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Entry
- #131100 - MULTIPLE ENDOCRINE NEOPLASIA, TYPE I; MEN1
- OMIM
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<span class="h4">#131100</span>
<br />
<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/131100"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS131100"> <strong>Phenotypic Series</strong> </a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#clinicalManagement">Clinical Management</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://hprd.org/summary?hprd_id=00564&isoform_id=00564_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://clinicaltrials.gov/search?cond=MULTIPLE ENDOCRINE NEOPLASIA, TYPE I" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=121&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/a2d53674-b569-4310-a2eb-4f9463e19a54/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:10017" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/131100" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:10017" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:131100" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 30664006<br />
<strong>ICD10CM:</strong> E31.21<br />
<strong>ICD9CM:</strong> 258.01<br />
<strong>ORPHA:</strong> 652<br />
<strong>DO:</strong> 10017<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
131100
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
MULTIPLE ENDOCRINE NEOPLASIA, TYPE I; MEN1
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
MEN I<br />
ENDOCRINE ADENOMATOSIS, MULTIPLE<br />
MEA I<br />
WERMER 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">
MEN1 SOMATIC MUTATIONS, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/561?start=-3&limit=10&highlight=561">
11q13.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Multiple endocrine neoplasia 1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/131100"> 131100 </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">
MEN1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613733"> 613733 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/131100" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/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>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/131100" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/131100" 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">
- Intractable peptic ulcer <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851699&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851699</a>]</span><br /> -
Diarrhea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/267060006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">267060006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/62315008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">62315008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R19.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R19.7</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011991&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011991</a>, <a href="https://bioportal.bioontology.org/search?q=C2169706&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2169706</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002014" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002014</a>]</span><br /> -
Zollinger-Ellison syndrome <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/53132006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">53132006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E16.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E16.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0043515&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0043515</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002044" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002044</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002044" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002044</a>]</span><br /> -
Esophagitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16761005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16761005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K20.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K20.90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K20.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K20.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/530.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">530.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/530.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">530.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0014868&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014868</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100633" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100633</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100633" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100633</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">
- Subcutaneous lipomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/762396004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">762396004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1403035&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1403035</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001031" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001031</a>]</span><br /> -
Facial angiofibromas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36025004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36025004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0265319&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265319</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009720" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009720</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009720" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009720</a>]</span><br /> -
Collagenomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/399926001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">399926001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0265978&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265978</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:6000022" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:6000022</a>]</span><br /> -
Cafe-au-lait macules <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/201281002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">201281002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L81.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L81.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221263&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221263</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000957" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000957</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000957" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000957</a>]</span><br /> -
Confetti-like hypopigmented macules <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851705&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851705</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007449" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007449</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007449" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007449</a>]</span><br /> -
Multiple gingival papules <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851706&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851706</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">
- Pancreatic islet cell adenoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851697&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851697</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008261" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008261</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008261" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008261</a>]</span><br /> -
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 /> -
Pituitary adenoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254956000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254956000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0032000&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0032000</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002893" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002893</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002893" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002893</a>]</span><br /> -
Adrenocortical adenomas <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1156661006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1156661006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302826002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302826002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/255036008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">255036008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0206667&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0206667</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008256</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008256</a>]</span><br /> -
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 /> -
Prolactinoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/134209002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">134209002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/34337008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">34337008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0033375&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033375</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006767" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006767</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006767" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006767</a>]</span><br /> -
Glucagonoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/16424000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">16424000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0017689&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017689</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030404" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030404</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030404" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030404</a>]</span><br /> -
Insulinoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0021670&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0021670</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012197" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012197</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012197" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012197</a>]</span><br /> -
Vasointestinal peptide tumor <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851698&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851698</a>]</span><br /> -
Gastrinoma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302824004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302824004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/53132006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">53132006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E16.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E16.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5848106&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5848106</a>, <a href="https://bioportal.bioontology.org/search?q=C0043515&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0043515</a>, <a href="https://bioportal.bioontology.org/search?q=C0017150&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0017150</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002044" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002044</a>]</span><br /> -
Acromegaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74107003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74107003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0001206&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0001206</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033794" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033794</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033794" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033794</a>]</span><br /> -
Thyroid disease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14304000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14304000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E00-E07" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E00-E07</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/E07.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E07.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/240-246.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">240-246.99</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/246.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">246.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2186538&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2186538</a>, <a href="https://bioportal.bioontology.org/search?q=C0040128&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0040128</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000820" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000820</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000820" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000820</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEOPLASIA </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Carcinoid tumors <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D3A.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D3A.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0007095&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0007095</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100570" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100570</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100570" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100570</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Elevated ACTH <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851700&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851700</a>]</span><br /> -
Abnormal secretin test <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851701&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851701</a>]</span><br /> -
Elevated gastrin concentration <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851702&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851702</a>]</span><br /> -
Hypercalcemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/166702002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">166702002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/66931009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">66931009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E83.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E83.52</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/275.42" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">275.42</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020437&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020437</a>, <a href="https://bioportal.bioontology.org/search?q=C5700155&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5700155</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003072</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003072</a>]</span><br /> -
Hypoglycemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237630007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237630007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271327008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271327008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/302866003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">302866003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1179458001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1179458001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E16.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E16.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/251.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">251.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020615&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020615</a>, <a href="https://bioportal.bioontology.org/search?q=C5767385&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5767385</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001943</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001943" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001943</a>]</span><br /> -
Elevated PTH (parathyroid hormone) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851703&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851703</a>]</span><br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the menin gene (MEN1, <a href="/entry/613733#0001">613733.0001</a>)<br />
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<h5>
Multiple endocrine neoplasia
- <a href="/phenotypicSeries/PS131100">PS131100</a>
- 4 Entries
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<strong>Phenotype</strong>
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<strong>Inheritance</strong>
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<strong>Phenotype<br />mapping key</strong>
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<strong>Phenotype<br />MIM number</strong>
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<strong>Gene/Locus</strong>
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<strong>Gene/Locus<br />MIM number</strong>
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<span class="mim-font">
<a href="/geneMap/10/158?start=-3&limit=10&highlight=158"> 10q11.21 </a>
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<span class="mim-font">
<a href="/entry/162300"> Multiple endocrine neoplasia IIB </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/162300"> 162300 </a>
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<span class="mim-font">
<a href="/entry/164761"> RET </a>
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<span class="mim-font">
<a href="/entry/164761"> 164761 </a>
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<span class="mim-font">
<a href="/geneMap/10/158?start=-3&limit=10&highlight=158"> 10q11.21 </a>
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<a href="/entry/171400"> Multiple endocrine neoplasia IIA </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/171400"> 171400 </a>
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<span class="mim-font">
<a href="/entry/164761"> RET </a>
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<span class="mim-font">
<a href="/entry/164761"> 164761 </a>
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<span class="mim-font">
<a href="/geneMap/11/561?start=-3&limit=10&highlight=561"> 11q13.1 </a>
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<a href="/entry/131100"> Multiple endocrine neoplasia 1 </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/131100"> 131100 </a>
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<a href="/entry/613733"> MEN1 </a>
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<span class="mim-font">
<a href="/entry/613733"> 613733 </a>
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<span class="mim-font">
<a href="/geneMap/12/181?start=-3&limit=10&highlight=181"> 12p13.1 </a>
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<a href="/entry/610755"> Multiple endocrine neoplasia, type IV </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
<a href="/entry/610755"> 610755 </a>
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<a href="/entry/600778"> CDKN1B </a>
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<span class="mim-font">
<a href="/entry/600778"> 600778 </a>
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because multiple endocrine neoplasia type I (MEN1) is caused by heterozygous mutation in the MEN1 gene (<a href="/entry/613733">613733</a>) on chromosome 11q13.</p>
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<strong>Description</strong>
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<p>Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant disorder characterized by varying combinations of tumors of parathyroids, pancreatic islets, duodenal endocrine cells, and the anterior pituitary, with 94% penetrance by age 50. Less commonly associated tumors include foregut carcinoids, lipomas, angiofibromas, thyroid adenomas, adrenocortical adenomas, angiomyolipomas, and spinal cord ependymomas. Except for gastrinomas, most of the tumors are nonmetastasizing, but many can create striking clinical effects because of the secretion of endocrine substances such as gastrin, insulin, parathyroid hormone, prolactin, growth hormone, glucagon, or adrenocorticotropic hormone (summary by <a href="#21" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. &lt;strong&gt;Positional cloning of the gene for multiple endocrine neoplasia-type 1.&lt;/strong&gt; Science 276: 404-406, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9103196/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9103196&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.276.5311.404&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9103196">Chandrasekharappa et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" 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>Familial isolated hyperparathyroidism (see <a href="/entry/145000">145000</a>) occasionally results from the incomplete expression of MEN1 (summary by <a href="#95" class="mim-tip-reference" title="Simonds, W. F., Robbins, C. M., Agarwal, S. K., Hendy, G. N., Carpten, J. D., Marx, S. J. &lt;strong&gt;Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome.&lt;/strong&gt; J. Clin. Endocr. Metab. 89: 96-102, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14715834/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14715834&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2003-030675&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14715834">Simonds et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14715834" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Genetic Heterogeneity of Multiple Endocrine Neoplasia</em></strong></p><p>
Other forms of multiple endocrine neoplasia include MEN2A (<a href="/entry/171400">171400</a>) and MEN2B (<a href="/entry/162300">162300</a>), both of which are caused by mutation in the RET gene (<a href="/entry/164761">164761</a>), and MEN4 (<a href="/entry/610755">610755</a>), which is caused by mutation in the CDKN1B gene (<a href="/entry/600778">600778</a>).</p>
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<strong>Clinical Features</strong>
