of multiple endocrine neoplasms, including medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid adenomas. MEN2B (162300), characterized by MTC with or without pheochromocytoma and with characteristic clinical abnormalities such as ganglioneuromas of the lips, tongue and colon, but without hyperparathyroidism, is also caused by mutation in the RET gene (summary by Lore et al., 2001). </p><p>For a discussion of genetic heterogeneity of multiple endocrine neoplasia, see MEN1 (131100).</p>
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<strong>Clinical Features</strong>
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<p>Schimke and Hartmann (1965) described a syndrome of pheochromocytoma and medullary thyroid carcinoma with abundant amyloid stroma. A similar but distinct condition is described under neuromata, mucosal, with endocrine tumors (MEN2B; 162300). Steiner et al. (1968) described a family with 11 cases in successive generations. The pheochromocytomas were bilateral, parathyroid adenoma was present in several, and one patient had Cushing syndrome. Steiner et al. (1968) referred to this disorder as 'multiple endocrine neoplasia, type II' to distinguish it from the multiple endocrine adenomatosis described by Wermer (MEN1; 131100) and called type I by Steiner et al. (1968). Urbanski (1967) found parathyroid adenoma to be part of the syndrome also. </p><p>Meyer and Abdel-Bari (1968) presented observations consistent with the view that medullary carcinoma is a thyrocalcitonin-producing neoplasm of parafollicular cells of the thyroid. Parathyroid hyperplasia or adenomas in some of these patients may be secondary to hypocalcemic effects of thyrocalcitonin. Johnston et al. (1970), as well as others, have shown calcitonin-secretion by medullary thyroid carcinoma. </p><p>Kaplan et al. (1970) showed that the adrenal medulla produces a calcitonin-like material indistinguishable from that of the thyroid by bio- and radioimmunoassay. They suggested that the parafollicular cells of the thyroid are of neural crest origin. The finding that medullary carcinoma of the thyroid arises from parafollicular cells and that, like the cell of origin, it sometimes produces thyrocalcitonin may account for the association of parathyroid hyperplasia and perhaps parathyroid adenoma. Poloyan et al. (1970) was impressed with the histologic similarity between the medullary thyroid cancer and pheochromocytoma metastases. Keiser et al. (1973) pointed out that histaminase is useful in the identification of metastases of medullary carcinoma. In their opinion parathyroid adenomas are a primary feature of the disorder. </p><p>Pearson et al. (1973) studied 21 members of a kindred with surgically confirmed multiple endocrine neoplasms. All 21 had medullary carcinoma of the thyroid. Adrenal pheochromocytomas were present in 10 and were bilateral in 6. Three had one or more parathyroid glands showing adenomatous hyperplasia and 10 showed chief cell hyperplasia. The thyroid cancer metastasized to other areas including the liver, lungs, and bone in several of the patients. All patients had elevated peripheral thyrocalcitonin. Peripheral parathyroid hormone was elevated in only 2; however, parathyroid hormone was elevated in the inferior thyroid vein of all patients examined. Hamilton et al. (1978) suggested that an increased urinary epinephrine fraction is a sensitive and reliable screening test for pheochromocytoma in MEN II, comparable to the calcitonin radioimmunoassay for medullary carcinoma of the thyroid. </p><p>Carney et al. (1975) found bilateral adrenal medullary hyperplasia in an asymptomatic 12-year-old girl. She had bilateral thyroid carcinoma and hyperparathyroidism. The adrenals were explored because of elevated urinary levels of vanillylmandelic acid. Migrating neural crest cells are able to decarboxylate and store precursors of aromatic amines that fluoresce after exposure to formaldehyde vapor. The last is a method for identifying neural crest origin of enterochromaffin, argyrophil cells of the bronchi, islets of Langerhans, and parafollicular cells of the thyroid, among others. These are collectively termed the amine precursor uptake and decarboxylase (APUD) system (Pearse, 1969). Tischler et al. (1976) extended the evidence of neural origin by demonstrating that cultured cells from medullary carcinoma of the thyroid, bronchial carcinoid, and pheochromocytoma display all-or-nothing action potentials of short duration. </p><p>Easton et al. (1989) estimated on the basis of clinical history that 41% of gene carriers are asymptomatic at age 70. Screening by the standard tests for detecting the earliest manifestations of the syndrome increased the penetrance to an estimated 93% by age 31. There was some suggestion of an earlier onset of medullary thyroid cancer in female gene carriers, and of a tendency for pheochromocytoma to cluster in families. </p><p>Chen et al. (2023) reported a 3-generation family with MEN2A. The proband was diagnosed with a left adrenal pheochromocytoma at age 31 years and bilateral multiple medullary thyroid carcinoma (MTC) with lymph node metastasis at age 41 years. At age 28 years, his sister had a left adrenal pheochromocytoma and right follicular thyroid carcinoma (later diagnosed pathologically as MTC when she presented with left thyroid MTC at age 45 years). Their father had been diagnosed with left MTC and left pheochromocytoma at age 42 years. The proband's daughter, aged 18 years, had the RET mutation seen in the rest of the family but was without evidence of disease. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Other Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Le Marec et al. (1980) reported congenital megacolon with plexus hyperplasia in a family with Sipple syndrome. Megacolon of this type seems to be more usual in MEN III than in MEN II. Cameron et al. (1978) described the Zollinger-Ellison syndrome with type II MEA, a first. These families represent an overlap of phenotypic features in the 3 forms of MEN. </p><p>Gagel et al. (1989), Nunziata et al. (1989), and Kousseff et al. (1991) observed primary localized cutaneous amyloidosis (PLCA) in association with MEN2A. Gagel et al. (1989) and Kousseff et al. (1991) referred to it as cutaneous lichen amyloidosis. In a family with 6 affected members in 5 generations, a mother and her daughter had interscapular cutaneous pruritic lesions (Kousseff et al., 1991). Kousseff (1992) provided a pedigree and photographs of the skin lesions. Cutaneous lichen amyloidosis as an apparently independent autosomal dominant trait has also been described (105250). The skin deposits of amyloid associated with pruritus in the interscapular region represents a form of 'friction amyloidosis' (Wong and Lin, 1988). It is related to notalgia paresthetica, an inherited neuropathy of the posterior dorsal nerve rami. ('Notalgia' means 'back pain.') The neuropathy hypothesis was supported by the finding of mutations in the RET protooncogene which is expressed in the peripheral and central nervous system. Ceccherini et al. (1994) demonstrated a specific cys634-to-tyr missense mutation (164761.0004) in affected members of a pedigree in which MEN2A was combined with localized cutaneous lichen amyloidosis. </p><p>Skinner et al. (2008) identified 10 different heterozygous mutations in the RET gene (see, e.g., 164761.0053 and 164761.0054) in paraffin-embedded tissue from 7 (37%) of 19 stillborn fetuses with bilateral renal agenesis and in 2 (20%) of 10 stillborn fetuses with unilateral renal agenesis. Two fetuses had 2 RET mutations. Parental DNA was not studied. In vitro functional expression studies showed that the mutations resulted in either constitutive RET phosphorylation or absent phosphorylation. Skinner et al. (2008) postulated a loss-of-function effect. The fetuses did not have evidence of Hirschsprung disease (HSCR; 142623), MEN2A, MEN2B (162300), or familial medullary thyroid carcinoma (155240). However, Skinner et al. (2008) noted that these conditions generally present with clinical findings later in childhood; they may have been present in the fetuses and not detected by standard autopsy. </p><p>Jeanpierre et al. (2011) identified heterozygous variations in the RET gene in 7 (6.6%) of 105 fetuses with severe kidney developmental defects leading to death or termination in utero. Four of the variants were also present in unaffected fathers. In vitro functional studies of most the variants were not performed, but at least 1 was likely a neutral polymorphism. Analysis of 171 additional cases with renal developmental defects showed that the frequency of RET variants was significantly higher in cases compared to controls, suggesting that variants may confer predisposition to a spectrum of renal developmental defects. However, Jeanpierre et al. (2011) concluded that genetic alteration of RET is not a major mechanism leading to renal agenesis or kidney developmental defects. </p><p>Hibi et al. (2014) reported a family with MEN2A associated with a heterozygous RET mutation (C618R; 164761.0025). The female proband had MTC and pheochromocytoma, and her brother died of MTC at age 45 years. The proband had 3 asymptomatic sons, all of whom carried the C618R mutation. Two of the sons were found to have unilateral renal agenesis, and 1 also had Hirschsprung disease. Hibi et al. (2014) noted that knockout of Ret in mice results in loss of enteric neurons as well as renal agenesis or severe dysgenesis (Schuchardt et al., 1994). The findings in the family reported by Hibi et al. (2014) supported the hypothesis that a constitutively active RET mutation might partially impair RET function and thereby cause loss of function phenotypes, such as renal agenesis or HSCR. However, Hibi et al. (2014) concluded that renal agenesis/dysgenesis is probably extremely rare in patients with RET mutations. </p><p>Hwang et al. (2014) identified 3 different heterozygous RET missense mutations in 3 of 650 different families with various congenital anomalies of the kidney and urinary tract (CAKUT) who were screened for mutations in the coding regions of 12 known dominant renal disease-causing genes. Although clinical details were sparse, the renal phenotype of these patients included renal hypodysplasia, unilateral renal agenesis, vesicoureteral reflux, ureteropelvic junction obstruction, duplex collecting system, and ureterocele. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Eisenhofer et al. (2001) examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in MEN2 and von Hippel-Lindau syndrome to underlying differences in the expression of tyrosine hydroxylase (TH; 191290), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT; 171190), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN2 patients and 30 von Hippel-Lindau patients with adrenal pheochromocytomas. MEN2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than von Hippel-Lindau patients. MEN2 patients all had elevated plasma concentrations of the epinephrine metabolite metanephrine, whereas von Hippel-Lindau patients showed specific increases in the norepinephrine metabolite normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from von Hippel-Lindau than from MEN2 patients. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>In affected members of 7 families, Van Dyke et al. (1982) found a small deletion of chromosome 20p12.2 segregating with MEN II. Van Dyke et al. (1981) demonstrated the 20p deletion in 16 cases of MEN II in 7 families, and in 1 case of MEN III. Hsu et al. (1981) found a higher frequency of metaphases with chromosome and chromatid abnormalities (average, 11.0%) in cases of Sipple syndrome than in controls (average, 3.8%). In one pair of sibs, they failed to find the same deletion in chromosome 20. Jackson (1982) stated that his group had correctly identified 18 persons in blinded studies. A small deletion was found in 18 members of 8 families with Sipple syndrome and also in 2 unrelated patients with MEN III. See Babu et al. (1982). Although, as they pointed out, their experience is not proof of the absence of deletion, Gustavson et al. (1983) could not demonstrate such by high resolution banding in either MEN I or MEN II. </p><p>High resolution cytogenetics in 5 persons studied by Emmertsen et al. (1983) showed no deletion in band 20p12.2. In both MEN2A and MEN2B, Babu et al. (1984) reported the finding of an interstitial deletion in band 20p12.2. In a double-blind study, 2 of 13 controls were thought to have the deletion; all 9 blood samples from 8 affected members of 4 MEN2A families were found to have the deletion; from 3 MEN2B families, 5 blood samples from 4 affected members showed the deletion, whereas 3 did not. The authors suggested that these 2 entities are genetically closely related; that the dominant expression of the mutation at 20p12.2 is hyperplasia of thyroid C cells and adrenal medullary cells; that in accordance with Knudson's 2-mutation-event theory and in analogy to retinoblastoma, thyroid cancer and pheochromocytoma are recessive manifestations. Zatterale et al. (1984) could not detect a 20p12.2 deletion in prometaphase banding studies. </p><p>Babu et al. (1987) reported on an expanded double-blind study of chromosome 20 deletion in MEN2A and MEN2B. A deletion in 20p12.2 was found in 15 of 21 MEN2A patients and in 4 of 8 MEN2B patients. These findings await explanation since the locus for these disorders maps elsewhere. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Jackson et al. (1976) found a suggestion of linkage to P blood group (111400) but not to HLA. Simpson et al. (1979) found 23.1% recombination between MEN II and HLA, but this linkage was rendered highly unlikely by further studies by Simpson and Falk (1982). Jackson et al. (1979) concluded that medullary thyroid cancer fits a 2-mutation theory. They suggested that C-cell hyperplasia is the gene-determined first mutational event and cancer the second. </p><p>Emmertsen et al. (1983) found no significantly positive lod scores between MEN II and 25 different genetic markers. </p><p>Simpson et al. (1984) assigned the calcitonin gene to chromosome 11 by use of a cDNA clone isolated from medullary thyroid carcinoma and a somatic cell hybrid panel. With a TaqI RFLP detected by this probe, they studied linkage of the calcitonin locus and MEN2; negative lod scores were found at all recombination values. Goodfellow et al. (1984) studied linkage between MEN2 and DNA probes assigned to 20p12.2 by in situ hybridization. Negative lod scores were obtained.</p><p>In 2 large MEN2A pedigrees, Goodfellow et al. (1985) studied linkage with 2 RFLPs found in an anonymous DNA segment D20S5, which had been isolated from a chromosome 19/20 flow-sorted library and shown by in situ hybridization to be located at 20p12. Linkage was excluded at theta equal to or less than 0.13. In studies of a single large kindred, Kruger et al. (1986) excluded close linkage with several markers and found no statistically significant linkage with any marker. Low positive lod scores were obtained with GC (139200), GPT (138200) and HP (140100). Perrier et al. (1987) found no linkage of MEN2 and HLA. By multipoint linkage analysis, Farrer et al. (1987) excluded a large portion of chromosome 13 as the site of the MEN2A locus. Farrer et al. (1987) could find no linkage of MEN2A to 3 DNA markers that mapped to chromosome 20. </p><p>Simpson et al. (1987) performed linkage studies in 5 families, each with at least 1 member found to have a deletion at 20p12.2. In these families, the MEN2 locus was found to be linked to a DNA marker on chromosome 10, D10S5, which by in situ hybridization maps to 