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<p><a href="#111" class="mim-tip-reference" title="Underwood, L. E., Jacobs, N. M. &lt;strong&gt;Familial endocrine adenomatosis.&lt;/strong&gt; Am. J. Dis. Child. 106: 218-223, 1963.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14056823/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14056823&lt;/a&gt;]" pmid="14056823">Underwood and Jacobs (1963)</a> identified an affected father, son, and daughter. Hypoglycemia was the presenting manifestation in all 3. In addition to islet cell adenomas, the father had bronchial carcinoma and hyperparathyroidism (<a href="/entry/145000">145000</a>) from parathyroid adenomas. The son and daughter had been followed from childhood as cases of idiopathic epilepsy unresponsive to anticonvulsive therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14056823" 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="#44" class="mim-tip-reference" title="Guida, P. M., Todd, J. E., Moore, S. W., Beal, J. M. &lt;strong&gt;Zollinger-Ellison syndrome with interesting variations: report of twelve cases including one of carcinoid of the duodenum.&lt;/strong&gt; Am. J. Surg. 112: 807-817, 1966.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4288594/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4288594&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9610(66)90130-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4288594">Guida et al. (1966)</a> described pituitary adenoma and duodenal carcinoid in patients with this condition. Bronchial carcinoid was described as a feature of the disorder by <a href="#120" class="mim-tip-reference" title="Williams, E. D., Celestin, L. R. &lt;strong&gt;The association of bronchial carcinoid and pluriglandular adenomatosis.&lt;/strong&gt; Thorax 17: 120-127, 1962.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14007148/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14007148&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/thx.17.2.120&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14007148">Williams and Celestin (1962)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4288594+14007148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Some kindreds (e.g., <a href="#9" class="mim-tip-reference" title="Ballard, H. S., Frame, B., Hartsock, R. J. &lt;strong&gt;Familial multiple endocrine adenoma-peptic ulcer complex.&lt;/strong&gt; Medicine 43: 481-516, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14183520/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14183520&lt;/a&gt;]" pmid="14183520">Ballard et al., 1964</a>; <a href="#119" class="mim-tip-reference" title="Wermer, P. &lt;strong&gt;Genetic aspects of adenomatosis of endocrine glands.&lt;/strong&gt; Am. J. Med. 16: 363-371, 1954.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13138607/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13138607&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(54)90353-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13138607">Wermer, 1954</a>) have a high frequency of severe peptic ulcer disease with islet cell tumors, whereas other kindreds (e.g., <a href="#54" class="mim-tip-reference" title="Johnson, G. J., Summerskill, W. H. J., Anderson, V. E., Keating, F. R. &lt;strong&gt;Clinical and genetic investigation of a large kindred with multiple endocrine adenomatosis.&lt;/strong&gt; New Eng. J. Med. 277: 1379-1385, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4384073/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4384073&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM196712282772601&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4384073">Johnson et al., 1967</a>) are devoid of peptic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14183520+13138607+4384073" 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>Bilateral pheochromocytomas occur in MEN2A and MEN2B and pancreatic islet cell tumors in MEN1. <a href="#104" class="mim-tip-reference" title="Tateishi, R., Wada, A., Ishiguro, S., Ehara, M., Sakamoto, H., Miki, T., Mori, Y., Matsui, Y., Ishikawa, O. &lt;strong&gt;Coexistence of bilateral pheochromocytoma and pancreatic islet cell tumor: report of a case and review of the literature.&lt;/strong&gt; Cancer 42: 2928-2934, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/215301/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;215301&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1097-0142(197812)42:6&lt;2928::aid-cncr2820420657&gt;3.0.co;2-s&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="215301">Tateishi et al. (1978)</a> described a patient with both forms of endocrine neoplasia. They also reviewed 14 reported cases of MEN with features overlapping MEN I and II. For example, 7 patients with acromegaly (<a href="/entry/102200">102200</a>) due to pituitary adenoma had pheochromocytoma, 2 with Sipple syndrome (MEN2A) had pituitary adenoma, and so on. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=215301" 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="#82" class="mim-tip-reference" title="Prosser, P. R., Karam, J. H., Townsend, J. J., Frosham, P. H. &lt;strong&gt;Prolactin-secreting pituitary adenomas in multiple endocrine adenomatosis, type I.&lt;/strong&gt; Ann. Intern. Med. 91: 41-44, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/37794/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;37794&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.7326/0003-4819-91-1-41&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="37794">Prosser et al. (1979)</a> found 4 patients in 3 unrelated families who had prolactin-secreting pituitary adenomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37794" 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="#32" class="mim-tip-reference" title="Farid, N. R., Buehler, S., Russell, N. A., Maroun, F. B., Allerdice, P., Smyth, H. S. &lt;strong&gt;Prolactinomas in familial multiple endocrine neoplasia syndrome type I: relationship to HLA and carcinoid tumors.&lt;/strong&gt; Am. J. Med. 69: 874-880, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6108714/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6108714&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0002-9343(80)80013-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6108714">Farid et al. (1980)</a> observed 4 kindreds in the Burin Peninsula of Newfoundland, whose ancestors came from the same small community in the British Isles, with hyperparathyroidism and prolactinoma, but no documented pancreatic tumors. Two kindreds had carcinoid tumors at unusual sites, either thymus or peripheral lung parenchyma. In contrast to the benign course of the prolactinomas and the primary hyperparathyroidism, 2 persons with thymic carcinoid died from metastatic disease. <a href="#11" class="mim-tip-reference" title="Bear, J. C., Briones-Urbina, R., Fahey, J. F., Farid, N. R. &lt;strong&gt;Variant multiple endocrine neoplasia I (MEN I-Burin): further studies and non-linkage to HLA.&lt;/strong&gt; Hum. Hered. 35: 15-20, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2857681/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2857681&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000153508&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2857681">Bear et al. (1985)</a> referred to the disorder in these families as MEN1-Burin (see <a href="/entry/613733#0016">613733.0016</a>). <a href="#52" class="mim-tip-reference" title="Hershon, K. S., Kelly, W. A., Shaw, C. M., Schwartz, R., Bierman, E. L. &lt;strong&gt;Prolactinomas as part of the multiple endocrine neoplastic syndrome type 1.&lt;/strong&gt; Am. J. Med. 74: 713-720, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6837595/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6837595&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(83)91032-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6837595">Hershon et al. (1983)</a> described a phenotypically similar but unrelated kindred from the Pacific Northwest, in which 6 of 7 living affected members had prolactinomas and none had pancreatic islet tumors. <a href="#33" class="mim-tip-reference" title="Farid, N. R. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Riyadh, Saudi Arabia 1/11/1994."None>Farid (1994)</a> reported that the Burin Peninsula families were in fact related. All 4 families had ancestors who lived in the Harbor Breton region a century earlier and all affected members of the 4 families carried the same PYGM (<a href="/entry/608455">608455</a>) allele segregating with the disorder. <a href="#80" class="mim-tip-reference" title="Petty, E. M., Green, J. S., Marx, S. J., Taggart, R. T., Farid, N., Bale, A. E. &lt;strong&gt;Mapping the gene for hereditary hyperparathyroidism and prolactinoma (MEN1-Burin) to chromosome 11q: evidence for a founder effect in patients from Newfoundland.&lt;/strong&gt; Am. J. Hum. Genet. 54: 1060-1066, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7911003/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7911003&lt;/a&gt;]" pmid="7911003">Petty et al. (1994)</a> demonstrated by linkage studies that the gene in both the Newfoundland kindreds and the kindred from the Pacific Northwest mapped to 11q in the same region as the MEN1 gene. No recombinants were seen with PYGM in either kindred, but the PYGM allele associated with the disease was different in the 2 kindreds. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6837595+2857681+6108714+7911003" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The Zollinger-Ellison syndrome (ZES) may present purely as hyperparathyroidism. For example, 1 member of the family described as having hereditary hyperparathyroidism by <a href="#26" class="mim-tip-reference" title="Cutler, R. E., Reiss, E., Ackerman, L. V. &lt;strong&gt;Familial hyperparathyroidism: a kindred involving eleven cases, with a discussion of primary chief-cell hyperplasia.&lt;/strong&gt; New Eng. J. Med. 270: 859-865, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14110030/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14110030&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM196404232701701&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14110030">Cutler et al. (1964)</a> was later reported to have a malignant schwannoma, pituitary adenomas, multiple pancreatic islet cell adenomas, and multiple adrenocortical adenomas. <a href="#97" class="mim-tip-reference" title="Snyder, N., III, Scurry, M. T., Deiss, W. P., Jr. &lt;strong&gt;Five families with multiple endocrine adenomatosis.&lt;/strong&gt; Ann. Intern. Med. 76: 53-58, 1972.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4401787/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4401787&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.7326/0003-4819-76-1-53&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4401787">Snyder et al. (1972)</a> reported 5 families and noted the previously described association of lipomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14110030+4401787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The Zollinger-Ellison syndrome is merely hypergastrinism and may have causes other than MEN I. For example, <a href="#66" class="mim-tip-reference" title="Long, T. T., Barton, T. K., Draffin, R., Reeves, W. J., McCarty, K. S., Jr. &lt;strong&gt;Conservative management of the Zollinger-Ellison syndrome: ectopic gastrin production by an ovarian cystadenoma.&lt;/strong&gt; JAMA 243: 1837-1839, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7365959/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7365959&lt;/a&gt;]" pmid="7365959">Long et al. (1980)</a> reported the Zollinger-Ellison syndrome with ectopic production of gastrin by a mucinous cystadenoma of the ovary. <a href="#71" class="mim-tip-reference" title="McCarthy, D. M. &lt;strong&gt;Zollinger-Ellison syndrome.&lt;/strong&gt; Ann. Rev. Med. 33: 197-215, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7044271/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7044271&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1146/annurev.me.33.020182.001213&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7044271">McCarthy (1982)</a> distinguished 2 common forms of the Zollinger-Ellison syndrome: the sporadic and usually malignant type, seen most often in later life, and the genetic variety that occurs as part of MEN I. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7365959+7044271" 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="#99" class="mim-tip-reference" title="Stacpoole, P. W., Jaspan, J., Kasselberg, A. G., Halter, S. A., Polonsky, K., Gluck, F. W., Liljenquist, J. E., Rabin, D. &lt;strong&gt;A familial glucagonoma syndrome: genetic, clinical and biochemical features.&lt;/strong&gt; Am. J. Med. 70: 1017-1026, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6112877/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6112877&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(81)90858-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6112877">Stacpoole et al. (1981)</a> observed a family in which 3 persons had A-cell pancreatic tumors (glucagonomas) as part of MEN I. Two had the classic glucagonoma syndrome with skin rash, glucose intolerance, and hypoaminoacidemia. Administered secretin and somatostatin gave anomalous metabolic responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6112877" 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="Bahn, R. S., Scheithauer, B. W., van Heerden, J. A., Laws, E. R., Jr., Horvath, E., Gharib, H. &lt;strong&gt;Nonidentical expressions of multiple endocrine neoplasia, type I, in identical twins.&lt;/strong&gt; Mayo Clin. Proc. 61: 689-696, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2875227/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2875227&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0025-6196(12)62767-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2875227">Bahn et al. (1986)</a> reported 25-year-old monozygotic twins with MEN I who had impressive differences in expression of the disorder. One had epigastric pain and diarrhea at presentation; was found to have primary hyperparathyroidism, Zollinger-Ellison syndrome, Cushing disease, and hyperprolactinemia; and underwent hypophysectomy. The second twin was asymptomatic but had primary hyperparathyroidism and hyperprolactinemia. A large, histologically benign pituitary adenoma 'that invaded dura and bone' was removed by a transsphenoidal approach 2 days after parathyroidectomy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2875227" 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="#69" class="mim-tip-reference" title="Maton, P. N., Gardner, J. D., Jensen, R. T. &lt;strong&gt;Cushing&#x27;s syndrome in patients with the Zollinger-Ellison syndrome.&lt;/strong&gt; New Eng. J. Med. 315: 1-5, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2872593/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2872593&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198607033150101&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2872593">Maton et al. (1986)</a> suggested that the Cushing syndrome is more common in patients with the Zollinger-Ellison syndrome than previously reported, occurring in 8% of all cases. Three of 16 patients with the Zollinger-Ellison syndrome and MEN1 had the Cushing syndrome due to pituitary overproduction of ACTH. In all sporadic cases of ZES, Cushing syndrome was due to ectopic production of ACTH by the gastrinoma. <a href="#40" class="mim-tip-reference" title="Gaitan, D., Loosen, P. T., Orth, D. N. &lt;strong&gt;Two patients with Cushing&#x27;s disease in a kindred with multiple endocrine neoplasia type I.&lt;/strong&gt; J. Clin. Endocr. Metab. 76: 1580-1582, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8099078/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8099078&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.76.6.8099078&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8099078">Gaitan et al. (1993)</a> described mother and daughter who, in addition to other manifestations of MEN1, had Cushing disease due to ACTH-secreting tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8099078+2872593" 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="#122" class="mim-tip-reference" title="Yu, F., Venzon, D. J., Serrano, J., Goebel, S. U., Doppman, J. L., Gibril, F., Jensen, R. T. &lt;strong&gt;Prospective study of the clinical course, prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome.&lt;/strong&gt; J. Clin. Oncol. 17: 615-630, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10080607/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10080607&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1200/JCO.1999.17.2.615&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10080607">Yu et al. (1999)</a> reported on the long-term clinical course of unselected patients with gastrinomas as well as other functional pancreatic endocrine tumors in whom the excess hormone state was controlled. They studied 212 patients with Zollinger-Ellison syndrome. All had controlled acid hypersecretion and were assessed yearly, with a mean follow-up of 13.8 years (range, 0.1 to 31 years). Death had occurred in 31% of patients, all from non-acid-related causes. One-half died of a ZES-related cause; they differed from those who died of non-ZES deaths by having a large primary tumor, more frequently a pancreatic tumor; lymph node, liver, or bone metastases; ectopic Cushing syndrome; or higher gastrin levels. The extent of liver metastases correlated with survival rate. <a href="#122" class="mim-tip-reference" title="Yu, F., Venzon, D. J., Serrano, J., Goebel, S. U., Doppman, J. L., Gibril, F., Jensen, R. T. &lt;strong&gt;Prospective study of the clinical course, prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome.&lt;/strong&gt; J. Clin. Oncol. 17: 615-630, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10080607/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10080607&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1200/JCO.1999.17.2.615&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10080607">Yu et al. (1999)</a> concluded that in ZES, gastrinoma growth is the main single determinant of long-term survival, with 50% of patients dying a gastrinoma-related death and none an acid-related death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10080607" 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="Bordi, C., Corleto, V. D., Azzoni, C., Pizzi, S., Ferraro, G., Gibril, F., Delle Fave, G., Jensen, R. T. &lt;strong&gt;The antral mucosa as a new site for endocrine tumors in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndromes.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 2236-2242, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11344233/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11344233&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.5.7479&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11344233">Bordi et al. (2001)</a> identified carcinoid tumors in the antropyloric mucosa of 4 patients with MEN1/Zollinger-Ellison syndrome, accounting for 8.7% of 46 patients with this condition examined by endoscopy and histology. In contrast, no tumors were found in the antral biopsies from 124 cases of sporadic ZES (p less than 0.001), indicating a prominent role for the MEN1 gene defects in tumor development. Immunohistochemically, the tumors did not express the hormones produced by antral endocrine cells (gastrin, somatostatin, serotonin). In contrast, 2 of them were diffusely immunoreactive for the isoform 2 of the vesicular monoamine transporter (VMAT2; <a href="/entry/193001">193001</a>), a marker specific for the gastric nonantral enterochromaffin-like (ECL) cells. In 1 of these patients, a second antral VMAT2-positive carcinoid was seen 21 months after the first diagnosis. The authors concluded that the antral mucosa is an additional tissue that may harbor endocrine tumors in MEN1 syndrome. These tumors did not express the phenotype of normal antral endocrine cells and, in at least 2 cases, were identified as ectopic ECL cell carcinoids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11344233" 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="#96" class="mim-tip-reference" title="Skogseid, B., Larsson, C., Lindgren, P.-G., Kvanta, E., Rastad, J., Theodorsson, E., Wide, L., Wilander, E., Oberg, K. &lt;strong&gt;Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1.&lt;/strong&gt; J. Clin. Endocr. Metab. 75: 76-81, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1352309/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1352309&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.75.1.1352309&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1352309">Skogseid et al. (1992)</a> reviewed adrenocortical lesions in 31 MEN I patients. In 12 (37%), they found adrenal enlargement, which was bilateral in 7. One person developed unilateral adrenocortical carcinoma manifested by rapid adrenal expansion, feminization, and an abnormal urinary steroid profile after 4 years of observation for bilateral minor adrenal enlargement. In the other patients, adrenal enlargement was not associated with ascertainable biochemical disturbances in the hypothalamic-pituitary-adrenocortical axis. Pancreatic endocrine tumors were significantly overrepresented in the patients with adrenal lesions, being present in all 12. In agreement with findings in sporadic cases, the MEN1 adrenocortical carcinoma showed loss of constitutional heterozygosity for alleles at 17p, 13q, 11p, and 11q. The benign adrenal lesions retained heterozygosity for the MEN1 locus at 11q13. <a href="#96" class="mim-tip-reference" title="Skogseid, B., Larsson, C., Lindgren, P.-G., Kvanta, E., Rastad, J., Theodorsson, E., Wide, L., Wilander, E., Oberg, K. &lt;strong&gt;Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1.&lt;/strong&gt; J. Clin. Endocr. Metab. 75: 76-81, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1352309/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1352309&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.75.1.1352309&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1352309">Skogseid et al. (1992)</a> concluded that the pituitary-independent adrenocortical proliferation is not the result of the primary lesion in MEN I but may represent a secondary phenomenon, perhaps related to the pancreatic endocrine tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1352309" 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="#114" class="mim-tip-reference" title="Verges, B., Boureille, F., Goudet, P., Murat, A., Beckers, A., Sassolas, G., Cougard, P., Chambe, B., Montvernay, C., Calender, A., Groupe d&#x27;Etude des Neoplasies Endocriniennes Multiples. &lt;strong&gt;Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study.&lt;/strong&gt; J. Clin. Endocr. Metab. 87: 457-465, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11836268/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11836268&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.87.2.8145&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11836268">Verges et al. (2002)</a> analyzed data on pituitary adenomas in 324 MEN1 patients from a French and Belgian multicenter study. Data on pituitary disease were compared with those from 110 non-MEN1 patients with pituitary adenomas, matched for age, year of diagnosis, and follow-up period. In the authors' MEN1 series, pituitary disease occurred in 136 of 324 (42%), less frequently than hyperparathyroidism (95%, p less than 0.001) and endocrine enteropancreatic tumors (54%, p less than 0.01). Mean age of onset of pituitary tumors was 38.0 +/- 15.3 years (range, 12 to 83 years). Pituitary disease was associated with hyperparathyroidism in 90% of cases, with enteropancreatic tumors in 47%, with adrenal tumors in 16%, and with thoracic neuroendocrine tumors in 4%. Pituitary disease was the initial lesion of MEN1 in 17% of all MEN1 patients. MEN1 pituitary adenomas were significantly more frequent in women than in men (50% vs 31%, p less than 0.001). Eighty-five percent of MEN1-related pituitary lesions were macroadenomas, including 32% of invasive cases. Among secreting adenomas, hormonal hypersecretion was normalized, after treatment, in only 42%, with a median follow-up of 11.4 years. No correlation was found between the type of MEN1 germline mutation and the presence or absence of pituitary adenoma. The authors concluded that their study shows that pituitary adenomas occur in 42% of cases and are characterized by a larger size and a more aggressive presentation than without MEN1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11836268" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Darling, T. N., Skarulis, M. C., Steinberg, S. M., Marx, S. J., Spiegel, A. M., Turner, M. &lt;strong&gt;Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1.&lt;/strong&gt; Arch. Derm. 133: 853-857, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9236523/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9236523&lt;/a&gt;]" pmid="9236523">Darling et al. (1997)</a> performed a complete cutaneous evaluation on 32 consecutive patients with established diagnoses of MEN1. They observed multiple facial angiofibromas in 88%, collagenomas in 72%, cafe-au-lait macules in 38%, lipomas in 34%, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% of these individuals. <a href="#27" class="mim-tip-reference" title="Darling, T. N., Skarulis, M. C., Steinberg, S. M., Marx, S. J., Spiegel, A. M., Turner, M. &lt;strong&gt;Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1.&lt;/strong&gt; Arch. Derm. 133: 853-857, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9236523/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9236523&lt;/a&gt;]" pmid="9236523">Darling et al. (1997)</a> noted that there is considerable overlap between the cutaneous findings in MEN1 and those in tuberous sclerosis (see <a href="/entry/191100">191100</a>). However, facial angiofibromas in MEN1 tend to be smaller and fewer and to occur in different areas (upper lip and vermilion border) in comparison to those seen in tuberous sclerosis. <a href="#27" class="mim-tip-reference" title="Darling, T. N., Skarulis, M. C., Steinberg, S. M., Marx, S. J., Spiegel, A. M., Turner, M. &lt;strong&gt;Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1.&lt;/strong&gt; Arch. Derm. 133: 853-857, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9236523/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9236523&lt;/a&gt;]" pmid="9236523">Darling et al. (1997)</a> suggested that these cutaneous findings may be helpful in presymptomatic diagnosis of MEN1 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9236523" 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="#94" class="mim-tip-reference" title="Schussheim, D. H., Skarulis, M. C., Agarwal, S. K., Simonds, W. F., Burns, A. L., Spiegel, A. M., Marx, S. J. &lt;strong&gt;Multiple endocrine neoplasia type 1: new clinical and basic findings.&lt;/strong&gt; Trends Endocr. Metab. 12: 173-178, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11295574/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11295574&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s1043-2760(00)00372-6&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11295574">Schussheim et al. (2001)</a> reviewed new clinical features of MEN1. These included multiple facial angiofibromas, previously considered pathognomonic for tuberous sclerosis; these had been reported in approximately 90% of MEN1 patients, with 50% having 5 or more. MEN1-related angiofibromas differ from those associated with tuberous sclerosis in that they are smaller, fewer, and located on the upper lip and vermilion border of the lip, areas that appear to be spared in tuberous sclerosis patients. Collagenomas had also been identified in more than 70% of MEN1 cases. These lesions can be subtle, and diagnosis might require consultation and biopsy by a dermatologist. Lipomas, both cutaneous and visceral, had been described in up to one-third of MEN1 patients compared with 6% of controls. This moderately high prevalence of lipoma in the general population made it difficult to use this lesion as a marker for MEN1 disease. In contrast to pheochromocytoma in MEN2 (<a href="/entry/171400">171400</a>), pheochromocytoma occurring in association with MEN1 is rare. In all cases the tumors were unilateral, and it was malignant in only one patient. Leiomyomas had been observed in patients with MEN1. Adrenal cortical lesions were common in MEN1, occurring in up to 40% of patients. The majority of these tumors were bilateral, hyperplastic, and nonfunctional, and caused minimal morbidity; however, tumors that cause hypercortisolemia and hyperaldosteronism had been reported. Thyroid tumors, which include follicular adenomas, goiters, and carcinoma, had long been observed in more than 25% of MEN1 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11295574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Asgharian, B., Turner, M. L., Gibril, F., Entsuah, L. K., Serrano, J., Jensen, R. T. &lt;strong&gt;Cutaneous tumors in patients with multiple endocrine neoplasm type 1 (MEN1) and gastrinomas: prospective study of frequency and development of criteria with high sensitivity and specificity for MEN1.&lt;/strong&gt; J. Clin. Endocr. Metab. 89: 5328-5336, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15531478/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15531478&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2004-0218&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15531478">Asgharian et al. (2004)</a> prospectively assessed the frequency and sensitivity/specificity of various cutaneous criteria for MEN1 in 110 consecutive patients with gastrinomas with or without MEN1. All patients had hormonal and functional studies to determine MEN1 status, dermatologic evaluation, and tumor imaging studies. Combinations of the occurrence of angiofibromas, collagenomas, and lipomas were analyzed. The combination criterion of more than 3 angiofibromas or any collagenoma had the highest sensitivity (75%) and specificity (95%). <a href="#3" class="mim-tip-reference" title="Asgharian, B., Turner, M. L., Gibril, F., Entsuah, L. K., Serrano, J., Jensen, R. T. &lt;strong&gt;Cutaneous tumors in patients with multiple endocrine neoplasm type 1 (MEN1) and gastrinomas: prospective study of frequency and development of criteria with high sensitivity and specificity for MEN1.&lt;/strong&gt; J. Clin. Endocr. Metab. 89: 5328-5336, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15531478/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15531478&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2004-0218&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15531478">Asgharian et al. (2004)</a> concluded that this diagnostic criterion has greater sensitivity for MEN1 than pituitary or adrenal disease and has comparable sensitivity to hyperparathyroidism reported in some studies of patients with MEN1 with gastrinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15531478" 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="#49" class="mim-tip-reference" title="Hao, W., Skarulis, M. C., Simonds, W. F., Weinstein, L. S., Agarwal, S. K., Mateo, C., James-Newton, L., Hobbs, G. R., Gibril, F., Jensen, R. T., Marx, S. J. &lt;strong&gt;Multiple endocrine neoplasia type 1 variant with frequent prolactinoma and rare gastrinoma.&lt;/strong&gt; J. Clin. Endocr. Metab. 89: 3776-3784, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15292304/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15292304&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2003-031511&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15292304">Hao et al. (2004)</a> examined 2 large kindreds with a MEN1 variant that were followed up for 20 to 30 years, with MEN1 tumors in 30 members. Cases from the 2 kindreds had parathyroid adenomas (93%), pituitary tumors (40%) (always prolactinoma), and enteropancreatic endocrine tumors (27%). The latter included insulinoma (10%) and nonfunctioning islet tumor (7%), but only 10% gastrinoma. Compared with prior large series, this lower prevalence of gastrinoma (10% vs 42%, p less than 0.01) and higher prevalence of prolactinoma (40% vs 22%, p less than 0.01) defined this variant. DNA showed no characteristic MEN1 mutation in these 2 kindreds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15292304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Reviews</em></strong></p><p>
<a href="#121" class="mim-tip-reference" title="Wolfe, M. M., Jensen, R. T. &lt;strong&gt;Zollinger-Ellison syndrome: current concepts in diagnosis and management.&lt;/strong&gt; New Eng. J. Med. 317: 1200-1209, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3309661/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3309661&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198711053171907&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3309661">Wolfe and Jensen (1987)</a> reviewed diagnosis and treatment of the Zollinger-Ellison syndrome. For a review of MEN1, see <a href="#108" class="mim-tip-reference" title="Thakker, R. V. &lt;strong&gt;Multiple endocrine neoplasia: syndromes of the twentieth century. (Editorial)&lt;/strong&gt; J. Clin. Endocr. Metab. 83: 2617-2620, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9709920/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9709920&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.83.8.5045&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9709920">Thakker (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3309661+9709920" 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="Guo, S.S., Sawicki, M. P. &lt;strong&gt;Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type-1.&lt;/strong&gt; Molec. Endocr. 15: 1653-1664, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11579199/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11579199&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/mend.15.10.0717&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11579199">Guo and Sawicki (2001)</a> reviewed the various clinical manifestations of MEN1 syndrome, potential mechanisms of MEN1 tumorigenesis, and mutations associated with MEN and sporadic endocrine tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11579199" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#15" class="mim-tip-reference" title="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. &lt;strong&gt;Guidelines for diagnosis and therapy of MEN type 1 and type 2.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 5658-5671, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11739416/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11739416&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.12.8070&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11739416">Brandi et al. (2001)</a> authored a consensus statement covering the diagnosis and management of MEN1 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. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of enteropancreatic hormones, except insulin. The roles for surgery of most enteropancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. <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>
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<p><a href="#14" class="mim-tip-reference" title="Brandi, M. L., Aurbach, G. D., Fitzpatrick, L. A., Quarto, R., Spiegel, A. M., Bliziotes, M. M., Norton, J. A., Doppman, J. L., Marx, S. J. &lt;strong&gt;Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type 1.&lt;/strong&gt; New Eng. J. Med. 314: 1287-1293, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2871488/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2871488&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198605153142004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2871488">Brandi et al. (1986)</a> cultured bovine parathyroid cells to test for mitogenic activity in plasma from patients with type I MEN. Whereas normal plasma stimulated incorporation of labeled thymidine to the same extent as did plasma-free culture medium, the plasma from the patients increased mitogenic activity 2400% over the control value. Bovine parathyroid cells were stimulated to proliferation, whereas plasma from normal subjects inhibited proliferation of the bovine parathyroid cells. The mitogenic activity had an apparent molecular weight of 50,000 to 55,000. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2871488" 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>MEN I is an autosomal dominant disorder. <a href="#21" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. &lt;strong&gt;Positional cloning of the gene for multiple endocrine neoplasia-type 1.&lt;/strong&gt; Science 276: 404-406, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9103196/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9103196&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.276.5311.404&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9103196">Chandrasekharappa et al. (1997)</a> suggested that affected individuals inherit one altered copy of the MEN1 gene from an affected parent, but the tumors lose the remaining copy (the wildtype allele) as a somatic event. Thus, the inheritance pattern is autosomal dominant, but the mechanism of tumorigenesis is recessive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" 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>Bale et al. (<a href="#8" class="mim-tip-reference" title="Bale, S. J., Marx, S. J., Langfield, D., Bale, A. E., Mulvihill, J., Green, J., III. &lt;strong&gt;Multiple endocrine neoplasia type 1 (MEN1): genetic linkage studies. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 46: 575, 1987."None>1987</a>, <a href="#5" class="mim-tip-reference" title="Bale, A. E., Friedman, E., Sakaguchi, K., Nakamura, Y., McBride, O. W., Spiegel, A. M., Aurbach, G. D., Marx, S. J. &lt;strong&gt;Allelic loss in hereditary and sporadic tumors associated with MEN1. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 45 (suppl.): A15, 1989."None>1989</a>) studied linkage with multiple markers in a single large kindred with MEN I. INT2 (<a href="/entry/164950">164950</a>), which is located at 11q13, was found to be closely linked to MEN1. In studies of 3 families, <a href="#107" class="mim-tip-reference" title="Thakker, R. V., Bouloux, P., Wooding, C., Chotai, K., Broad, P. M., Spurr, N. K., Besser, G. M., O&#x27;Riordan, J. L. H. &lt;strong&gt;Association of parathyroid tumors in multiple endocrine neoplasia type I with loss of alleles on chromosome 11.&lt;/strong&gt; New Eng. J. Med. 321: 218-224, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2568587/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2568587&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198907273210403&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2568587">Thakker et al. (1989)</a> established linkage with INT2; peak lod score = 3.30 at theta = 0.00. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2568587" 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="#62" class="mim-tip-reference" title="Larsson, C., Skogseid, B., Oberg, K., Nakamura, Y., Nordenskjold, M. &lt;strong&gt;Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma.&lt;/strong&gt; Nature 332: 85-87, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2894610/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2894610&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/332085a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2894610">Larsson et al. (1988)</a> mapped the MEN1 locus to chromosome 11 by demonstrating linkage to a DNA probe derived from the PYGM locus (<a href="/entry/608455">608455</a>), which, in turn, has been mapped to 11q13-qter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2894610" 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 comparing constitutional and tumor tissue genotypes of insulinomas from 2 brothers who had inherited the disorder from their mother, <a href="#62" class="mim-tip-reference" title="Larsson, C., Skogseid, B., Oberg, K., Nakamura, Y., Nordenskjold, M. &lt;strong&gt;Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma.&lt;/strong&gt; Nature 332: 85-87, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2894610/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2894610&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/332085a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2894610">Larsson et al. (1988)</a> demonstrated loss of the linked locus in tumor tissue. Tumors in both showed loss of 1 constitutional allele at all informative loci on chromosome 11. The informative markers extended from HRAS1, located at 11p15.5, to APOA1 (<a href="/entry/107680">107680</a>), located at 11q13. (<a href="#62" class="mim-tip-reference" title="Larsson, C., Skogseid, B., Oberg, K., Nakamura, Y., Nordenskjold, M. &lt;strong&gt;Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma.&lt;/strong&gt; Nature 332: 85-87, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2894610/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2894610&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/332085a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2894610">Larsson et al. (1988)</a> quoted a paper in press indicating that the APOA1 locus is in band q23.) In 3 families, the authors observed a total maximum lod score of 4.37 at theta = 0.00. <a href="#63" class="mim-tip-reference" title="Larsson, C., Skogseid, B., Oberg, K., Nordenskjold, M. &lt;strong&gt;Linkage of multiple endocrine neoplasia type 1 (MEN1) to markers at 11q13. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 51: 1029, 1989."None>Larsson et al. (1989)</a> and <a href="#74" class="mim-tip-reference" title="Nordenskjold, M., Jones, C. A., Glaser, T., Werelius, B., Larsson, C., Jansson, M. &lt;strong&gt;Mapping of chromosome 11q probes on somatic cell hybrids. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 51: 1054, 1989."None>Nordenskjold et al. (1989)</a> both provided linkage data for markers at 11q13 with multiple endocrine neoplasia type I. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2894610" 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="#73" class="mim-tip-reference" title="Nakamura, Y., Larsson, C., Julier, C., Bystrom, C., Skogseid, B., Wells, S., Oberg, K., Carlson, M., Taggart, T., O&#x27;Connell, P., Leppert, M., Lalouel, J.-M., Nordenskjold, M., White, R. &lt;strong&gt;Localization of the genetic defect in multiple endocrine neoplasia type I within a small region of chromosome 11.&lt;/strong&gt; Am. J. Hum. Genet. 44: 751-755, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2565085/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2565085&lt;/a&gt;]" pmid="2565085">Nakamura et al. (1989)</a> identified 6 closely linked markers in the vicinity of 11q13 which are useful for identification of carriers in MEN I families. The target region containing the gene was narrowed to about 12 cM. <a href="#36" class="mim-tip-reference" title="Friedman, E., Sakaguchi, K., Bale, A. E., Falchetti, A., Streeten, E., Zimering, M. B., Weinstein, L. S., McBride, W. O., Nakamura, Y., Brandi, M.-L., Norton, J. A., Aurbach, G. D., Spiegel, A. M., Marx, S. J. &lt;strong&gt;Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1.&lt;/strong&gt; New Eng. J. Med. 321: 213-218, 1989. Note: Erratum: New Eng. J. Med. 321: 1057 only, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2568586/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2568586&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198907273210402&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2568586">Friedman et al. (1989)</a> and <a href="#107" class="mim-tip-reference" title="Thakker, R. V., Bouloux, P., Wooding, C., Chotai, K., Broad, P. M., Spurr, N. K., Besser, G. M., O&#x27;Riordan, J. L. H. &lt;strong&gt;Association of parathyroid tumors in multiple endocrine neoplasia type I with loss of alleles on chromosome 11.&lt;/strong&gt; New Eng. J. Med. 321: 218-224, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2568587/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2568587&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198907273210403&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2568587">Thakker et al. (1989)</a> demonstrated loss of heterozygosity (LOH) for chromosome 11 alleles in parathyroid tumors from patients with MEN I. <a href="#36" class="mim-tip-reference" title="Friedman, E., Sakaguchi, K., Bale, A. E., Falchetti, A., Streeten, E., Zimering, M. B., Weinstein, L. S., McBride, W. O., Nakamura, Y., Brandi, M.-L., Norton, J. A., Aurbach, G. D., Spiegel, A. M., Marx, S. J. &lt;strong&gt;Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1.&lt;/strong&gt; New Eng. J. Med. 321: 213-218, 1989. Note: Erratum: New Eng. J. Med. 321: 1057 only, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2568586/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2568586&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198907273210402&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2568586">Friedman et al. (1989)</a> found such loss in 10 of 16 tumors from 14 patients. In 7 of 10 tumors, the subregion of loss was less than the full length of chromosome 11 but always included 1 copy of the MEN I locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2568587+2568586+2565085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Bale, A. E., Friedman, E., Sakaguchi, K., Nakamura, Y., McBride, O. W., Spiegel, A. M., Aurbach, G. D., Marx, S. J. &lt;strong&gt;Allelic loss in hereditary and sporadic tumors associated with MEN1. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 45 (suppl.): A15, 1989."None>Bale et al. (1989)</a> studied the DNA from 66 tumors removed from patients with MEN I. They demonstrated allelic loss of chromosome 11 RFLPs in 10 of 16 parathyroid tumors from MEN I patients and in 9 of 34 sporadic parathyroid adenomas. The smallest consistent region of loss was between INT2 and D11S149. <a href="#18" class="mim-tip-reference" title="Bystrom, C., Larsson, C., Blomberg, C., Sandelin, K., Falkmer, U., Skogseid, B., Oberg, K., Werner, S., Nordenskjold, M. &lt;strong&gt;Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors.&lt;/strong&gt; Proc. Nat. Acad. Sci. 87: 1968-1972, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1968641/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1968641&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.87.5.1968&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1968641">Bystrom et al. (1990)</a> showed that the pathogenesis of MEN1-associated parathyroid lesions involves unmasking of a recessive mutation at the disease locus and that sporadic primary hyperparathyroidism shares the same mechanisms. By examination of allele losses in MEN1-associated lesions, they defined deletions of chromosome 11 and mapped the MEN1 locus to a small region within 11q13, telomeric to PYGM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1968641" 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="#85" class="mim-tip-reference" title="Richard, C. W., III, Withers, D. A., Meeker, T. C., Maurer, S., Evans, G. A., Myers, R. M., Cox, D. R. &lt;strong&gt;A radiation hybrid map of the proximal long arm of human chromosome 11 containing the multiple endocrine neoplasia type 1 (MEN-1) and bcl-1 disease loci.&lt;/strong&gt; Am. J. Hum. Genet. 49: 1189-1196, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1684084/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1684084&lt;/a&gt;]" pmid="1684084">Richard et al. (1991)</a> created a high-resolution radiation hybrid map of the proximal long arm of chromosome 11 containing the MEN1 and BCL1 (<a href="/entry/168461">168461</a>) gene loci. By statistical analysis of the cosegregation of markers in radiation hybrids, they arrived at the following most likely order of loci: C1NH (<a href="/entry/606860">606860</a>)--OSBP (<a href="/entry/167040">167040</a>)--CD5 (<a href="/entry/153340">153340</a>)/CD20(<a href="/entry/112210">112210</a>)--PGA (<a href="/entry/169710">169710</a>)--FTH1 (<a href="/entry/134770">134770</a>)--COX8 (<a href="/entry/123870">123870</a>)--PYGM--SEA (<a href="/entry/165110">165110</a>)--KRN1 (<a href="/entry/148021">148021</a>)--HSTF1 (<a href="/entry/164980">164980</a>)/INT2--GST3 (<a href="/entry/134660">134660</a>)--PPP1A (<a href="/entry/176875">176875</a>). They suggested that the localization of the protooncogene SEA between PYGM and INT2, 2 markers that flank MEN1, makes SEA a potential candidate for the MEN1 locus. The positions of PPP1A and GST3 are such that neither is likely to be directly involved in CLL (<a href="/entry/151400">151400</a>) or MEN1. <a href="#39" class="mim-tip-reference" title="Fujimori, M., Wells, S. A., Jr., Nakamura, Y. &lt;strong&gt;Fine-scale mapping of the gene responsible for multiple endocrine neoplasia type 1 (MEN1).&lt;/strong&gt; Am. J. Hum. Genet. 50: 399-403, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1734719/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1734719&lt;/a&gt;]" pmid="1734719">Fujimori et al. (1992)</a> placed the MEN1 locus within an 8-cM region between D11S480 and D11S546. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1684084+1734719" 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="#61" class="mim-tip-reference" title="Larsson, C., Shepherd, J., Nakamura, Y., Blomberg, C., Weber, G., Werelius, B., Hayward, N., Teh, B., Tokino, T., Seizinger, B., Skogseid, B., Oberg, K., Nordenskjold, M. &lt;strong&gt;Predictive testing for multiple endocrine neoplasia type 1 using DNA polymorphisms.&lt;/strong&gt; J. Clin. Invest. 89: 1344-1349, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1348254/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1348254&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI115720&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1348254">Larsson et al. (1992)</a> found that 13 marker systems tested with 17 DNA probes were located within a region on chromosome 11 spanning a 14% meiotic recombination region, with the MEN1 locus in the middle: based on meiotic crossovers, 4 systems were on the telomeric side and 4 on the centromeric side of MEN1. The remaining 5 were closely linked to MEN1, with no crossovers in their set of 6 families including 59 affected persons. The calculated accuracy of prediction of MEN1 was more than 99.5% when 3 of the marker systems were informative. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1348254" 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="#89" class="mim-tip-reference" title="Sawicki, M. P., Wan, Y.-J. Y., Johnson, C. L., Berenson, J., Gatti, R., Passaro, E., Jr. &lt;strong&gt;Loss of heterozygosity on chromosome 11 in sporadic gastrinomas.&lt;/strong&gt; Hum. Genet. 89: 445-449, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1352275/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1352275&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00194320&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1352275">Sawicki et al. (1992)</a> reported loss of heterozygosity on chromosome 11 in 5 of 11 sporadic gastrinomas. Four of these tumors had LOH for markers flanking the MEN1 region. LOH on chromosome 11 had previously been found in 3 types of tumors that occur in patients with the MEN I syndrome: sporadic pituitary adenomas, sporadic and familial parathyroid neoplasms, and pancreatic endocrine tumors including insulinoma, glucagonoma, vasointestinal peptide tumor, and nonfunctional tumors. Although gastrinomas account for the majority of both sporadic and familial pancreatic endocrine tumors, LOH had not previously been demonstrated for this form. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1352275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Courseaux, A., Grosgeorge, J., Gaudray, P., Pannett, A. A. J., Forbes, S. A., Williamson, C., Bassett, D., Thakker, R. V., Teh, B. T., Farnebo, F., Shepherd, J., Skogseid, B., Larsson, C., Giraud, S., Zhang, C. X., Salandre, J., Calender, A. &lt;strong&gt;Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13.&lt;/strong&gt; Genomics 37: 354-365, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8938448/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8938448&lt;/a&gt;]" pmid="8938448">Courseaux et al. (1996)</a> used a combination of methods to refine maps of the approximately 5-Mb region of 11q13 that includes MEN1. They proposed the following gene order: cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1--[MLK3, RELA]--FOSL1--SEA--CFL1--tel. The location of MEN1 was narrowed to a 2-Mb region beginning centromeric to COX8 and extending to approximately CAPN1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8938448" 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="Guru, S. C., Agarwal, S. K., Manickam, P., Olufemi, S.