10q21.1. The maximal lod score was 3.58 for a recombination fraction of 0.19. With 2 RFLPs recognized by an RBP3 probe (180290), Simpson et al. (1987) found a maximal lod score of 8.0 at theta = 0.11. </p><p>In studies of 5 Japanese families, Yamamoto et al. (1989) found that MEN2A is closely linked to RBP3; the maximum lod score was 5.19 at a recombination fraction of 0.00. In 2 kindreds, Mathew et al. (1987) found a maximal lod score of 3.88 at theta = 0.04 for linkage with RBP3, which has been positioned at 10p11.2-q11.2. </p><p>Sobol et al. (1989) reported on linkage studies in 35 families with medullary carcinoma of the thyroid with or without pheochromocytoma. Their results suggested that a susceptibility gene for hereditary medullary carcinoma of the thyroid may be located at the same locus on chromosome 10 as that of MEN2A. Narod et al. (1989) did linkage studies in 18 families, 9 with MEN2A and 9 with medullary carcinoma of the thyroid without pheochromocytoma, with probes specific for the pericentromeric region of chromosome 10 and concluded that the mutations for the 2 presentations are closely situated. Genetic heterogeneity of the susceptibility locus was not seen among these 18 families. The genetic mutation for medullary carcinoma was in disequilibrium with alleles at 2 closely linked markers. </p><p>Using a panel of markers from the pericentric region of chromosome 10, Lairmore et al. (1991) performed linkage studies in 2 large families with medullary thyroid carcinoma (MTC1) and 6 families with MEN2B. The maximum lod score between MTC1 and marker D10Z1 was 5.88 with 0% recombination. MEN2B showed similarly tight linkage to D10Z1, with a maximum lod score of 3.58 at 0% recombination. The multipoint lod score for MEN2B at D10Z1 was 4.08. Linkage studies in a single large MEN2A kindred showed tight linkage to D10Z1 in this condition as well, with a maximum multipoint lod score of 7.04 at a recombination fraction of 0. The highest lod score obtained was between MEN2A and the haplotyped locus RBP3 with a lod score of 11.33 at a recombination fraction of 0. Linkage data between MEN2A and 3 additional markers on 10q, as well as between MEN2A and the FNRB locus (135630) on 10p11.2, were also presented. Lairmore et al. (1991) found no evidence for genetic heterogeneity among families with MEN2A, MEN2B, and MTC. In 2 families with medullary thyroid carcinoma with parathyroid tumors alone, Carson et al. (1990) demonstrated that the disorder was closely linked to 2 markers in the vicinity of the centromere of chromosome 10, namely, RBP3 and D10Z1. Using a centromeric marker at the D10Z1 locus in 30 families with MEN2A, Narod et al. (1991) demonstrated tight linkage with the centromere. </p><p>Brooks-Wilson et al. (1992) characterized a dense cluster of CpG islands at D10S94 in proximal 10q11.2. No recombinants between D10S94 and MEN2A had been identified. They generated a 570-kb restriction map by pulsed field gel electrophoresis. Six CpG islands were clustered within a 180-kb region. They suggested that these CpG islands may represent the 5-prime ends of candidate genes for MEN2A, MEN2B, and/or MTC1. </p><p>McDonald et al. (1992) further identified an MEN2A candidate gene by use of an evolutionarily conserved sequence from D10S94. The gene spanned 11 kb and had an unmethylated CpG island at its 5-prime end. It encoded a putative 415-amino acid polypeptide similar in sequence to nucleolin (164035), an abundant nucleolar protein. In a patient with MEN2A, they found no difference in the candidate gene, termed mcs94-1, from the MEN2A chromosome or its wildtype homolog. </p><p>By genetic linkage analysis, Gardner et al. (1993) demonstrated that the MEN2A gene is located in a small region of 10q11.2 flanked by D10S141 proximally and D10S94 distally, these 2 markers being separated by a sex-average genetic distance of 0.55 cM. Mole et al. (1993) constructed a YAC contig spanning 1.1 Mb of band 10q11.2 which must include MEN2A because it encompassed 3 markers, D10S141, RET, and D10S94. A 480-kb region separated D10S141 and D10S94. </p><p>Janson et al. (1991) constructed a physical map of the MEN2 region by combining data from pulsed field gel electrophoresis (PFGE) with those generated from a panel of radiation-reduced somatic cell hybrids. Comparison of the physical map with the linkage map showed a recombination rate higher than expected: thus, for the closest pair of linked markers on the centromeric side of MEN2, 1 centimorgan corresponded to approximately 300 kb, and for markers on the telomeric side, 1 centimorgan corresponded to approximately 350 to 600 kb. There is evidence from other sources that the 11q12-q13 region is unusual in having a high G-C content, suggesting a high concentration of genes and other characteristics including increased meiotic recombination usually associated with telomeric regions (Saccone et al., 1992). </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</h4>
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<p>Mathew et al. (1987) found deletion of a hypervariable region of DNA on 1p in 7 of 14 tumors (pheochromocytomas and medullary carcinomas) developing in patients with MEN2. In 1 of 2 families examined, the deleted chromosome was that inherited from the affected parent. Thus, the site of deletion presumably does not represent the location of the inherited gene. The deleted region was distal to the breakpoint commonly detected in neuroblastomas (256700), which share with the tumors of MEN2 embryologic origin from neuroectoderm. The most frequent breakpoint involved in neuroblastomas is 1p32, whereas the genes deleted in the tumors studied by Mathew et al. (1987) were located at 1p35-p33. </p><p>In an analysis of tumor DNA from 42 patients with MEN2A, Landsvater et al. (1989) showed that markers on chromosome 10 were lost in only 1 tumor, a result that contrasts with studies in other tumors for which both familial and sporadic cases are known. </p><p>That MEN2A is genetically heterogeneous is suggested by the linkage in some families to markers at the 10q11.2 region and the lack of linkage in other families. The basis of the above subclassification, whether different mutations in one gene or mutations in adjacent genes in the 10q11.2 region, is not clear (Simpson, 1992). The subclasses do seem to 'breed true' in different families.</p><p>In a panel of 34 families with MEN2A, Narod et al. (1992) found no evidence of genetic heterogeneity. No recombination was observed between MEN2A and any of 4 DNA marker loci. Narod et al. (1992) constructed haplotypes for 11 polymorphisms in the MEN2A region for mutation-bearing chromosomes in 24 French families and for 100 spouse controls. One haplotype was present in 4 MEN2A families but was not observed in any control (P = less than 0.01). Two additional families shared a core segment of this haplotype near the MEN2A gene. Narod et al. (1992) suggested that these 6 families had a common affected ancestor. Because the incidence of pheochromocytoma among carriers varied from 0.0 to 74% in these 6 families, they suggested that additional factors modify the expression of the gene. </p><p>Curiously, the most consistent molecular genetic abnormality that has been found in pheochromocytomas and medullary thyroid cancers, either sporadic or part of MEN2, is loss of heterozygosity (LOH) on 1p. Using RFLP analysis, Moley et al. (1992) identified loss of all or a portion of 1p in 12 of 18 pheochromocytomas. LOH of 1p was found in all 9 pheochromocytomas in MEN2A and MEN2B patients, compared with only 2 of 7 sporadic pheochromocytomas. They also found 1p LOH in the pheochromocytoma of 1 of 2 von Hippel-Lindau patients (193300). LOH on 1p was noted in only 3 of 24 informative medullary thyroid carcinomas, and these were from patients with MEN2A. </p><p>Mulligan et al. (1993) identified missense mutations in the RET protooncogene in 20 of 23 apparently distinct MEN2A families, but not in 23 normal controls. Of these 20 mutations, 19 affected the same conserved cysteine residue at the boundary of the RET extracellular and intracellular domains. </p><p>Quadro et al. (2001) reported a patient affected by MEN2A bearing a heterozygous cys634-to-arg (164761.0011) germline mutation in exon 11 and an additional somatic mutation (164761.0012) of the RET protooncogene. A large intragenic deletion spanning exon 4 to exon 16 affected the normal allele and was detected by quantitative PCR, Southern blot analysis, and screening of several polymorphic markers. This deletion causes RET loss of heterozygosity exclusively in the metastasis and not in the primary tumor, thus suggesting a role for this second mutational event in tumor progression. No additional mutations were found in the other exons analyzed. The authors concluded that this unusual genetic profile may be related to the clinical course and very poor outcome. </p><p>Huang et al. (2000) and Koch et al. (2001) identified 2 second-hit mechanisms involved in the development of MEN2-associated tumors: trisomy 10 with duplication of the mutant RET allele and loss of the wildtype RET allele. However, some of the MEN2-associated tumors investigated did not demonstrate either mechanism. Huang et al. (2003) studied the TT cell line, derived from MEN2-associated medullary thyroid carcinoma with a RET germline mutation in codon 634, for alternative mechanisms of tumorigenesis. Although they observed a 2-to-1 ratio between mutant and wildtype RET at the genomic DNA level in this cell line, FISH analysis revealed neither trisomy 10 nor loss of the normal chromosome 10. Instead, a tandem duplication event was responsible for amplification of mutant RET. In further studies Huang et al. (2003) demonstrated for the first time that the genomic chromosome 10 abnormalities in this cell line cause an increased production of mutant RET mRNA. The authors concluded that these findings provided evidence for a third second-hit mechanism resulting in overrepresentation and overexpression of mutant RET in MEN2-associated tumors. </p><p>Abu-Amero et al. (2006) identified nonsynonymous germline mitochondrial DNA (mtDNA) mutations in both normal and tumor tissue from 20 (76.9%) of 26 cases of medullary thyroid carcinoma, including 9 (69.2%) of 13 sporadic cases and 11 (84.6%) of 13 familial cases; 10 of 13 familial cases were patients with MEN2. The familial cases tended to have transversion mtDNA mutations rather than transition mutations. All 13 familial cases also had germline RET mutations. Abu-Amero et al. (2006) suggested that mtDNA mutations may be involved in medullary thyroid carcinoma tumorigenesis and/or progression. </p><p>In a 3-generation family with MEN2A, Chen et al. (2023) identified a C634G mutation in the RET gene (164761.0003) in 4 family members. Three of them had been diagnosed with pheochromocytoma and medullary thyroid cancer, while the youngest, aged 18 years, had no evidence of disease. </p>