-E., Crabtree, J. S., Weisemann, J. M., Kester, M. B., Kim, Y. S., Wang, Y., Emmert-Buck, M. R., Liotta, L. A., Spiegel, A. M., Boguski, M. S., Roe, B. A., Collins, F. S., Marx, S. J., Burns, L., Chandrasekharappa, S. C. &lt;strong&gt;A transcript map for the 2.8-Mb region containing the multiple endocrine neoplasia type 1 locus.&lt;/strong&gt; Genome Res. 7: 725-735, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9253601/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9253601&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=9253601[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1101/gr.7.7.725&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9253601">Guru et al. (1997)</a> mapped and sequenced the MEN1 genomic region. They produced a precisely ordered map of 33 transcribed genes within this 2-Mb region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9253601" 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="#109" class="mim-tip-reference" title="The European Consortium on MEN1. &lt;strong&gt;Construction of a 1.2-Mb sequence-ready contig of chromosome 11q13 encompassing the multiple endocrine neoplasia type 1 (MEN1) gene.&lt;/strong&gt; Genomics 44: 94-100, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9286704/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9286704&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/geno.1997.4872&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9286704">The European Consortium on MEN1 (1997)</a> constructed a 1.2-Mb sequence-ready contig encompassing the MEN1 region. They described 3 gene clusters, including the central cluster which contains the MEN1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9286704" 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>From a comparative mapping analysis of 10q and the pericentric region of 11q in the human and mouse chromosome 19, <a href="#86" class="mim-tip-reference" title="Rochelle, J. M., Watson, M. L., Oakey, R. J., Seldin, M. F. &lt;strong&gt;A linkage map of mouse chromosome 19:definition of comparative mapping relationships with human chromosomes 10 and 11 including the MEN1 locus.&lt;/strong&gt; Genomics 14: 26-31, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1358795/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1358795&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0888-7543(05)80278-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1358795">Rochelle et al. (1992)</a> concluded that the murine homolog of the MEN1 locus may lie in the proximal segment of chromosome 19. By FISH, <a href="#47" class="mim-tip-reference" title="Guru, S. C., Crabtree, J. S., Brown, K. D., Dunn, K. J., Manickam, P., Prasad, N. B., Wangsa, D., Burns, A. L., Spiegel, A. M., Marx, S. J., Pavan, W. J., Collins, F. S., Chandrasekharappa, S. C. &lt;strong&gt;Isolation, genomic organization, and expression analysis of Men1, the murine homolog of the MEN1 gene.&lt;/strong&gt; Mammalian Genome 10: 592-596, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10341092/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10341092&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s003359901051&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10341092">Guru et al. (1999)</a> mapped the mouse Men1 gene to chromosome 19 in a region showing homology of synteny to human chromosome 11q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1358795+10341092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p><a href="#21" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. &lt;strong&gt;Positional cloning of the gene for multiple endocrine neoplasia-type 1.&lt;/strong&gt; Science 276: 404-406, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9103196/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9103196&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.276.5311.404&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified several MEN1 candidate genes in a previously identified minimal interval on 11q13. <a href="#21" class="mim-tip-reference" title="Chandrasekharappa, S. C., Guru, S. C., Manickam, P., Olufemi, S.-E., Collins, F. S., Emmert-Buck, M. R., Debelenko, L. V., Zhuang, Z., Lubensky, I. A., Liotta, L. A., Crabtree, J. S., Wang, Y., Roe, B. A., Weisemann, J., Boguski, M. S., Agarwal, S. K., Kester, M. B., Kim, Y. S., Heppner, C., Dong, Q., Spiegel, A. M., Burns, A. L., Marx, S. J. &lt;strong&gt;Positional cloning of the gene for multiple endocrine neoplasia-type 1.&lt;/strong&gt; Science 276: 404-406, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9103196/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9103196&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.276.5311.404&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9103196">Chandrasekharappa et al. (1997)</a> identified mutations in one of these genes, designated MEN1, in 14 probands from 15 families. Twelve different heterozygous mutations (<a href="/entry/613733#0001">613733.0001</a>-<a href="/entry/613733#0012">613733.0012</a>) were identified (5 frameshift, 3 nonsense, 2 missense, and 2 in-frame deletions). Most of the mutations predicted loss of function of the protein, consistent with a tumor suppressor mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9103196" 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="#64" class="mim-tip-reference" title="Lemmens, I., Van de Ven, W. J. M., Kas, K., Zhang, C. X., Giraud, S., Wautot, V., Buisson, N., De Witte, K., Salandre, J., Lenoir, G., Pugeat, M., Calender, A., and 19 others. &lt;strong&gt;Identification of the multiple endocrine neoplasia type 1 (MEN1) gene.&lt;/strong&gt; Hum. Molec. Genet. 6: 1177-1183, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9215690/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9215690&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/6.7.1177&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9215690">Lemmens et al. (1997)</a> independently identified the MEN1 gene, which they had designated SCG2, and found 9 different heterozygous mutations in 10 unrelated MEN1 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9215690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Agarwal, S. K., Kester, M. B., Debelenko, L. V., Heppner, C., Emmert-Buck, M. R., Skarulis, M. C., Doppman, J. L., Kim, Y. S., Lubensky, I. A., Zhuang, Z., Green, J. S., Guru, S. C., Manickam, P., Olufemi, S.-E., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L., Marx, S. J. &lt;strong&gt;Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states.&lt;/strong&gt; Hum. Molec. Genet. 6: 1169-1175, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9215689/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9215689&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/6.7.1169&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9215689">Agarwal et al. (1997)</a> extended their mutation analysis to 34 more unrelated familial MEN1 probands (to a total of 50 kindreds) and to 2 related disorders, sporadic MEN1 and familial hyperparathyroidism (<a href="/entry/145000">145000</a>). In 8 of 11 cases of sporadic MEN1, they found heterozygous germline MEN1 mutations (e.g., <a href="/entry/613733#0014">613733.0014</a>); such mutations were found in 47 of 50 familial MEN1 probands. They proved that the mutation was new in 1 case of sporadic MEN1. Among the familial MEN1 cases, 8 mutations were observed more than once. In all, 40 different mutations (32 familial and 8 sporadic) were distributed across the MEN1 gene. A predicted loss of function of the encoded menin protein supported the prediction that MEN1 is a tumor suppressor gene. No MEN1 germline mutations were found in 5 probands with familial hyperparathyroidism, suggesting that this disorder is often caused by mutation in another gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9215689" 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 affected members of the 4 families with MEN1 from the Burin peninsula in Newfoundland, who were previously described by <a href="#32" class="mim-tip-reference" title="Farid, N. R., Buehler, S., Russell, N. A., Maroun, F. B., Allerdice, P., Smyth, H. S. &lt;strong&gt;Prolactinomas in familial multiple endocrine neoplasia syndrome type I: relationship to HLA and carcinoid tumors.&lt;/strong&gt; Am. J. Med. 69: 874-880, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6108714/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6108714&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0002-9343(80)80013-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6108714">Farid et al. (1980)</a> and <a href="#11" class="mim-tip-reference" title="Bear, J. C., Briones-Urbina, R., Fahey, J. F., Farid, N. R. &lt;strong&gt;Variant multiple endocrine neoplasia I (MEN I-Burin): further studies and non-linkage to HLA.&lt;/strong&gt; Hum. Hered. 35: 15-20, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2857681/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2857681&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000153508&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2857681">Bear et al. (1985)</a>, <a href="#76" class="mim-tip-reference" title="Olufemi, S.-E., Green, J. S., Manickam, P., Guru, S. C., Agarwal, S. K., Kester, M. B., Dong, Q., Burns, A. L., Spiegel, A. M., Marx, S. J., Collins, F. S., Chandrasekharappa, S. C. &lt;strong&gt;Common ancestral mutation in the MEN1 gene is likely responsible for the prolactinoma variant of MEN1 (MEN1-Burin) in four kindreds from Newfoundland.&lt;/strong&gt; Hum. Mutat. 11: 264-269, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9554741/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9554741&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(SICI)1098-1004(1998)11:4&lt;264::AID-HUMU2&gt;3.0.CO;2-V&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9554741">Olufemi et al. (1998)</a> identified a mutation in the MEN1 gene (<a href="/entry/613733#0016">613733.0016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9554741+2857681+6108714" 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="Bassett, J. H. D., Forbes, S. A., Pannett, A. A. J., Lloyd, S. E., Christie, P. T., Wooding, C., Harding, B., Besser, G. M., Edwards, C. R., Monson, J. P., Sampson, J., Wass, J. A. H., Wheeler, M. H., Thakker, R. V. &lt;strong&gt;Characterization of mutations in patients with multiple endocrine neoplasia type 1.&lt;/strong&gt; Am. J. Hum. Genet. 62: 232-244, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9463336/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9463336&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/301729&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9463336">Bassett et al. (1998)</a> investigated 63 unrelated MEN1 kindreds (195 affected and 396 unaffected members) for mutations in the 2,790-bp coding region and splice sites, by SSCP and DNA sequence analysis. They identified 47 mutations (12 nonsense mutations, 21 deletions, 7 insertions, 1 donor splice site mutation, and 6 missense mutations) that were scattered throughout the coding region, together with 6 polymorphisms that had heterozygosity frequencies of 2 to 44%. More than 10% of the mutations arose de novo, and 4 mutation hotspots accounted for more than 25% of the mutations. SSCP was found to be a sensitive and specific mutational screening method that detected more than 85% of the mutations. MEN1 mutant-gene carrier status was detected in 201 individuals (155 affected and 46 unaffected). By analysis of these cases, they defined the age-related penetrance of MEN1 as 7%, 52%, 87%, 98%, 99%, and 100% at 10, 20, 30, 40, 50, and 60 years of age, respectively. The number of disease alleles and the frequent occurrence of de novo mutations, often at hotspots with short repeat sequences, suggested that haplotype analysis is of limited use for the diagnosis of MEN1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9463336" 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="#103" class="mim-tip-reference" title="Tanaka, C., Yoshimoto, K., Yamada, S., Nishioka, H., Ii, S., Moritani, M., Yamaoka, T., Itakura, M. &lt;strong&gt;Absence of germ-line mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in familial pituitary adenoma in contrast to MEN1 in Japanese.&lt;/strong&gt; J. Clin. Endocr. Metab. 83: 960-965, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9506756/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9506756&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.83.3.4653&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9506756">Tanaka et al. (1998)</a> studied germline mutations of the MEN1 gene in 5 cases of familial and 4 cases of sporadic multiple endocrine neoplasia type I, 6 cases in 3 independent pedigrees of familial pituitary adenoma without MEN1, and 3 cases of familial primary hyperparathyroidism in Japanese patients. Eight different types of germline mutations in all 9 MEN1 cases were distributed in exons 2, 3, 7, and 10 and intron 7 of the MEN1 gene. Loss of heterozygosity (LOH) on 11q13 was detected in all 9 tumors of the cases with microsatellite analysis. No germline mutation of the MEN1 gene was detected in 3 pedigrees of familial pituitary adenoma and 3 cases of familial primary hyperparathyroidism. LOH on 11q13 was detected in 2 cases in 1 pedigree of familial pituitary adenoma, and 1 of them showed a heterozygous somatic mutation of the MEN1 gene. No LOH on 11q13 was detected in 3 cases of familial primary hyperparathyroidism. The authors concluded that the loss of function of MEN1 causes familial or sporadic MEN1, but does not cause familial primary hyperparathyroidism or most familial pituitary adenoma without MEN1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9506756" 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>Both alleles of the MEN1 gene at 11q13 are mutated in the majority of MEN1 tumors. <a href="#53" class="mim-tip-reference" title="Hessman, O., Skogseid, B., Westin, G., Akerstrom, G. &lt;strong&gt;Multiple allelic deletions and intratumoral genetic heterogeneity in MEN1 pancreatic tumors.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 1355-1361, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11238532/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11238532&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.3.7332&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11238532">Hessman et al. (2001)</a> performed a genomewide LOH screening of 23 pancreatic lesions, 1 duodenal tumor, and 1 thymic carcinoid from 13 MEN1 patients. Multiple allelic deletions were found. Fractional allelic loss varied from 6 to 75% (mean 31%). All pancreatic tumors displayed LOH on chromosome 11, whereas the frequency of losses for chromosomes 3, 6, 8, 10, 18, and 21 was over 30%. Different lesions from individual patients had discrepant patterns of LOH. Intratumoral heterogeneity was revealed, with chromosome 6 and 11 deletions in most tumor cells, whereas other chromosomal loci were deleted in portions of the analyzed tumor. Chromosome 6 deletions were mainly found in lesions from patients with malignant features. Fractional allelic loss did not correlate to malignancy or to tumor size. The authors concluded that MEN1 pancreatic tumors fail to maintain DNA integrity and demonstrate signs of chromosomal instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11238532" 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>Lipomatous tumors are known to occur in a relatively high proportion of patients with MEN1. By fluorescence in situ hybridization analysis of lipomas from 2 patients with MEN1, <a href="#115" class="mim-tip-reference" title="Vortmeyer, A. O., Boni, R., Pak, E., Pack, S., Zhuang, Z. &lt;strong&gt;Multiple endocrine neoplasia 1 gene alterations in MEN1-associated and sporadic lipomas. (Letter)&lt;/strong&gt; J. Nat. Cancer Inst. 90: 398-399, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9498491/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9498491&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/jnci/90.5.398&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9498491">Vortmeyer et al. (1998)</a> demonstrated deletion of 1 MEN1 allele in 53% of cells examined from case 1 and in 63% of cells examined from case 2. In both cases, both MEN1 gene copies were visualized in normal cellular constituents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9498491" 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="Giraud, S., Zhang, C. X., Serova-Sinilnikova, O., Wautot, V., Salandre, J., Buisson, N., Waterlot, C., Bauters, C., Porchet, N., Aubert, J.-P., Emy, P., Cadiot, G., and 29 others. &lt;strong&gt;Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders.&lt;/strong&gt; Am. J. Hum. Genet. 63: 455-467, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9683585/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9683585&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/301953&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9683585">Giraud et al. (1998)</a> studied a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors. They screened for MEN1 germline mutations by heteroduplex and sequence analysis of the gene-coding region of the MEN1 gene and its untranslated exon 1. Germline MEN1 alterations were identified in 47 of 54 (87%) MEN1 families, in 9 of 11 (82%) isolated MEN1 patients, and in only 6 of 19 (31.5%) atypical MEN1-related inherited cases. They characterized 52 distinct mutations in a total of 62 MEN1 germline alterations. Truncating mutations, frameshifts and nonsense mutations, accounted for 35 of the 52 alterations. No genotype/phenotype correlation could be made. Age-related penetrance was estimated to be more than 95% over age 30 years. No MEN1 germline mutations were found in 7 of 54 (13%) MEN1 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683585" 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="#106" class="mim-tip-reference" title="Teh, B. T., Kytola, S., Farnebo, F., Bergman, L., Wong, F. K., Weber, G., Hayward, N., Larsson, C., Skogseid, B., Beckers, A., Phelan, C., Edwards, M., and 29 others. &lt;strong&gt;Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism.&lt;/strong&gt; J. Clin. Endocr. Metab. 83: 2621-2626, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9709921/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9709921&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.83.8.5059&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9709921">Teh et al. (1998)</a> performed MEN1 mutation analysis in 55 MEN1 families from 7 countries, 13 isolated MEN1 cases without family history of the disease, 8 acromegaly families, and 4 familial isolated hyperparathyroidism (FIHP) families. Mutations were identified in samples from 27 MEN1 families and 9 isolated cases. The 22 different mutations were distributed across most of the 9 translated exons and included 11 frameshift, 6 nonsense, 2 splice site, and 2 missense mutations, and 1 in-frame deletion. Among the 19 Finnish MEN1 probands, a 1466del12 (<a href="/entry/613733#0032">613733.0032</a>) mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases, indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was identified in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common 'warm' spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case, 1 mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved, and that additional families of these types need to be analyzed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9709921" 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="Sato, M., Matsubara, S., Miyauchi, A., Ohye, H., Imachi, H., Murao, K., Takahara, J. &lt;strong&gt;Identification of five novel germline mutations of the MEN1 gene in Japanese multiple endocrine neoplasia type 1 (MEN1) families.&lt;/strong&gt; J. Med. Genet. 35: 915-919, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9832038/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9832038&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.35.11.915&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9832038">Sato et al. (1998)</a> studied 8 unrelated Japanese families. These included 5 with familial MEN1, 2 with sporadic MEN1, and 1 with familial hyperparathyroidism. Six different mutations were identified, including 1 missense mutation, 3 deletions, and 2 nonsense mutations. In 1 proband with familial MEN1, no mutation was identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9832038" 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 Spain, <a href="#20" class="mim-tip-reference" title="Cebrian, A., Herrera-Pombo, J. L., Diez, J. J., Sanchez-Vilar, O., Lara, J. I., Vazquez, C., Pico, A., Osorio, A., Martinez-Delgado, B., Benitez, J., Robledo, M. &lt;strong&gt;Genetic and clinical analysis in 10 Spanish patients with multiple endocrine neoplasia type 1.&lt;/strong&gt; Europ. J. Hum. Genet. 7: 585-589, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10439966/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10439966&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.ejhg.5200336&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10439966">Cebrian et al. (1999)</a> studied 10 unrelated MEN1 kindreds by a complete sequencing analysis of the entire MEN1 gene. Mutations were identified in 9 of them: 5 deletions, 1 insertion, 2 nonsense mutations, and a complex alteration consisting of a deletion and an insertion that can be explained by a hairpin loop model. Two of the mutations had been described; the other 7 were novel, and they were scattered throughout the coding sequence of the gene. As in previous series, no correlation was found between phenotype and genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10439966" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The observation of LOH involving 11q13 in MEN1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the '2-hit' model of hereditary cancer. The second hit in MEN1 tumors typically involves large chromosomal deletions that include 11q13. However, this only represents one mechanism by which the second hit may occur. <a href="#77" class="mim-tip-reference" title="Pannett, A. A. J., Thakker, R. V. &lt;strong&gt;Somatic mutations in MEN type 1 tumors, consistent with the Knudson &#x27;two-hit&#x27; hypothesis.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 4371-4374, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11549677/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11549677&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.9.7844&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11549677">Pannett and Thakker (2001)</a> searched for other mechanisms, such as intragenic deletions or point mutations that inactivate the MEN1 gene, in 6 MEN1 tumors (4 parathyroid tumors, 1 insulinoma, and 1 lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883, and PYGM centromerically and D11S449 and D11S913 telomerically. They found 4 somatic mutations, which consisted of 2 missense mutations and 2 frameshift mutations, in 2 parathyroid tumors, 1 insulinoma, and 1 lipoma. The authors concluded that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by the Knudson '2-hit' hypothesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11549677" 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="#79" class="mim-tip-reference" title="Perren, A., Anlauf, M., Henopp, T., Rudolph, T., Schmitt, A., Raffel, A., Gimm, O., Weihe, E., Knoefel, W. T., Dralle, H., Heitz, P. U., Komminoth, P., Kloppel, G. &lt;strong&gt;Multiple endocrine neoplasia type 1 (MEN1): loss of one MEN1 allele in tumors and monohormonal endocrine cell clusters but not in islet hyperplasia of the pancreas.&lt;/strong&gt; J. Clin. Endocr. Metab. 92: 1118-1128, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17179192/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17179192&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2006-1944&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17179192">Perren et al. (2007)</a> hypothesized that monohormonal endocrine cell clusters observed in MEN1 patients are small neoplasms with loss of heterozygosity of the MEN1 locus. Loss of one MEN1 allele was found in all 27 microadenomas and 19 of 20 (95%) monohormonal endocrine cell clusters. By contrast, it was absent in islets and ductal or acinar structures. <a href="#79" class="mim-tip-reference" title="Perren, A., Anlauf, M., Henopp, T., Rudolph, T., Schmitt, A., Raffel, A., Gimm, O., Weihe, E., Knoefel, W. T., Dralle, H., Heitz, P. U., Komminoth, P., Kloppel, G. &lt;strong&gt;Multiple endocrine neoplasia type 1 (MEN1): loss of one MEN1 allele in tumors and monohormonal endocrine cell clusters but not in islet hyperplasia of the pancreas.&lt;/strong&gt; J. Clin. Endocr. Metab. 