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<h4>
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<span class="mim-font">
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<strong>Diagnosis</strong>
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</h4>
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<p>In the Netherlands, Vasen et al. (1987) demonstrated the usefulness of screening and a central registry for the long-term follow-up of cases. In an 18-year study of a large kindred, Gagel et al. (1988) found that prospective screening and early treatment of manifestations of multiple endocrine neoplasia can prevent metastasis of medullary thyroid carcinoma and the morbidity and mortality of pheochromocytoma. Medullary carcinoma of the thyroid is the most consistent single manifestation of this disorder and occurs in almost all cases by age 40. Before age 40 in particular, it is necessary to use a provocative test of the combined calcitonin secretagogues enterogastrone and calcium in order to detect the disorder since the basal levels are not elevated (Baylin, 1989). </p><p>As part of a French national program, Sobol et al. (1989) used DNA probes in a genetic linkage study of 130 members of 11 families of European and North African origin who were ascertained through members with MEN2A. No recombination was found between the mutation causing MEN2A and 2 of 3 markers used. All 11 families were informative for at least 1 of the markers and linkage information was adequate to permit genetic counseling in 8 families. Sobol et al. (1989) concluded that RFLP analysis is more useful in predicting the carrier state than conventional endocrine challenge, especially in younger persons, but accuracy is maximal when both methods are used.</p><p>Mathew et al. (1991), including 23 members of the MEN2A International Collaborative Group, described 4 markers from the pericentric region of chromosome 10 that are tightly linked to MEN2A and are useful for testing for carrier status in individuals genetically at risk but showing a negative biochemical screening test for thyroid C-cell hyperplasia. The tests were also accurate for prenatal diagnosis. </p><p>Calmettes et al. (1992) reported the consensus on biochemical and genetic screening formulated by the European Community Concerted Action on the subject of medullary thyroid carcinoma. For biochemical screening, measurement of the basal and pentagastrin- and/or calcium-stimulated serum levels of calcitonin by radioimmunoassay was considered essential starting at the age of 3 and continuing annually until the age of 35. Furthermore, annual screening for pheochromocytoma by measurement of urinary excretion of catecholamines and for hyperparathyroidism by serum calcium determination was considered indicated. Biochemical screening can be reserved for gene carriers in some families; genetic screening using genetic markers can be done with 95% accuracy in informative families whenever DNA is available from at least 2 family members proven to be affected. Total thyroidectomy at an early stage usually cures the patient with medullary thyroid carcinoma. </p><p>On the basis of studies in a very large kindred, Landsvater et al. (1993) found 7 individuals with abnormal calcitonin test results. Five of these people were thyroidectomized, and C-cell hyperplasia was diagnosed. Four were the offspring of a mother at risk for the development of MEN2A who showed, however, normal calcitonin test results throughout the years, whereas the father, who was not at risk, had abnormal test results over a period of 10 years, without evidence of progressive elevation. None of the 7 individuals developed other manifestations of MEN2A. DNA analysis using markers linked to the MEN2A gene demonstrated, with more than 99% likelihood, that none of the persons who could be genotyped was a gene carrier. Thus, C-cell hyperplasia due to some mechanism other than the presence of the MEN2A gene may occur in MEN2A kindreds. </p><p>Schuffenecker et al. (1997) reported that 5.6% to 9% of cases of MEN2A/MTC are de novo cases with no family history. They reported further that new mutations in the RET oncogene in these cases were demonstrated exclusively on the paternal allele. Retrospective analysis on 274 MEN2A cases revealed that in 40.2% of patients pheochromocytoma occurred 2 to 11 years subsequent to MTC. Schuffenecker et al. (1997) concluded that all apparently sporadic MTC patients should be examined for de novo RET mutations. </p><p>Sporadic medullary thyroid carcinoma has usually been found to result from a mutational event occurring at the single-cell level, indicating that they are monoclonal. By clonality assay of medullary carcinoma