92: 1118-1128, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17179192/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17179192&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2006-1944&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17179192">Perren et al. (2007)</a> concluded that the frequent presence of single nonneoplastic insulin cells in microadenomas and the occurrence of microadenomas in islets suggest an islet origin of microadenomas. Islet hyperplasia does not seem to be an obligatory stage in pancreatic MEN1-associated tumor development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17179192" 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 exhaustive sequence analysis of probands belonging to 170 unrelated MEN1 families collected through a French clinical network, <a href="#117" class="mim-tip-reference" title="Wautot, V., Vercherat, C., Lespinasse, J., Chambe, B., Lenoir, G. M., Zhang, C. X., Porchet, N., Cordier, M., Beroud, C., Calender, A. &lt;strong&gt;Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein.&lt;/strong&gt; Hum. Mutat. 20: 35-47, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12112656/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12112656&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.10092&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12112656">Wautot et al. (2002)</a> identified 165 mutations located in coding parts of the MEN1 gene, which represented 114 distinct MEN1 germline alterations. The mutations, which were spread over the entire coding sequence, included 56 frameshifts, 23 nonsense, 27 missense, and 8 deletion or insertion in-frame mutations. These mutations were included in a MEN1 locus-specific database available on the Internet together with approximately 240 germline and somatic MEN1 mutations listed from international published data. Taken together, most missense and in-frame MEN1 genomic alterations affected 1 or all domains of menin interacting with JUND (<a href="/entry/165162">165162</a>), SMAD3, and nuclear factor kappa-B (NFKB1; <a href="/entry/164011">164011</a>), 3 major effectors in transcription and cell growth regulation. No correlation was observed between genotype and MEN1 phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12112656" 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="#110" class="mim-tip-reference" title="Turner, J. J. O., Leotlela, P. D., Pannett, A. A. J., Forbes, S. A., Bassett, J. H. D., Harding, B., Christie, P. T., Bowen-Jones, D., Ellard, S., Hattersley, A., Jackson, C. E., Pope, R., Quarrell, O. W., Trembath, R., Thakker, R. V. &lt;strong&gt;Frequent occurrence of an intron 4 mutation in multiple endocrine neoplasia type I.&lt;/strong&gt; J. Clin. Endocr. Metab. 87: 2688-2693, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12050235/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12050235&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.87.6.8607&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12050235">Turner et al. (2002)</a> ascertained 34 unrelated MEN1 probands and performed DNA sequence analysis. They identified 17 different mutations in 24 probands: 2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletion-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a G-to-A transition that resulted in a novel acceptor splice site in IVS4 (<a href="/entry/613733#0024">613733.0024</a>). The IVS4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this IVS4 mutation is the most frequently occurring germline MEN1 mutation, accounting for approximately 10% of all mutations, and together with 5 others at codons 83-84, 118-119 (<a href="/entry/613733#0025">613733.0025</a>), 209-211 (<a href="/entry/613733#0026">613733.0026</a>), 418 (<a href="/entry/613733#0027">613733.0027</a>), and 516 (<a href="/entry/613733#0028">613733.0028</a>) accounts for 36.6% of all mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050235" 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 3 members of a Japanese family with MEN1 and a predisposition to insulinoma, <a href="#75" class="mim-tip-reference" title="Okamoto, H., Tamada, A., Hai, N., Doi, M., Uchimura, I., Hirata, Y., Kosugi, S. &lt;strong&gt;A novel six-nucleotide insertion in exon 4 of the MEN1 gene, 878insCTGCAG, in three patients with familial insulinoma and primary hyperparathyroidism.&lt;/strong&gt; Jpn. J. Clin. Oncol. 32: 368-370, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12417605/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12417605&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/jjco/hyf079&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12417605">Okamoto et al. (2002)</a> identified a heterozygous germline mutation in exon 4 of the MEN1 gene (<a href="/entry/613733#0030">613733.0030</a>). Chi square analysis of 72 MEN1 patients with or without germline mutations in exon 4 and with or without insulinomas showed a significant difference (p = 0.0022), suggesting a possible correlation between insulinoma development and mutations in exon 4 where JunD binding occurs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12417605" 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="Park, J.-H., Kim, I.-J., Kang, H. C., Lee, S.-H., Shin, Y., Kim, K.-H., Lim, S.-B., Kang, S.-B., Lee, K. U., Kim, S. Y., Lee, M.-S., Lee, M.-K., Park, J.-H., Moon, S.-D., Park, J.-G. &lt;strong&gt;Germline mutations of the MEN1 gene in Korean families with multiple endocrine neoplasia type 1 (MEN1) or MEN1-related disorders.&lt;/strong&gt; Clin. Genet. 64: 48-53, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12791038/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12791038&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1034/j.1399-0004.2003.00091.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12791038">Park et al. (2003)</a> investigated 5 Korean families with MEN1, 1 family with familial isolated hyperparathyroidism and 1 family with familial pituitary adenoma. Four germline mutations were identified in 5 typical MEN1 families. All of these mutations led to truncated proteins or a change in the amino acids of the functional domains. No MEN1 germline mutations were detected in the 2 families with FIHP or familial pituitary adenoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791038" 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 church records and MEN1 family information for the 2 founder MEN1 mutations in Northern Finland, 1466del12 (<a href="/entry/613733#0032">613733.0032</a>) and 1657insC (<a href="/entry/613733#0033">613733.0033</a>), <a href="#29" class="mim-tip-reference" title="Ebeling, T., Vierimaa, O., Kytola, S., Leisti, J., Salmela, P. I. &lt;strong&gt;Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations.&lt;/strong&gt; J. Clin. Endocr. Metab. 89: 3392-3396, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15240620/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15240620&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2003-031513&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15240620">Ebeling et al. (2004)</a> traced back common ancestors born in the beginning of the 1700s (1466del12) and approximately 1850 (1657insC) and found 67 probable carriers born between 1728 and 1929, among their offspring. Information was gathered from 34 obligatory MEN1 gene carriers and 31 spouses. The mean age of death of affected males was 61.1 years versus 65.8 years for unaffected males, and for affected females was 67.2 years versus 67.7 years for unaffected females. The ages of death of the obligatory heterozygotes did not differ from that of the spouses in sex groups or from the sex matched life expectancy estimates derived from Finnish national statistics. The authors concluded that obligatory MEN1 gene carrier status did not show a harmful effect on survival in this retrospective analysis tracing back to almost 300 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15240620" 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="#65" class="mim-tip-reference" title="Lemos, M. C., Thakker, R. V. &lt;strong&gt;Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene.&lt;/strong&gt; Hum. Mutat. 29: 22-32, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17879353/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17879353&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.20605&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17879353">Lemos and Thakker (2008)</a> provided a detailed review of the clinical aspects and molecular genetics of MEN1. The majority of the 1,336 mutations reported to date are predicted to result in truncated forms of menin and are scattered throughout the gene. There were no apparent genotype/phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17879353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Primary Isolated Hyperparathyroidism, MEN1 Variant</em></strong></p><p>
In a Caucasian English family in which 7 family members from 2 generations had primary isolated hyperparathyroidism (see <a href="/entry/145000">145000</a>), <a href="#105" class="mim-tip-reference" title="Teh, B. T., Esapa, C. T., Houlston, R., Grandell, U., Farnebo, F., Nordenskjold, M., Pearce, C. J., Carmichael, D., Larsson, C., Harris, P. E. &lt;strong&gt;A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors. (Letter)&lt;/strong&gt; Am. J. Hum. Genet. 63: 1544-1549, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9792884/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9792884&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302097&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9792884">Teh et al. (1998)</a> found that affected members had a germline missense mutation in the MEN1 gene (<a href="/entry/613733#0020">613733.0020</a>). This appeared to be the first study to demonstrate that familial isolated primary hyperparathyroidism can occur as a variant of MEN1. The pattern of transmission was autosomal dominant with high penetrance. Clinically, the hyperparathyroidism ran a rather mild course, as evidenced by 2 affected subjects who declined surgery and yet developed no obvious complications. Pathologically, the multiglandular parathyroid disease was consistent with that of MEN1. In 2 individuals, <a href="#105" class="mim-tip-reference" title="Teh, B. T., Esapa, C. T., Houlston, R., Grandell, U., Farnebo, F., Nordenskjold, M., Pearce, C. J., Carmichael, D., Larsson, C., Harris, P. E. &lt;strong&gt;A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors. (Letter)&lt;/strong&gt; Am. J. Hum. Genet. 63: 1544-1549, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9792884/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9792884&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/302097&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9792884">Teh et al. (1998)</a> demonstrated loss of heterozygosity (LOH) in the parathyroid tumors, consistent with the Knudson 2-hit model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9792884" 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 61-year-old Japanese woman and 2 of her sons, aged 38 and 33 years, all with hyperparathyroidism due to parathyroid adenomas. <a href="#38" class="mim-tip-reference" title="Fujimori, M., Shirahama, S., Sakurai, A., Hashizume, K., Hama, Y., Ito, K., Shingu, K., Kobayashi, S., Amano, J., Fukushima, Y. &lt;strong&gt;Novel V184E MEN1 germline mutation in a Japanese kindred with familial hyperparathyroidism.&lt;/strong&gt; Am. J. Med. Genet. 80: 221-222, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9843042/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9843042&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19981116)80:3&lt;221::aid-ajmg8&gt;3.0.co;2-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9843042">Fujimori et al. (1998)</a> identified a missense mutation in the MEN1 gene (<a href="/entry/613733#0021">613733.0021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9843042" 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="#116" class="mim-tip-reference" title="Warner, J., Epstein, M., Sweet, A., Singh, D., Burgess, J., Stranks, S., Hill, P., Perry-Deene, D., Learoyd, D., Robinson, B., Birdsey, P., Mackenzie, E., Teh, B. T., Prins, J. B., Cardinal, J. &lt;strong&gt;Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications.&lt;/strong&gt; J. Med. Genet. 41: 155-160, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14985373/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14985373&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2003.016725&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14985373">Warner et al. (2004)</a> screened 22 unrelated patients with FIHP for mutations in the MEN1, CASR (<a href="/entry/601199">601199</a>) and HRPT2 (CDC73; <a href="/entry/607393">607393</a>) genes. They identified 5 patients with MEN1 mutations, 4 with CASR mutations, and none with HRPT2 mutations. All 9 patients in whom mutations were found had multiglandular hyperparathyroidism. The patients with CASR mutations did not have biochemical findings of hypocalciuric hypercalcemia. <a href="#116" class="mim-tip-reference" title="Warner, J., Epstein, M., Sweet, A., Singh, D., Burgess, J., Stranks, S., Hill, P., Perry-Deene, D., Learoyd, D., Robinson, B., Birdsey, P., Mackenzie, E., Teh, B. T., Prins, J. B., Cardinal, J. &lt;strong&gt;Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications.&lt;/strong&gt; J. Med. Genet. 41: 155-160, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14985373/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14985373&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.2003.016725&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14985373">Warner et al. (2004)</a> recommended MEN1 and CASR genotyping in patients with multiglandular FIHP, regardless of urinary calcium excretion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14985373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MEN1 Somatic Mutations</em></strong></p><p>
<a href="#50" class="mim-tip-reference" title="Heppner, C., Kester, M. B., Agarwal, S. K., Debelenko, L. V., Emmert-Buck, M. R., Guru, S. C., Manickam, P., Olufemi, S.-E., Skarulis, M. C., Doppman, J. L., Alexander, R. H., Kim, Y. S., Saggar, S. K., Lubensky, I. A., Zhuang, Z., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L., Marx, S. J. &lt;strong&gt;Somatic mutation of the MEN1 gene in parathyroid tumours.&lt;/strong&gt; Nature Genet. 16: 375-378, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9241276/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9241276&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0897-375&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9241276">Heppner et al. (1997)</a> found somatic mutation of the MEN1 gene in 21% of parathyroid tumors not associated with MEN1, representing 54% of parathyroid tumors with 11q13 LOH. The authors suggested that parathyroid tumor formation in kindreds with somatic mutation of MEN1 may be initiated by germline mutation of an unidentified tumor suppressor gene or oncogene. The finding of somatic mutation (<a href="/entry/613733#0013">613733.0013</a>) in a single tumor from a member of such a kindred indicated that somatic MEN1 gene mutation may also contribute to tumorigenesis in such individuals. Previous studies had found frequent 11q13 LOH in sporadic tumors as follows: gastrinoma (45%), insulinoma (19%), anterior pituitary gland tumors (3 to 30%), carcinoid tumors (78%), thyroid follicular tumors (15%), and aldosteronomas (36%). <a href="#50" class="mim-tip-reference" title="Heppner, C., Kester, M. B., Agarwal, S. K., Debelenko, L. V., Emmert-Buck, M. R., Guru, S. C., Manickam, P., Olufemi, S.-E., Skarulis, M. C., Doppman, J. L., Alexander, R. H., Kim, Y. S., Saggar, S. K., Lubensky, I. A., Zhuang, Z., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L., Marx, S. J. &lt;strong&gt;Somatic mutation of the MEN1 gene in parathyroid tumours.&lt;/strong&gt; Nature Genet. 16: 375-378, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9241276/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9241276&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0897-375&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9241276">Heppner et al. (1997)</a> suggested that many of these tumors likewise may have MEN1 somatic mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9241276" 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="Carling, T., Correa, P., Hessman, O., Hedberg, J., Skogseid, B., Lindberg, D., Rastad, J., Westin, G., Akerstrom, G. &lt;strong&gt;Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism.&lt;/strong&gt; J. Clin. Endocr. Metab. 83: 2960-2963, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9709976/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9709976&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.83.8.4977&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9709976">Carling et al. (1998)</a> used microsatellite analysis for LOH at 11q13 and DNA sequencing of the coding exons to study the MEN1 gene in 49 parathyroid lesions of patients with nonfamilial primary hyperparathyroidism. Allelic loss at 11q13 was detected in 13 tumors, 6 of which had previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of these mutations were predicted to encode a nonfunctional menin protein, consistent with a tumor suppressor mechanism. While the clinical and biochemical characteristics of hyperparathyroidism were apparently unrelated to LOH at 11q13 and the MEN1 gene mutations, the demonstration of LOH and MEN1 gene mutations in small parathyroid adenomas of patients who had slight hypercalcemia and normal serum parathyroid hormone (<a href="/entry/168450">168450</a>) levels suggested that altered MEN1 gene function may also be important for the development of mild sporadic primary hyperparathyroidism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9709976" 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="#35" class="mim-tip-reference" title="Farnebo, F., Teh, B. T., Kytola, S., Svensson, A., Phelan, C., Sandelin, K., Thompson, N. W., Hoog, A., Weber, G., Farnebo, L.-O., Larsson, C. &lt;strong&gt;Alterations of the MEN1 gene in sporadic parathyroid tumors.&lt;/strong&gt; J. Clin. Endocr. Metab. 83: 2627-2630, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9709922/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9709922&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.83.8.4846&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9709922">Farnebo et al. (1998)</a> screened 45 sporadic tumors from 40 patients for alterations involving the MEN1 gene. Thirteen tumors showed LOH at 11q13, and in 6 of these cases, a somatic mutation of the MEN1 gene was detected. In tumors without LOH, no mutations were detected. The mutations consisted of 3 small deletions, 1 insertion, and 2 missense mutations that had not been reported in MEN1 patients or parathyroid tumors previously. Using mRNA in situ hybridization, the expression of the MEN1 gene was studied. The authors concluded that there was no difference in MEN1 expression between normal and tumor tissue, and that their findings of inactivating mutations in tumors with LOH at 11q13 confirmed the role of the MEN1 tumor suppressor gene in a subset of sporadic parathyroid tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9709922" 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 comparative genomic hybridization, <a href="#34" class="mim-tip-reference" title="Farnebo, F., Kytola, S., Teh, B. T., Dwight, T., Wong, F. K., Hoog, A., Elvius, M., Wassif, W. S., Thompson, N. W., Farnebo, L.-O., Sandelin, K., Larsson, C. &lt;strong&gt;Alternative genetic pathways in parathyroid tumorigenesis.&lt;/strong&gt; J. Clin. Endocr. Metab. 84: 3775-3780, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10523029/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10523029&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.84.10.6057&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10523029">Farnebo et al. (1999)</a> screened DNAs from 44 parathyroid tumors from 26 sporadic cases, 10 cases previously given irradiation to the neck, and 8 familial cases for sequence copy number alterations. In the sporadic adenomas, commonly occurring minimal regions of loss could be defined to chromosome 11 (38%), 15q15-qter (27%), and 1p34-pter (19%), whereas gains preferentially involved 19p13.2-pter (15%) and 7pter-qter (12%). Multiple aberrations were found in sporadic tumors with a somatic mutation and/or LOH of the MEN1 gene. The irradiation-associated tumors also showed multiple comparative genomic hybridization alterations and frequent losses of 11q (50%), and subsequent analysis of the MEN1 gene demonstrated mutations in 4 of 8 cases (50%). The majority of these alterations were found in tumors with confirmed involvement of the MEN1 gene, in agreement with a role of the MEN1 gene in genomic stability. The authors concluded that the frequent occurrence of MEN1 mutations in irradiation-associated parathyroid tumors suggests that inactivation of the MEN1 gene is an important genetic alteration involved in the development of parathyroid tumors in post-irradiation patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10523029" 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="#81" class="mim-tip-reference" title="Prezant, T. R., Levine, J., Melmed, S. &lt;strong&gt;Molecular characterization of the Men1 tumor suppressor gene in sporadic pituitary tumors.&lt;/strong&gt; J. Clin. Endocr. Metab. 83: 1388-1391, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9543172/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9543172&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.83.4.4859&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9543172">Prezant et al. (1998)</a> screened the complete coding sequence of the MEN1 gene for mutations in 45 sporadic anterior pituitary tumors, including 14 hormone-secreting tumors and 31 nonsecreting tumors, by dideoxy fingerprinting and sequence analysis. No pathogenic sequence changes were found in the MEN1 coding region. The MEN1 gene was expressed in 43 of these tumors with sufficient RNA, including 1 tumor with LOH for several polymorphic markers on chromosomal region 11q13. Also, both alleles were expressed in 19 tumors in which the constitutional DNA was heterozygous for intragenic polymorphisms. The authors concluded that inactivation of the MEN1 tumor suppressor gene, by mutation or by imprinting, does not appear to play a prominent role in sporadic pituitary adenoma pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9543172" 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="#51" class="mim-tip-reference" title="Heppner, C., Reincke, M., Agarwal, S. K., Mora, P., Allolio, B., Burns, A. L., Spiegel, A. M., Marx, S. J. &lt;strong&gt;MEN1 gene analysis in sporadic adrenocortical neoplasms.&lt;/strong&gt; J. Clin. Endocr. Metab. 84: 216-219, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9920087/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9920087&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.84.1.5388&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9920087">Heppner et al. (1999)</a> studied whether somatic inactivation of the MEN1 gene contributes to the pathogenesis of sporadic adrenocortical neoplasms. Thirty-three tumors and cell lines were screened for mutations throughout the MEN1 open reading frame and adjacent splice junctions. No mutations were detected within the MEN1 coding region. The authors concluded that somatic mutations within the MEN1 coding region do not occur commonly in sporadic adrenocortical tumors, although the majority of adrenocortical carcinomas exhibited 11q13 LOH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9920087" 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>To investigate the role of the MEN1 gene in sporadic lipomas, <a href="#115" class="mim-tip-reference" title="Vortmeyer, A. O., Boni, R., Pak, E., Pack, S., Zhuang, Z. &lt;strong&gt;Multiple endocrine neoplasia 1 gene alterations in MEN1-associated and sporadic lipomas. (Letter)&lt;/strong&gt; J. Nat. Cancer Inst. 90: 398-399, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9498491/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9498491&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/jnci/90.5.398&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9498491">Vortmeyer et al. (1998)</a> analyzed 6 sporadic tumors. In 1 case, SSCP analysis and subsequent sequencing revealed a 4-bp deletion in exon 2 (<a href="/entry/613733#0017">613733.0017</a>). This deletion was present only in the tumor tissue, and not in the normal tissue from the same patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9498491" 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>To identify chromosomal regions that may contain loci for tumor suppressor genes involved in adrenocortical tumor development, <a href="#56" class="mim-tip-reference" title="Kjellman, M., Roshani, L., Teh, B. T., Kallioniemi, O.-P., Hoog, A., Gray, S., Farnebo, L.-O., Holst, M., Backdahl, M., Larsson, C. &lt;strong&gt;Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16.&lt;/strong&gt; J. Clin. Endocr. Metab. 84: 730-735, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10022445/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10022445&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.84.2.5506&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10022445">Kjellman et al. (1999)</a> screened a panel of 60 tumors (39 carcinomas and 21 adenomas) for loss of heterozygosity. The vast majority of LOH detected was in the carcinomas involving chromosomes 2, 4, 11, and 18; little was found in the adenomas. The Carney complex (<a href="/entry/160980">160980</a>) and the MEN1 loci on 2p16 and 11q13, respectively, were further studied in 27 (13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of the 2p16 region mapped a minimal area of overlapping deletions to a 1-cM region that is separate from the Carney complex locus. LOH for PYGM was detected in all 8 informative carcinomas and in 2 of 14 adenomas. Of the cases analyzed in detail, 13 of 27 (11 carcinomas and 2 adenomas) showed LOH on chromosome 11, and these were selected for MEN1 mutation analysis. In 6 cases a common polymorphism was found, but no mutation was detected. The authors concluded that LOH in 2p16 was strongly associated with the malignant phenotype, and LOH in 11q13 occurred frequently in carcinomas, but was not associated with a MEN1 mutation, suggesting the involvement of a different tumor suppressor gene on this chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10022445" 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>Hibernomas are benign tumors of brown fat, frequently characterized by aberrations of chromosome band 11q13. <a href="#42" class="mim-tip-reference" title="Gisselsson, D., Hoglund, M., Mertens, F., Del Cin, P., Mandahl, N. &lt;strong&gt;Hibernomas are characterized by homozygous deletions in the multiple endocrine neoplasia type I region: metaphase fluorescence in situ hybridization reveals complex rearrangements not detected by conventional cytogenetics.&lt;/strong&gt; Am. J. Path. 155: 61-66, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10393837/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10393837&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=10393837[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0002-9440(10)65099-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10393837">Gisselsson et al. (1999)</a> analyzed chromosome 11 changes in 5 hibernomas in detail by metaphase fluorescence in situ hybridization. In all cases, complex rearrangements leading to loss of chromosome 11 material were found. Deletions were present not only in those chromosomes that were shown to be rearranged by G-banding, but in 4 cases also in the ostensibly normal homologs, resulting in homozygous loss of several loci. Among these, the MEN1 gene was most frequently deleted. In addition to the MEN1 deletions, heterozygous loss of a second region, approximately 3 Mb distal to MEN1, was found in all 5 cases, adding to previous evidence for a second tumor suppressor locus in 11q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10393837" 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="#102" class="mim-tip-reference" title="Tahara, H., Imanishi, Y., Yamada, T., Tsujimoto, Y., Tabata, T., Inoue, T., Inaba, M., Morii, H., Nishizawa, Y. &lt;strong&gt;Rare somatic inactivation of the multiple endocrine neoplasia type 1 gene in secondary hyperparathyroidism of uremia.&lt;/strong&gt; J. Clin. Endocr. Metab. 85: 4113-4117, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11095441/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11095441&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.85.11.6950&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11095441">Tahara et al. (2000)</a> analyzed 81 parathyroid glands from 22 Japanese uremic patients for allelic loss on chromosomal arm 11q13 DNA using 3 flanking markers (PYGM, <a href="/entry/608455">608455</a>; D11S4946; and D11S449), and for mutations of the MEN1-coding exons by PCR-based SSCP analysis and sequencing. Allelic loss on 11q13 was observed in 6 glands (7%), and 1 of 6 demonstrated a previously unrecognized somatic frameshift deletion in MEN1. They inferred that this mutation would result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and pathologic characteristics of hyperparathyroidism were unrelated to the presence or absence of loss of heterozygosity on 11q13 and MEN1 gene mutations. The authors concluded that somatic inactivation of the MEN1 gene contributes to the pathogenesis of uremia-associated parathyroid tumors, but its role in this disease appears to be very limited. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11095441" 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="#87" class="mim-tip-reference" title="Sato, K., Obara, T., Yamazaki, K., Kanbe, M., Nakajima, K., Yamada, A., Yanagisawa, T., Kato, Y., Nishikawa, T., Takano, K. &lt;strong&gt;Somatic mutations of the MEN1 gene and microsatellite instability in a case of tertiary hyperparathyroidism occurring during high phosphate therapy for acquired, hypophosphatemic osteomalacia.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 5564-5571, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11701736/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11701736&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.11.7978&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11701736">Sato et al. (2001)</a> reported a male patient with adult-onset, hypophosphatemic osteomalacia who had been treated with 1-alpha-hydroxyvitamin D3 and oral phosphate for 13 years when tertiary hyperparathyroidism developed. Sequence analysis of the coding exons of the MEN1 gene revealed somatic MEN1 mutations in 2 of the 4 hyperplastic parathyroid glands, accompanied by loss of heterozygosity at the 11q13 locus in 1 gland. These findings suggested that the repeated increase in serum phosphate concentrations for a prolonged period may be related to tumorigenesis of the parathyroid gland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11701736" 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="#22" class="mim-tip-reference" title="Chedid, A., Hoversland, R. C., Chejfec, G., McCune, S. A., Jurin, R. R., Evans, E. E. &lt;strong&gt;Hereditary pituitary prolactinomas: a new rat model.&lt;/strong&gt; Acta Endocr. 119: 535-542, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3059738/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3059738&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1530/acta.0.1190535&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3059738">Chedid et al. (1988)</a> described hereditary pituitary prolactinomas in the rat. It was thought to be an autosomal dominant characteristic with incomplete penetrance and a greater incidence in males. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3059738" 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>To examine the role of MEN1 in tumor formation, <a href="#25" class="mim-tip-reference" title="Crabtree, J. S., Scacheri, P. C., Ward, J. M., Garrett-Beal, L., Emmert-Buck, M. R., Edgemon, K. A., Lorang, D., Libutti, S. K., Chandrasekharappa, S. C., Marx, S. J., Spiegel, A. M., Collins, F. S. &lt;strong&gt;A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors.&lt;/strong&gt; Proc. Nat. Acad. Sci. 98: 1118-1123, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11158604/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11158604&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11158604[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.98.3.1118&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11158604">Crabtree et al. (2001)</a> generated a mouse model through homologous recombination of the mouse homolog Men1. Homozygous null mice died in utero at embryonic days 11.5 to 12.5, whereas heterozygous mice developed features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets showed a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas were frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary were seen by 16 months. All of the tumors tested showed loss of the wildtype Men1 allele, further supporting the role of MEN1 as a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11158604" 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>Most tumor suppressor genes show a widespread pattern of expression, yet individuals with germline, heterozygous loss of function of such genes develop tumors in a restricted set of tissues. To investigate the paradox of tissue-specific tumor phenotype in MEN1, <a href="#90" class="mim-tip-reference" title="Scacheri, P. C., Crabtree, J. S., Kennedy, A. L., Swain, G. P., Ward, J. M., Marx, S. J., Spiegel, A. M., Collins, F. S. &lt;strong&gt;Homozygous loss of menin is well tolerated in liver, a tissue not affected in MEN1.&lt;/strong&gt; Mammalian Genome 15: 872-877, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15672591/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15672591&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00335-004-2395-z&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15672591">Scacheri et al. (2004)</a> bred mice homozygous for an Men1 gene with exons 3-8 flanked by loxP sites to transgenic mice expressing cre from the albumin promoter. This strategy allowed them to generate mice with homozygous deletion of the Men1 gene in liver, a tissue not normally predisposed to developing tumors in humans or mice with heterozygous MEN1 loss-of-function mutations. Livers that were completely null for menin expression appeared entirely normal and remained tumor free until late adulthood. These results narrowed the possible mechanisms of tissue specificity in MEN1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15672591" 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="Busygina, V., Suphapeetiporn, K., Marek, L. R., Stowers, R. S., Xu, T., Bale, A. E. &lt;strong&gt;Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1.&lt;/strong&gt; Hum. Molec. Genet. 13: 2399-2408, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15333582/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15333582&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddh271&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15333582">Busygina et al. (2004)</a> generated a null allele of Mnn1, the Drosophila homolog of the MEN1 gene, and showed that homozygous inactivation resulted in morphologically normal flies that are hypersensitive to ionizing radiation and 2 DNA crosslinking agents (nitrogen mustard and cisplatinum). The spectrum of agents to which mutant flies were sensitive and analysis of the molecular mechanisms of this sensitivity suggested a defect in nucleotide excision repair. Drosophila Mnn1 mutants had an elevated rate of both sporadic and DNA damage-induced mutations. In a genetic background heterozygous for lats (LATS1; <a href="/entry/603473">603473</a>), which is a Drosophila and vertebrate tumor suppressor gene, homozygous inactivation of Mnn1 enhanced somatic mutation of the second allele of lats and formation of multiple primary tumors. <a href="#17" class="mim-tip-reference" title="Busygina, V., Suphapeetiporn, K., Marek, L. R., Stowers, R. S., Xu, T., Bale, A. E. &lt;strong&gt;Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1.&lt;/strong&gt; Hum. Molec. Genet. 13: 2399-2408, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15333582/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15333582&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddh271&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15333582">Busygina et al. (2004)</a> concluded that Mnn1 is a novel member of the class of autosomal dominant cancer genes that function in maintenance of genomic integrity, similar to the BRCA1 (<a href="/entry/113705">113705</a>) and MSH2 (<a href="/entry/609309">609309</a>) genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15333582" 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>Wermer first reported 'his' syndrome in 1954, and Zollinger and Ellison 'theirs' in 1955 (see <a href="#119" class="mim-tip-reference" title="Wermer, P. &lt;strong&gt;Genetic aspects of adenomatosis of endocrine glands.&lt;/strong&gt; Am. J. Med. 16: 363-371, 1954.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13138607/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13138607&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(54)90353-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13138607">Wermer, 1954</a>; <a href="#123" class="mim-tip-reference" title="Zollinger, R. M., Ellison, E. H. &lt;strong&gt;Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas.&lt;/strong&gt; Ann. Surg. 142: 709-728, 1955.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13259432/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13259432&lt;/a&gt;]" pmid="13259432">Zollinger and Ellison, 1955</a>). The Zollinger-Ellison syndrome of intractable peptic ulcer with pancreatic islet adenoma is a facet of multiple endocrine adenomatosis. Recognition that the 2 eponymic syndromes are one subsequently occurred (<a href="#67" class="mim-tip-reference" title="Lulu, D. J., Corcoran, T. E., Andre, M. &lt;strong&gt;Familial endocrine adenomatosis with associated Zollinger-Ellison syndrome: Wermer&#x27;s syndrome.&lt;/strong&gt; Am. J. Surg. 115: 695-701, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4384624/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4384624&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9610(68)90104-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4384624">Lulu et al., 1968</a>), with multiple endocrine neoplasia type I (MEN1) as the preferred designation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4384624+13259432+13138607" 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 of 8 affected members of a family, <a href="#112" class="mim-tip-reference" title="Vance, J. E., Stoll, R. W., Kitabchi, A. E., Buchanan, K. D., Hollander, D., Williams, R. H. &lt;strong&gt;Familial nesidioblastosis as the predominant manifestation of multiple endocrine adenomatosis.&lt;/strong&gt; Am. J. Med. 52: 211-227, 1972.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4400504/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4400504&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0002-9343(72)90071-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4400504">Vance et al. (1972)</a> suggested that the primary genetic lesion in endocrine adenomatosis is one that leads to neoplasia and hyperfunction of the islets of Langerhans and that the other endocrine tumors arise as secondary effects of hypersecretion of islet hormones. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4400504" 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="#14" class="mim-tip-reference" title="Brandi, M. L., Aurbach, G. D., Fitzpatrick, L. A., Quarto, R., Spiegel, A. M., Bliziotes, M. M., Norton, J. A., Doppman, J. L., Marx, S. J. &lt;strong&gt;Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type 1.&lt;/strong&gt; New Eng. J. Med. 314: 1287-1293, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2871488/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2871488&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198605153142004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2871488">Brandi et al. (1986)</a> concluded that primary hyperparathyroidism in familial MEN type I may have a humoral cause. Since the mitogenic factor persists after parathyroidectomy, it evidently is not secreted by the hyperplastic glands themselves. It did not seem to be identical to any of the well-recognized circulating growth factors, nor did it have similar mitogenic effects on pancreatic or pituitary cells in vitro, despite the presence of islet cell and pituitary tumors in some of the same patients. Curiously, <a href="#14" class="mim-tip-reference" title="Brandi, M. L., Aurbach, G. D., Fitzpatrick, L. A., Quarto, R., Spiegel, A. M., Bliziotes, M. M., Norton, J. A., Doppman, J. L., Marx, S. J. &lt;strong&gt;Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type 1.&lt;/strong&gt; New Eng. J. Med. 314: 1287-1293, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2871488/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2871488&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198605153142004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2871488">Brandi et al. (1986)</a> did not detect a parathyroid mitogenic factor in patients with MEN II who also had hyperparathyroidism. <a href="#93" class="mim-tip-reference" title="Schimke, R. N. &lt;strong&gt;Multiple endocrine neoplasia: search for the oncogenic trigger. (Editorial)&lt;/strong&gt; New Eng. J. Med. 314: 1315-1316, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2871489/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2871489&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM198605153142010&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2871489">Schimke (1986)</a> suggested: 'Considered within the framework of a 2-step model, the general event in the multiple endocrine neoplasia syndromes may be an abnormality of a plasma-membrane receptor in the affected endocrine glands. The somatic mutation may involve derepression of a primitive gene coding for a protein that promotes the growth of endocrine glands.' The 'primitive gene' might be an oncogene. This would represent a rather different 2-mutation theory than the one that applies to retinoblastoma (<a href="/entry/180200">180200</a>) and Wilms tumor (<a href="/entry/194070">194070</a>). In this case the mutations are presumably at different loci. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2871489+2871488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>See Also:</strong>
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<a href="#Aach1969" class="mim-tip-reference" title="Aach, R., Kissane, J. M. &lt;strong&gt;Clinicopathologic conference: multiple endocrine adenomatosis.&lt;/strong&gt; Am. J. Med. 47: 608-618, 1969.">Aach and Kissane (1969)</a>; <a href="#Bale1989" class="mim-tip-reference" title="Bale, S. J., Bale, A. E., Stewart, K., Dachowski, L., McBride, O. W., Glaser, T., Green, J. E., III, Mulvihill, J. J., Brandi, M. L., Sakaguchi, K., Aurbach, G. D., Marx, S. J. &lt;strong&gt;Linkage analysis of multiple endocrine neoplasia type 1 with INT2 and other markers on chromosome 11.&lt;/strong&gt; Genomics 4: 320-322, 1989. Note: Erratum: Genomics 5: 166 only, 1989.">Bale et al. (1989)</a>; <a href="#Bale1989" class="mim-tip-reference" title="Bale, S. J., Bale, A. E., Stewart, K., Dachowski, L., McBride, O. W., Glaser, T., Green, J. E., III, Mulvihill, J. J., Brandi, M. L., Sakaguchi, K., Aurbach, G. D., Marx, S. J. &lt;strong&gt;Linkage analysis of multiple endocrine neoplasia type 1 with INT2 and other markers on chromosome 11.&lt;/strong&gt; Genomics 4: 320-322, 1989. Note: Erratum: Genomics 5: 166 only, 1989.">Bale et al. (1989)</a>; <a href="#Betts1980" class="mim-tip-reference" title="Betts, J. B., O&#x27;Malley, B. P., Rosenthal, F. D. &lt;strong&gt;Hyperparathyroidism: a prerequisite for Zollinger-Ellison syndrome in multiple endocrine adenomatosis type 1--report of a further family and a review of the literature.&lt;/strong&gt; Quart. J. Med. 49: 69-76, 1980.">Betts et al. (1980)</a>; <a href="#Buchta1971" class="mim-tip-reference" title="Buchta, R. M., Kaplan, J. M. &lt;strong&gt;Zollinger-Ellison syndrome in a nine-year-old child: a case report and review of the entity in childhood.&lt;/strong&gt; Pediatrics 47: 594-598, 1971.">Buchta and Kaplan (1971)</a>; <a href="#Cocco1975" class="mim-tip-reference" title="Cocco, A. E., Conway, S. J. &lt;strong&gt;Zollinger-Ellison syndrome associated with ovarian mucinous cystadenocarcinoma.&lt;/strong&gt; New Eng. J. Med. 293: 485-486, 1975.">Cocco and Conway
(1975)</a>; <a href="#Deveney1978" class="mim-tip-reference" title="Deveney, C. W., Deveney, K. S., Way, L. W. &lt;strong&gt;The Zollinger-Ellison syndrome--23 years later.&lt;/strong&gt; Ann. Surg. 188: 384-391, 1978.">Deveney et al. (1978)</a>; <a href="#Ellison1964" class="mim-tip-reference" title="Ellison, E. H., Wilson, S. D. &lt;strong&gt;The Zollinger-Ellison syndrome. Re-appraisal and evaluation of 260 registered cases.&lt;/strong&gt; Ann. Surg. 160: 512-530, 1964.">Ellison and Wilson (1964)</a>; <a href="#Ellison1967" class="mim-tip-reference" title="Ellison, E. H., Wilson, S. D. &lt;strong&gt;The Zollinger-Ellison syndrome updated.&lt;/strong&gt; Surg. Clin. N. Am. 47: 1115-1124, 1967.">Ellison and
Wilson (1967)</a>; <a href="#Friesen1972" class="mim-tip-reference" title="Friesen, S. R., Schimke, R. N., Pearse, A. G. E. &lt;strong&gt;Genetic aspects of the Z-E syndrome: prospective studies in two kindred: antral gastrin cell hyperplasia.&lt;/strong&gt; Ann. Surg. 176: 370-383, 1972.">Friesen et al. (1972)</a>; <a href="#Groussin1980" class="mim-tip-reference" title="Groussin, P., Renard, J.-P., Chavanne, D., Bertrand, G., Avril, J., Simier, J.-L. &lt;strong&gt;Antigens HLA d&#x27;une famille ayant une adenomatose polyendocrienne de type I. (Letter)&lt;/strong&gt; Nouv. Presse Med. 9: 1033-1034, 1980.">Groussin et al. (1980)</a>; <a href="#Guru1998" class="mim-tip-reference" title="Guru, S. C., Goldsmith, P. K., Burns, A. L., Marx, S. J., Spiegel, A. M., Collins, F. S., Chandrasekharappa, S. C. &lt;strong&gt;Menin, the product of the MEN1 gene, is a nuclear protein.&lt;/strong&gt; Proc. Nat. Acad. Sci. 95: 1630-1634, 1998.">Guru et
al. (1998)</a>; <a href="#Jones1970" class="mim-tip-reference" title="Jones, B. S., O&#x27;Hagan, J. J., Phear, D. N., Sheville, E. &lt;strong&gt;A case of the Zollinger-Ellison syndrome associated with hyperplasia of salivary and Brunner&#x27;s glands.&lt;/strong&gt; Gut 11: 837-839, 1970.">Jones et al. (1970)</a>; <a href="#Koch1959" class="mim-tip-reference" title="Koch, G., Tiwisina, T. &lt;strong&gt;Beitrag zur Erblichkeit der Akromegalie und der Hyperostosis generalisata mit Pachydermie.&lt;/strong&gt; Aerztl. Forsch. 13: 489-504, 1959.">Koch and Tiwisina (1959)</a>; <a href="#Koch1949" class="mim-tip-reference" title="Koch, G. &lt;strong&gt;Erbliche Hirngeschwuelste.&lt;/strong&gt; Z. Menschl. Vererb. Konstitutionsl. 29: 400-423, 1949.">Koch
(1949)</a>; <a href="#Lamers1979" class="mim-tip-reference" title="Lamers, C. B. H. W., Froeling, P. G. A. M. &lt;strong&gt;Clinical significance of hyperparathyroidism in familial multiple endocrine adenomatosis.&lt;/strong&gt; Am. J. Med. 66: 422-424, 1979.">Lamers and Froeling (1979)</a>; <a href="#Lamers1978" class="mim-tip-reference" title="Lamers, C. B. H. W., Stadil, F., van Tongeren, J. H. &lt;strong&gt;Prevalence of endocrine abnormalities in patients with the Zollinger-Ellison syndrome in their families.&lt;/strong&gt; Am. J. Med. 64: 607-612, 1978.">Lamers et al. (1978)</a>; <a href="#Mallette1974" class="mim-tip-reference" title="Mallette, L. E., Bilezikian, J. P., Ketcham, A. S., Aurbach, G. D. &lt;strong&gt;Parathyroid carcinoma in familial hyperparathyroidism.&lt;/strong&gt; Am. J. Med. 57: 642-648, 1974.">Mallette et
al. (1974)</a>; <a href="#McCarthy1977" class="mim-tip-reference" title="McCarthy, D. M., Olinger, E. J., May, R. J., Long, B. W., Gardner, J. D. &lt;strong&gt;H2-histamine receptor blocking agents in the Zollinger-Ellison syndrome: experience in seven cases and implications for long-term therapy.&lt;/strong&gt; Ann. Intern. Med. 87: 668-675, 1977.">McCarthy et al. (1977)</a>; <a href="#Mee1983" class="mim-tip-reference" title="Mee, A. S., Ismail, S., Bornman, P. C., Marks, I. N. &lt;strong&gt;Changing concepts in the presentation, diagnosis and management of the Zollinger-Ellison syndrome.&lt;/strong&gt; Quart. J. Med. 52: 256-267, 1983.">Mee et al. (1983)</a>; <a href="#Regan1978" class="mim-tip-reference" title="Regan, P. T., Malagelada, J.-R. &lt;strong&gt;A reappraisal of clinical, roentgenographic, and endoscopic features of the Zollinger-Ellison syndrome.&lt;/strong&gt; Mayo Clin. Proc. 53: 19-23, 1978.">Regan and
Malagelada (1978)</a>; <a href="#Reimer1981" class="mim-tip-reference" title="Reimer, D., Singh, S. M. &lt;strong&gt;A kindred with 5 cases of multiple endocrine adenomatosis type I.&lt;/strong&gt; Hum. Hered. 31: 84-88, 1981.">Reimer and Singh (1981)</a>; <a href="#Schimke1976" class="mim-tip-reference" title="Schimke, R. N. &lt;strong&gt;Multiple endocrine adenomatosis syndromes.&lt;/strong&gt; Adv. Intern. Med. 21: 249-265, 1976.">Schimke (1976)</a>; <a href="#Schimke1984" class="mim-tip-reference" title="Schimke, R. N. &lt;strong&gt;Genetic aspects of multiple endocrine neoplasia.&lt;/strong&gt; Ann. Rev. Med. 35: 25-31, 1984.">Schimke
(1984)</a>; <a href="#Snyder1974" class="mim-tip-reference" title="Snyder, N., Scurry, M., Hughes, W. &lt;strong&gt;Hypergastrinemia in familial multiple endocrine adenomatosis.&lt;/strong&gt; Ann. Intern. Med. 80: 321-325, 1974.">Snyder et al. (1974)</a>; <a href="#Stadil1976" class="mim-tip-reference" title="Stadil, F., Stage, G., Rehfeld, J. F., Efsen, F., Fischerman, K. &lt;strong&gt;Treatment of Zollinger-Ellison syndrome with streptozotocin.&lt;/strong&gt; New Eng. J. Med. 294: 1440-1442, 1976.">Stadil et al. (1976)</a>; <a href="#Straus1977" class="mim-tip-reference" title="Straus, E., Johnson, G. F., Yalow, R. S. &lt;strong&gt;Canine Zollinger-Ellison syndrome.&lt;/strong&gt; Gastroenterology 72: 380-381, 1977.">Straus et al.