of the thyroid in MEN type 2, Ferraris et al. (1997) showed the carcinomas they studied to be polyclonal in most instances. They used a polymorphic trinucleotide repeat of the X-linked human androgen receptor gene (313700) to demonstrate that 10 out of 11 MTCs expressed a polyclonal pattern of X inactivation; furthermore, a significant percentage of cases clinically defined as sporadic showed a polyclonal pattern. </p><p>Brandi et al. (2001) authored a consensus statement covering the diagnosis and management of MEN1 (131100) and MEN2, including important contrasts between them. The most common tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial MTC. They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy. </p><p>Gourgiotis et al. (2003) reported the case of a 42-year-old woman with MEN2A in whom biopsy-proven recurrent MTC was detected by 6-[18F]fluorodopamine PET scanning. The study showed a focus of radionuclide accumulation corresponding to the parapharyngeal mass. After resection of the latter, pathology confirmed metastatic MTC. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Clinical Management</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Medullary thyroid carcinoma is the most common cause of death in patients with MEN2A. Skinner et al. (2005) sought to determine whether total thyroidectomy in asymptomatic young members of kindreds with this genetic disorder who had a mutated allele in the RET protooncogene (164761) could prevent or cure medullary thyroid carcinoma. In a total of 50 patients of 19 years of age or younger who were consecutively identified through a genetic screening program as carriers of a RET mutations characteristic of MEN2A underwent total thyroidectomy. Five to 10 years after surgery, each patient was evaluated by physical examination and by determination of plasma calcitonin levels after stimulation with provocative agents, mainly combined calcium and pentagastrin. In 44 of the 50 patients, basal and stimulated plasma calcitonin levels were at or below the limits of detection of the assay. The data suggested that there was a lower incidence of persistent or recurrent disease in children who underwent total thyroidectomy before 8 years of age and in children in whom there were no metastases to cervical lymph nodes. Skinner et al. (2005) concluded that a longer period of evaluation would be necessary to confirm that the subjects are cured. Moore and Dluhy (2005) reviewed considerations that led to several conclusions. First, this complex pediatric endocrine surgery should be conducted at centers with expert teams of surgeons, endocrinologists, anesthesiologists, geneticists, and pediatricians. An integral member of such a team at most centers should be a genetic counselor who constructs family pedigrees, arranges for screening of persons at risk, and provides information and emotional support to the patient and the family. Second, surgery should occur at the earliest stage at which the team can perform it safely. In the absence of completely definitive data linking genotype to phenotype, the age at which surgery is safe is likely to be 3 years or younger. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>See 171300 for a review of the original description of classic pheochromocytoma (Frankel, 1886) and follow-up of the patient's living relatives, which revealed the presence of MEN2A in the family.</p>
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</span>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Anderson et al. (1971); Baylin et al. (1978); Block et al. (1967);
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Cerny et al. (1982); Cushman (1962); Farrer et al. (1987); Francke
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(1985); Gagel et al. (1982); Graze (1978); Li et al. (1974); Lima and
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Smith (1971); Lips et al. (1978); Lips et al. (1981); Mathew et al.
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(1987); O'Dorisio et al. (1982); Pearson (1985); Ponder (1993);
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Sarosi and Doe (1968); Simpson et al. (1987); Sipple (1961); Sobol et
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al. (1989); Tashjian and Melvin (1968); Valk et al. (1981); Wood
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(1979)
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<ol>
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<li>
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<p class="mim-text-font">
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Abu-Amero, K. K., Alzahrani, A. S., Zou, M., Shi, Y.
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<strong>Association of mitochondrial DNA transversion mutations with familial medullary thyroid carcinoma/multiple endocrine neoplasia type 2 syndrome.</strong>
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Oncogene 25: 677-684, 2006.
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[PubMed: 16205644]
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[Full Text: https://doi.org/10.1038/sj.onc.1209094]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Anderson, T. E., Spackman, T. J., Schwartz, S. S.