(1977)</a>; <a href="#Vance1969" class="mim-tip-reference" title="Vance, J. E., Stoll, R. W., Kitabchi, A. E., Williams, R. H., Wood, F. C., Jr. &lt;strong&gt;Nesidioblastosis in familial endocrine adenomatosis.&lt;/strong&gt; JAMA 207: 1679-1682, 1969.">Vance et al. (1969)</a>; <a href="#Way1968" class="mim-tip-reference" title="Way, L., Goldman, L., Dunphy, J. E. &lt;strong&gt;Zollinger-Ellison syndrome: an analysis of twenty-five cases.&lt;/strong&gt; Am. J. Surg. 116: 293-304, 1968.">Way et al. (1968)</a>
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<a id="Aach1969" class="mim-anchor"></a>
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Aach, R., Kissane, J. M.
<strong>Clinicopathologic conference: multiple endocrine adenomatosis.</strong>
Am. J. Med. 47: 608-618, 1969.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4186264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4186264</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4186264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Agarwal1997" class="mim-anchor"></a>
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Agarwal, S. K., Kester, M. B., Debelenko, L. V., Heppner, C., Emmert-Buck, M. R., Skarulis, M. C., Doppman, J. L., Kim, Y. S., Lubensky, I. A., Zhuang, Z., Green, J. S., Guru, S. C., Manickam, P., Olufemi, S.-E., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L., Marx, S. J.
<strong>Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states.</strong>
Hum. Molec. Genet. 6: 1169-1175, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9215689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9215689</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9215689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/6.7.1169" target="_blank">Full Text</a>]
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<a id="Asgharian2004" class="mim-anchor"></a>
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Asgharian, B., Turner, M. L., Gibril, F., Entsuah, L. K., Serrano, J., Jensen, R. T.
<strong>Cutaneous tumors in patients with multiple endocrine neoplasm type 1 (MEN1) and gastrinomas: prospective study of frequency and development of criteria with high sensitivity and specificity for MEN1.</strong>
J. Clin. Endocr. Metab. 89: 5328-5336, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15531478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15531478</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15531478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jc.2004-0218" target="_blank">Full Text</a>]
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<a id="Bahn1986" class="mim-anchor"></a>
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Bahn, R. S., Scheithauer, B. W., van Heerden, J. A., Laws, E. R., Jr., Horvath, E., Gharib, H.
<strong>Nonidentical expressions of multiple endocrine neoplasia, type I, in identical twins.</strong>
Mayo Clin. Proc. 61: 689-696, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2875227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2875227</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2875227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0025-6196(12)62767-0" target="_blank">Full Text</a>]
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<a id="Bale1989" class="mim-anchor"></a>
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Bale, A. E., Friedman, E., Sakaguchi, K., Nakamura, Y., McBride, O. W., Spiegel, A. M., Aurbach, G. D., Marx, S. J.
<strong>Allelic loss in hereditary and sporadic tumors associated with MEN1. (Abstract)</strong>
Am. J. Hum. Genet. 45 (suppl.): A15, 1989.
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[<a href="https://doi.org/10.1016/0888-7543(89)90336-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/301729" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000153508" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.86.5.7479" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198605153142004" target="_blank">Full Text</a>]
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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/10.1093/hmg/ddh271" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.87.5.1968" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.276.5311.404" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1530/acta.0.1190535" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.98.3.1118" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2003-031513" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0039-6109(16)38333-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0002-9343(80)80013-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.84.10.6057" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.83.8.4846" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198907273210402" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00000658-197209000-00013" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.76.6.8099078" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/301953" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0002-9440(10)65099-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9610(66)90130-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.84.1.5388" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20605" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.7326/0003-4819-87-6-668" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1146/annurev.me.33.020182.001213" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:4&lt;264::AID-HUMU2&gt;3.0.CO;2-V" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.86.9.7844" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1034/j.1399-0004.2003.00091.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2006-1944" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.83.4.4859" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.7326/0003-4819-91-1-41" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000153183" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0888-7543(05)80278-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.35.11.915" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00194320" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1146/annurev.me.35.020184.000325" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.75.1.1352309" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.7326/0003-4819-76-1-53" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9343(81)90858-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302097" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.87.6.8607" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.87.2.8145" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/thx.17.2.120" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198711053171907" target="_blank">Full Text</a>]
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Yu, F., Venzon, D. J., Serrano, J., Goebel, S. U., Doppman, J. L., Gibril, F., Jensen, R. T.
<strong>Prospective study of the clinical course, prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome.</strong>
J. Clin. Oncol. 17: 615-630, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10080607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10080607</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10080607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1200/JCO.1999.17.2.615" target="_blank">Full Text</a>]
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Zollinger, R. M., Ellison, E. H.
<strong>Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas.</strong>
Ann. Surg. 142: 709-728, 1955.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13259432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13259432</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13259432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Cassandra L. Kniffin - updated : 3/6/2008
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John A. Phillips, III - updated : 2/13/2008<br>Patricia A. Hartz - updated : 8/10/2007<br>George E. Tiller - updated : 6/21/2007<br>John A. Phillips, III - updated : 5/23/2007<br>Marla J. F. O'Neill - updated : 2/12/2007<br>John A. Phillips, III - updated : 10/20/2006<br>Patricia A. Hartz - updated : 3/16/2006<br>John A. Phillips, III - updated : 8/2/2005<br>John A. Phillips, III - updated : 8/1/2005<br>John A. Phillips, III - updated : 4/13/2005<br>Victor A. McKusick - updated : 1/31/2005<br>Stylianos E. Antonarakis - updated : 11/24/2004<br>John A. Phillips, III - updated : 10/13/2004<br>Marla J. F. O'Neill - updated : 9/1/2004<br>Victor A. McKusick - updated : 8/20/2004<br>Gary A. Bellus - updated : 9/3/2003<br>Victor A. McKusick - updated : 7/18/2003<br>John A. Phillips, III - updated : 1/13/2003<br>John A. Phillips, III - updated : 10/29/2002<br>Victor A. McKusick - updated : 8/27/2002<br>John A. Phillips, III - updated : 7/30/2002<br>John A. Phillips, III - updated : 7/25/2002<br>John A. Phillips, III - updated : 6/7/2002<br>John A. Phillips, III - updated : 5/22/2002<br>John A. Phillips, III - updated : 2/26/2002<br>John A. Phillips, III - updated : 10/10/2001<br>John A. Phillips, III - updated : 9/19/2001<br>John A. Phillips, III - updated : 7/27/2001<br>John A. Phillips, III - updated : 7/10/2001<br>Victor A. McKusick - updated : 4/17/2001<br>Victor A. McKusick - updated : 3/5/2001<br>Victor A. McKusick - updated : 1/13/2000<br>John A. Phillips, III - updated : 10/3/1999<br>Victor A. McKusick - updated : 9/29/1999<br>Victor A. McKusick - updated : 9/8/1999<br>Carol A. Bocchini - updated : 7/12/1999<br>Victor A. McKusick - updated : 4/16/1999<br>John A. Phillips, III - updated : 3/26/1999<br>John A. Phillips, III - updated : 3/3/1999<br>Michael J. Wright - updated : 2/12/1999<br>Victor A. McKusick - updated : 2/3/1999<br>Stylianos E. Antonarakis - updated : 2/2/1999<br>Sheryl A. Jankowski - updated : 1/12/1999<br>Victor A. McKusick - updated : 12/29/1998<br>Victor A. McKusick - updated : 12/8/1998<br>Jennifer P. Macke - updated : 10/22/1998<br>Victor A. McKusick - updated : 10/14/1998<br>John A. Phillips, III - updated : 10/1/1998<br>Victor A. McKusick - updated : 9/11/1998<br>Victor A. McKusick - updated : 5/19/1998<br>Victor A. McKusick - updated : 4/29/1998<br>Victor A. McKusick - updated : 4/10/1998<br>Victor A. McKusick - updated : 3/27/1998<br>Victor A. McKusick - updated : 3/5/1998<br>Victor A. McKusick - updated : 12/19/1997<br>Victor A. McKusick - updated : 9/8/1997<br>Alan F. Scott - updated : 8/5/1997<br>Victor A. McKusick - updated : 7/31/1997<br>Victor A. McKusick - updated : 4/17/1997
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Victor A. McKusick : 6/4/1986
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carol : 07/21/2023
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<strong>#</strong> 131100
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MULTIPLE ENDOCRINE NEOPLASIA, TYPE I; MEN1
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<em>Alternative titles; symbols</em>
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MEN I<br />
ENDOCRINE ADENOMATOSIS, MULTIPLE<br />
MEA I<br />
WERMER SYNDROME
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Other entities represented in this entry:
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MEN1 SOMATIC MUTATIONS, INCLUDED
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<strong>SNOMEDCT:</strong> 30664006; &nbsp;
<strong>ICD10CM:</strong> E31.21; &nbsp;
<strong>ICD9CM:</strong> 258.01; &nbsp;
<strong>ORPHA:</strong> 652; &nbsp;
<strong>DO:</strong> 10017; &nbsp;
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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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11q13.1
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Multiple endocrine neoplasia 1
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131100
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Autosomal dominant
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3
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MEN1
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613733
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because multiple endocrine neoplasia type I (MEN1) is caused by heterozygous mutation in the MEN1 gene (613733) on chromosome 11q13.</p>
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<strong>Description</strong>
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<p>Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant disorder characterized by varying combinations of tumors of parathyroids, pancreatic islets, duodenal endocrine cells, and the anterior pituitary, with 94% penetrance by age 50. Less commonly associated tumors include foregut carcinoids, lipomas, angiofibromas, thyroid adenomas, adrenocortical adenomas, angiomyolipomas, and spinal cord ependymomas. Except for gastrinomas, most of the tumors are nonmetastasizing, but many can create striking clinical effects because of the secretion of endocrine substances such as gastrin, insulin, parathyroid hormone, prolactin, growth hormone, glucagon, or adrenocorticotropic hormone (summary by Chandrasekharappa et al., 1997). </p><p>Familial isolated hyperparathyroidism (see 145000) occasionally results from the incomplete expression of MEN1 (summary by Simonds et al., 2004). </p><p><strong><em>Genetic Heterogeneity of Multiple Endocrine Neoplasia</em></strong></p><p>
Other forms of multiple endocrine neoplasia include MEN2A (171400) and MEN2B (162300), both of which are caused by mutation in the RET gene (164761), and MEN4 (610755), which is caused by mutation in the CDKN1B gene (600778).</p>
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<strong>Clinical Features</strong>
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<p>Underwood and Jacobs (1963) identified an affected father, son, and daughter. Hypoglycemia was the presenting manifestation in all 3. In addition to islet cell adenomas, the father had bronchial carcinoma and hyperparathyroidism (145000) from parathyroid adenomas. The son and daughter had been followed from childhood as cases of idiopathic epilepsy unresponsive to anticonvulsive therapy. </p><p>Guida et al. (1966) described pituitary adenoma and duodenal carcinoid in patients with this condition. Bronchial carcinoid was described as a feature of the disorder by Williams and Celestin (1962). </p><p>Some kindreds (e.g., Ballard et al., 1964; Wermer, 1954) have a high frequency of severe peptic ulcer disease with islet cell tumors, whereas other kindreds (e.g., Johnson et al., 1967) are devoid of peptic disease. </p><p>Bilateral pheochromocytomas occur in MEN2A and MEN2B and pancreatic islet cell tumors in MEN1. Tateishi et al. (1978) described a patient with both forms of endocrine neoplasia. They also reviewed 14 reported cases of MEN with features overlapping MEN I and II. For example, 7 patients with acromegaly (102200) due to pituitary adenoma had pheochromocytoma, 2 with Sipple syndrome (MEN2A) had pituitary adenoma, and so on. </p><p>Prosser et al. (1979) found 4 patients in 3 unrelated families who had prolactin-secreting pituitary adenomas. </p><p>Farid et al. (1980) observed 4 kindreds in the Burin Peninsula of Newfoundland, whose ancestors came from the same small community in the British Isles, with hyperparathyroidism and prolactinoma, but no documented pancreatic tumors. Two kindreds had carcinoid tumors at unusual sites, either thymus or peripheral lung parenchyma. In contrast to the benign course of the prolactinomas and the primary hyperparathyroidism, 2 persons with thymic carcinoid died from metastatic disease. Bear et al. (1985) referred to the disorder in these families as MEN1-Burin (see 613733.0016). Hershon et al. (1983) described a phenotypically similar but unrelated kindred from the Pacific Northwest, in which 6 of 7 living affected members had prolactinomas and none had pancreatic islet tumors. Farid (1994) reported that the Burin Peninsula families were in fact related. All 4 families had ancestors who lived in the Harbor Breton region a century earlier and all affected members of the 4 families carried the same PYGM (608455) allele segregating with the disorder. Petty et al. (1994) demonstrated by linkage studies that the gene in both the Newfoundland kindreds and the kindred from the Pacific Northwest mapped to 11q in the same region as the MEN1 gene. No recombinants were seen with PYGM in either kindred, but the PYGM allele associated with the disease was different in the 2 kindreds. </p><p>The Zollinger-Ellison syndrome (ZES) may present purely as hyperparathyroidism. For example, 1 member of the family described as having hereditary hyperparathyroidism by Cutler et al. (1964) was later reported to have a malignant schwannoma, pituitary adenomas, multiple pancreatic islet cell adenomas, and multiple adrenocortical adenomas. Snyder et al. (1972) reported 5 families and noted the previously described association of lipomas. </p><p>The Zollinger-Ellison syndrome is merely hypergastrinism and may have causes other than MEN I. For example, Long et al. (1980) reported the Zollinger-Ellison syndrome with ectopic production of gastrin by a mucinous cystadenoma of the ovary. McCarthy (1982) distinguished 2 common forms of the Zollinger-Ellison syndrome: the sporadic and usually malignant type, seen most often in later life, and the genetic variety that occurs as part of MEN I. </p><p>Stacpoole et al. (1981) observed a family in which 3 persons had A-cell pancreatic tumors (glucagonomas) as part of MEN I. Two had the classic glucagonoma syndrome with skin rash, glucose intolerance, and hypoaminoacidemia. Administered secretin and somatostatin gave anomalous metabolic responses. </p><p>Bahn et al. (1986) reported 25-year-old monozygotic twins with MEN I who had impressive differences in expression of the disorder. One had epigastric pain and diarrhea at presentation; was found to have primary hyperparathyroidism, Zollinger-Ellison syndrome, Cushing disease, and hyperprolactinemia; and underwent hypophysectomy. The second twin was asymptomatic but had primary hyperparathyroidism and hyperprolactinemia. A large, histologically benign pituitary adenoma 'that invaded dura and bone' was removed by a transsphenoidal approach 2 days after parathyroidectomy. </p><p>Maton et al. (1986) suggested that the Cushing syndrome is more common in patients with the Zollinger-Ellison syndrome than previously reported, occurring in 8% of all cases. Three of 16 patients with the Zollinger-Ellison syndrome and MEN1 had the Cushing syndrome due to pituitary overproduction of ACTH. In all sporadic cases of ZES, Cushing syndrome was due to ectopic production of ACTH by the gastrinoma. Gaitan et al. (1993) described mother and daughter who, in addition to other manifestations of MEN1, had Cushing disease due to ACTH-secreting tumors. </p><p>Yu et al. (1999) reported on the long-term clinical course of unselected patients with gastrinomas as well as other functional pancreatic endocrine tumors in whom the excess hormone state was controlled. They studied 212 patients with Zollinger-Ellison syndrome. All had controlled acid hypersecretion and were assessed yearly, with a mean follow-up of 13.8 years (range, 0.1 to 31 years). Death had occurred in 31% of patients, all from non-acid-related causes. One-half died of a ZES-related cause; they differed from those who died of non-ZES deaths by having a large primary tumor, more frequently a pancreatic tumor; lymph node, liver, or bone metastases; ectopic Cushing syndrome; or higher gastrin levels. The extent of liver metastases correlated with survival rate. Yu et