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<strong>Roentgen findings in intestinal ganglioneuromatosis: its association with medullary thyroid carcinoma and pheochromocytoma.</strong>
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Radiology 101: 93-96, 1971.
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[PubMed: 5111989]
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[Full Text: https://doi.org/10.1148/101.1.93]
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</li>
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<li>
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<p class="mim-text-font">
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Babu, V. R., Jackson, C. E., Van Dyke, D. L.
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<strong>Chromosome 20 deletion in multiple endocrine neoplasia syndrome types 2A and 2B. (Abstract)</strong>
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Clin. Res. 30: 489A only, 1982.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Babu, V. R., Van Dyke, D. L., Flejter, W. L., Jackson, C. E.
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<strong>Chromosome 20 deletion in multiple endocrine neoplasia type 2: expanded double-blind studies.</strong>
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Am. J. Med. Genet. 27: 739-748, 1987.
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[PubMed: 2888311]
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[Full Text: https://doi.org/10.1002/ajmg.1320270336]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Babu, V. R., Van Dyke, D. L., Jackson, C. E.
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<strong>Chromosome 20 deletion in human multiple endocrine neoplasia types 2A and 2B: a double-blind study.</strong>
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Proc. Nat. Acad. Sci. 81: 2525-2528, 1984.
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[PubMed: 6585814]
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[Full Text: https://doi.org/10.1073/pnas.81.8.2525]
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</li>
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<li>
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<p class="mim-text-font">
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Baylin, S. B., Hsu, S. H., Gann, D. S., Smallridge, R. C., Wells, S. A., Jr.
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<strong>Inherited medullary thyroid carcinoma: a final monoclonal mutation in one of multiple clones of susceptible cells.</strong>
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Science 199: 429-431, 1978.
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[PubMed: 619463]
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[Full Text: https://doi.org/10.1126/science.619463]
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<li>
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<p class="mim-text-font">
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Baylin, S. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 4/22/1989.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Block, M. A., Horn, R. C., Jr., Miller, J. M., Barrett, J. L., Brush, B. E.
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<strong>Familial medullary carcinoma of the thyroid.</strong>
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Ann. Surg. 166: 403-412, 1967.
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[PubMed: 6039599]
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[Full Text: https://doi.org/10.1097/00000658-196709000-00008]
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<p class="mim-text-font">
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 4/3/2014<br>Marla J. F. O'Neill - updated : 2/12/2007<br>Cassandra L. Kniffin - updated : 5/2/2006<br>Victor A. McKusick - updated : 10/17/2005<br>John A. Phillips, III - updated : 9/11/2003<br>John A. Phillips, III - updated : 8/28/2003<br>Victor A. McKusick - updated : 9/26/2002<br>John A. Phillips, III - updated : 5/22/2002<br>John A. Phillips, III - updated : 7/11/2001<br>Victor A. McKusick - updated : 2/13/1997<br>Moyra Smith - updated : 1/27/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
|
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
|
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/2/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<br />
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carol : 11/20/2024<br>carol : 11/18/2024<br>carol : 01/11/2022<br>mcolton : 08/12/2014<br>carol : 4/8/2014<br>ckniffin : 4/3/2014<br>carol : 9/19/2013<br>carol : 7/8/2013<br>terry : 5/25/2012<br>wwang : 7/6/2010<br>terry : 6/3/2009<br>carol : 1/31/2008<br>alopez : 10/26/2007<br>carol : 5/3/2007<br>wwang : 2/12/2007<br>carol : 2/12/2007<br>wwang : 5/4/2006<br>ckniffin : 5/2/2006<br>ckniffin : 1/6/2006<br>alopez : 10/24/2005<br>terry : 10/17/2005<br>terry : 6/25/2004<br>alopez : 9/11/2003<br>alopez : 8/28/2003<br>alopez : 1/8/2003<br>carol : 9/30/2002<br>tkritzer : 9/26/2002<br>tkritzer : 9/26/2002<br>alopez : 5/22/2002<br>alopez : 7/11/2001<br>alopez : 3/13/2001<br>terry : 5/5/1999<br>mark : 7/16/1997<br>alopez : 7/10/1997<br>alopez : 7/10/1997<br>alopez : 7/10/1997<br>alopez : 6/2/1997<br>mark : 2/13/1997<br>mark : 2/13/1997<br>terry : 2/12/1997<br>terry : 1/27/1997<br>mark : 1/24/1997<br>mark : 8/18/1995<br>pfoster : 7/10/1995<br>carol : 9/23/1994<br>davew : 8/18/1994<br>mimadm : 5/5/1994<br>warfield : 4/12/1994
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