al. (1999) concluded that in ZES, gastrinoma growth is the main single determinant of long-term survival, with 50% of patients dying a gastrinoma-related death and none an acid-related death. </p><p>Bordi et al. (2001) identified carcinoid tumors in the antropyloric mucosa of 4 patients with MEN1/Zollinger-Ellison syndrome, accounting for 8.7% of 46 patients with this condition examined by endoscopy and histology. In contrast, no tumors were found in the antral biopsies from 124 cases of sporadic ZES (p less than 0.001), indicating a prominent role for the MEN1 gene defects in tumor development. Immunohistochemically, the tumors did not express the hormones produced by antral endocrine cells (gastrin, somatostatin, serotonin). In contrast, 2 of them were diffusely immunoreactive for the isoform 2 of the vesicular monoamine transporter (VMAT2; 193001), a marker specific for the gastric nonantral enterochromaffin-like (ECL) cells. In 1 of these patients, a second antral VMAT2-positive carcinoid was seen 21 months after the first diagnosis. The authors concluded that the antral mucosa is an additional tissue that may harbor endocrine tumors in MEN1 syndrome. These tumors did not express the phenotype of normal antral endocrine cells and, in at least 2 cases, were identified as ectopic ECL cell carcinoids. </p><p>Skogseid et al. (1992) reviewed adrenocortical lesions in 31 MEN I patients. In 12 (37%), they found adrenal enlargement, which was bilateral in 7. One person developed unilateral adrenocortical carcinoma manifested by rapid adrenal expansion, feminization, and an abnormal urinary steroid profile after 4 years of observation for bilateral minor adrenal enlargement. In the other patients, adrenal enlargement was not associated with ascertainable biochemical disturbances in the hypothalamic-pituitary-adrenocortical axis. Pancreatic endocrine tumors were significantly overrepresented in the patients with adrenal lesions, being present in all 12. In agreement with findings in sporadic cases, the MEN1 adrenocortical carcinoma showed loss of constitutional heterozygosity for alleles at 17p, 13q, 11p, and 11q. The benign adrenal lesions retained heterozygosity for the MEN1 locus at 11q13. Skogseid et al. (1992) concluded that the pituitary-independent adrenocortical proliferation is not the result of the primary lesion in MEN I but may represent a secondary phenomenon, perhaps related to the pancreatic endocrine tumor. </p><p>Verges et al. (2002) analyzed data on pituitary adenomas in 324 MEN1 patients from a French and Belgian multicenter study. Data on pituitary disease were compared with those from 110 non-MEN1 patients with pituitary adenomas, matched for age, year of diagnosis, and follow-up period. In the authors' MEN1 series, pituitary disease occurred in 136 of 324 (42%), less frequently than hyperparathyroidism (95%, p less than 0.001) and endocrine enteropancreatic tumors (54%, p less than 0.01). Mean age of onset of pituitary tumors was 38.0 +/- 15.3 years (range, 12 to 83 years). Pituitary disease was associated with hyperparathyroidism in 90% of cases, with enteropancreatic tumors in 47%, with adrenal tumors in 16%, and with thoracic neuroendocrine tumors in 4%. Pituitary disease was the initial lesion of MEN1 in 17% of all MEN1 patients. MEN1 pituitary adenomas were significantly more frequent in women than in men (50% vs 31%, p less than 0.001). Eighty-five percent of MEN1-related pituitary lesions were macroadenomas, including 32% of invasive cases. Among secreting adenomas, hormonal hypersecretion was normalized, after treatment, in only 42%, with a median follow-up of 11.4 years. No correlation was found between the type of MEN1 germline mutation and the presence or absence of pituitary adenoma. The authors concluded that their study shows that pituitary adenomas occur in 42% of cases and are characterized by a larger size and a more aggressive presentation than without MEN1. </p><p>Darling et al. (1997) performed a complete cutaneous evaluation on 32 consecutive patients with established diagnoses of MEN1. They observed multiple facial angiofibromas in 88%, collagenomas in 72%, cafe-au-lait macules in 38%, lipomas in 34%, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% of these individuals. Darling et al. (1997) noted that there is considerable overlap between the cutaneous findings in MEN1 and those in tuberous sclerosis (see 191100). However, facial angiofibromas in MEN1 tend to be smaller and fewer and to occur in different areas (upper lip and vermilion border) in comparison to those seen in tuberous sclerosis. Darling et al. (1997) suggested that these cutaneous findings may be helpful in presymptomatic diagnosis of MEN1 patients. </p><p>Schussheim et al. (2001) reviewed new clinical features of MEN1. These included multiple facial angiofibromas, previously considered pathognomonic for tuberous sclerosis; these had been reported in approximately 90% of MEN1 patients, with 50% having 5 or more. MEN1-related angiofibromas differ from those associated with tuberous sclerosis in that they are smaller, fewer, and located on the upper lip and vermilion border of the lip, areas that appear to be spared in tuberous sclerosis patients. Collagenomas had also been identified in more than 70% of MEN1 cases. These lesions can be subtle, and diagnosis might require consultation and biopsy by a dermatologist. Lipomas, both cutaneous and visceral, had been described in up to one-third of MEN1 patients compared with 6% of controls. This moderately high prevalence of lipoma in the general population made it difficult to use this lesion as a marker for MEN1 disease. In contrast to pheochromocytoma in MEN2 (171400), pheochromocytoma occurring in association with MEN1 is rare. In all cases the tumors were unilateral, and it was malignant in only one patient. Leiomyomas had been observed in patients with MEN1. Adrenal cortical lesions were common in MEN1, occurring in up to 40% of patients. The majority of these tumors were bilateral, hyperplastic, and nonfunctional, and caused minimal morbidity; however, tumors that cause hypercortisolemia and hyperaldosteronism had been reported. Thyroid tumors, which include follicular adenomas, goiters, and carcinoma, had long been observed in more than 25% of MEN1 patients. </p><p>Asgharian et al. (2004) prospectively assessed the frequency and sensitivity/specificity of various cutaneous criteria for MEN1 in 110 consecutive patients with gastrinomas with or without MEN1. All patients had hormonal and functional studies to determine MEN1 status, dermatologic evaluation, and tumor imaging studies. Combinations of the occurrence of angiofibromas, collagenomas, and lipomas were analyzed. The combination criterion of more than 3 angiofibromas or any collagenoma had the highest sensitivity (75%) and specificity (95%). Asgharian et al. (2004) concluded that this diagnostic criterion has greater sensitivity for MEN1 than pituitary or adrenal disease and has comparable sensitivity to hyperparathyroidism reported in some studies of patients with MEN1 with gastrinoma. </p><p>Hao et al. (2004) examined 2 large kindreds with a MEN1 variant that were followed up for 20 to 30 years, with MEN1 tumors in 30 members. Cases from the 2 kindreds had parathyroid adenomas (93%), pituitary tumors (40%) (always prolactinoma), and enteropancreatic endocrine tumors (27%). The latter included insulinoma (10%) and nonfunctioning islet tumor (7%), but only 10% gastrinoma. Compared with prior large series, this lower prevalence of gastrinoma (10% vs 42%, p less than 0.01) and higher prevalence of prolactinoma (40% vs 22%, p less than 0.01) defined this variant. DNA showed no characteristic MEN1 mutation in these 2 kindreds. </p><p><strong><em>Reviews</em></strong></p><p>
Wolfe and Jensen (1987) reviewed diagnosis and treatment of the Zollinger-Ellison syndrome. For a review of MEN1, see Thakker (1998). </p><p>Guo and Sawicki (2001) reviewed the various clinical manifestations of MEN1 syndrome, potential mechanisms of MEN1 tumorigenesis, and mutations associated with MEN and sporadic endocrine tumors. </p>
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<strong>Clinical Management</strong>
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<p>Brandi et al. (2001) authored a consensus statement covering the diagnosis and management of MEN1 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. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of enteropancreatic hormones, except insulin. The roles for surgery of most enteropancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. </p>
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<strong>Biochemical Features</strong>
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<p>Brandi et al. (1986) cultured bovine parathyroid cells to test for mitogenic activity in plasma from patients with type I MEN. Whereas normal plasma stimulated incorporation of labeled thymidine to the same extent as did plasma-free culture medium, the plasma from the patients increased mitogenic activity 2400% over the control value. Bovine parathyroid cells were stimulated to proliferation, whereas plasma from normal subjects inhibited proliferation of the bovine parathyroid cells. The mitogenic activity had an apparent molecular weight of 50,000 to 55,000. </p>
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<h4>
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<strong>Inheritance</strong>
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<p>MEN I is an autosomal dominant disorder. Chandrasekharappa et al. (1997) suggested that affected individuals inherit one altered copy of the MEN1 gene from an affected parent, but the tumors lose the remaining copy (the wildtype allele) as a somatic event. Thus, the inheritance pattern is autosomal dominant, but the mechanism of tumorigenesis is recessive. </p>
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<strong>Mapping</strong>
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<p>Bale et al. (1987, 1989) studied linkage with multiple markers in a single large kindred with MEN I. INT2 (164950), which is located at 11q13, was found to be closely linked to MEN1. In studies of 3 families, Thakker et al. (1989) established linkage with INT2; peak lod score = 3.30 at theta = 0.00. </p><p>Larsson et al. (1988) mapped the MEN1 locus to chromosome 11 by demonstrating linkage to a DNA probe derived from the PYGM locus (608455), which, in turn, has been mapped to 11q13-qter. </p><p>By comparing constitutional and tumor tissue genotypes of insulinomas from 2 brothers who had inherited the disorder from their mother, Larsson et al. (1988) demonstrated loss of the linked locus in tumor tissue. Tumors in both showed loss of 1 constitutional allele at all informative loci on chromosome 11. The informative markers extended from HRAS1, located at 11p15.5, to APOA1 (107680), located at 11q13. (Larsson et al. (1988) quoted a paper in press indicating that the APOA1 locus is in band q23.) In 3 families, the authors observed a total maximum lod score of 4.37 at theta = 0.00. Larsson et al. (1989) and Nordenskjold et al. (1989) both provided linkage data for markers at 11q13 with multiple endocrine neoplasia type I. </p><p>Nakamura et al. (1989) identified 6 closely linked markers in the vicinity of 11q13 which are useful for identification of carriers in MEN I families. The target region containing the gene was narrowed to about 12 cM. Friedman et al. (1989) and Thakker et al. (1989) demonstrated loss of heterozygosity (LOH) for chromosome 11 alleles in parathyroid tumors from patients with MEN I. Friedman et al. (1989) found such loss in 10 of 16 tumors from 14 patients. In 7 of 10 tumors, the subregion of loss was less than the full length of chromosome 11 but always included 1 copy of the MEN I locus. </p><p>Bale et al. (1989) studied the DNA from 66 tumors removed from patients with MEN I. They demonstrated allelic loss of chromosome 11 RFLPs in 10 of 16 parathyroid tumors from MEN I patients and in 9 of 34 sporadic parathyroid adenomas. The smallest consistent region of loss was between INT2 and D11S149. Bystrom et al. (1990) showed that the pathogenesis of MEN1-associated parathyroid lesions involves unmasking of a recessive mutation at the disease locus and that sporadic primary hyperparathyroidism shares the same mechanisms. By examination of allele losses in MEN1-associated lesions, they defined deletions of chromosome 11 and mapped the MEN1 locus to a small region within 11q13, telomeric to PYGM. </p><p>Richard et al. (1991) created a high-resolution radiation hybrid map of the proximal long arm of chromosome 11 containing the MEN1 and BCL1 (168461) gene loci. By statistical analysis of the cosegregation of markers in radiation hybrids, they arrived at the following most likely order of loci: C1NH (606860)--OSBP (167040)--CD5 (153340)/CD20(112210)--PGA (169710)--FTH1 (134770)--COX8 (123870)--PYGM--SEA (165110)--KRN1 (148021)--HSTF1 (164980)/INT2--GST3 (134660)--PPP1A (176875). They suggested that the localization of the protooncogene SEA between PYGM and INT2, 2 markers that flank MEN1, makes SEA a potential candidate for the MEN1 locus. The positions of PPP1A and GST3 are such that neither is likely to be directly involved in CLL (151400) or MEN1. Fujimori et al. (1992) placed the MEN1 locus within an 8-cM region between D11S480 and D11S546. </p><p>Larsson et al. (1992) found that 13 marker systems tested with 17 DNA probes were located within a region on chromosome 11 spanning a 14% meiotic recombination region, with the MEN1 locus in the middle: based on meiotic crossovers, 4 systems were on the telomeric side and 4 on the centromeric side of MEN1. The remaining 5 were closely linked to MEN1, with no crossovers in their set of 6 families including 59 affected persons. The calculated accuracy of prediction of MEN1 was more than 99.5% when 3 of the marker systems were informative. </p><p>Sawicki et al. (1992) reported loss of heterozygosity on chromosome 11 in 5 of 11 sporadic gastrinomas. Four of these tumors had LOH for markers flanking the MEN1 region. LOH on chromosome 11 had previously been found in 3 types of tumors that occur in patients with the MEN I syndrome: sporadic pituitary adenomas, sporadic and familial parathyroid neoplasms, and pancreatic endocrine tumors including insulinoma, glucagonoma, vasointestinal peptide tumor, and nonfunctional tumors. Although gastrinomas account for the majority of both sporadic and familial pancreatic endocrine tumors, LOH had not previously been demonstrated for this form. </p><p>Courseaux et al. (1996) used a combination of methods to refine maps of the approximately 5-Mb region of 11q13 that includes MEN1. They proposed the following gene order: cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1--[MLK3, RELA]--FOSL1--SEA--CFL1--tel. The location of MEN1 was narrowed to a 2-Mb region beginning centromeric to COX8 and extending to approximately CAPN1. </p><p>Guru et al. (1997) mapped and sequenced the MEN1 genomic region. They produced a precisely ordered map of 33 transcribed genes within this 2-Mb region. </p><p>The European Consortium on MEN1 (1997) constructed a 1.2-Mb sequence-ready contig encompassing the MEN1 region. They described 3 gene clusters, including the central cluster which contains the MEN1 gene. </p><p>From a comparative mapping analysis of 10q and the pericentric region of 11q in the human and mouse chromosome 19, Rochelle et al. (1992) concluded that the murine homolog of the MEN1 locus may lie in the proximal segment of chromosome 19. By FISH, Guru et al. (1999) mapped the mouse Men1 gene to chromosome 19 in a region showing homology of synteny to human chromosome 11q13. </p>
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<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
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<p>Chandrasekharappa et al. (1997) identified several MEN1 candidate genes in a previously identified minimal interval on 11q13. Chandrasekharappa et al. (1997) identified mutations in one of these genes, designated MEN1, in 14 probands from 15 families. Twelve different heterozygous mutations (613733.0001-613733.0012) were identified (5 frameshift, 3 nonsense, 2 missense, and 2 in-frame deletions). Most of the mutations predicted loss of function of the protein, consistent with a tumor suppressor mechanism. </p><p>Lemmens et al. (1997) independently identified the MEN1 gene, which they had designated SCG2, and found 9 different heterozygous mutations in 10 unrelated MEN1 families. </p><p>Agarwal et al. (1997) extended their mutation analysis to 34 more unrelated familial MEN1 probands (to a total of 50 kindreds) and to 2 related disorders, sporadic MEN1 and familial hyperparathyroidism (145000). In 8 of 11 cases of sporadic MEN1, they found heterozygous germline MEN1 mutations (e.g., 613733.0014); such mutations were found in 47 of 50 familial MEN1 probands. They proved that the mutation was new in 1 case of sporadic MEN1. Among the familial MEN1 cases, 8 mutations were observed more than once. In all, 40 different mutations (32 familial and 8 sporadic) were distributed across the MEN1 gene. A predicted loss of function of the encoded menin protein supported the prediction that MEN1 is a tumor suppressor gene. No MEN1 germline mutations were found in 5 probands with familial hyperparathyroidism, suggesting that this disorder is often caused by mutation in another gene. </p><p>In affected members of the 4 families with MEN1 from the Burin peninsula in Newfoundland, who were previously described by Farid et al. (1980) and Bear et al. (1985), Olufemi et al. (1998) identified a mutation in the MEN1 gene (613733.0016). </p><p>Bassett et al. (1998) investigated 63 unrelated MEN1 kindreds (195 affected and 396 unaffected members) for mutations in the 2,790-bp coding region and splice sites, by SSCP and DNA sequence analysis. They identified 47 mutations (12 nonsense mutations, 21 deletions, 7 insertions, 1 donor splice site mutation, and 6 missense mutations) that were scattered throughout the coding region, together with 6 polymorphisms that had heterozygosity frequencies of 2 to 44%. More than 10% of the mutations arose de novo, and 4 mutation hotspots accounted for more than 25% of the mutations. SSCP was found to be a sensitive and specific mutational screening method that detected more than 85% of the mutations. MEN1 mutant-gene carrier status was detected in 201 individuals (155 affected and 46 unaffected). By analysis of these cases, they defined the age-related penetrance of MEN1 as 7%, 52%, 87%, 98%, 99%, and 100% at 10, 20, 30, 40, 50, and 60 years of age, respectively. The number of disease alleles and the frequent occurrence of de novo mutations, often at hotspots with short repeat sequences, suggested that haplotype analysis is of limited use for the diagnosis of MEN1. </p><p>Tanaka et al. (1998) studied germline mutations of the MEN1 gene in 5 cases of familial and 4 cases of sporadic multiple endocrine neoplasia type I, 6 cases in 3 independent pedigrees of familial pituitary adenoma without MEN1, and 3 cases of familial primary hyperparathyroidism in Japanese patients. Eight different types of germline mutations in all 9 MEN1 cases were distributed in exons 2, 3, 7, and 10 and intron 7 of the MEN1 gene. Loss of heterozygosity (LOH) on 11q13 was detected in all 9 tumors of the cases with microsatellite analysis. No germline mutation of the MEN1 gene was detected in 3 pedigrees of familial pituitary adenoma and 3 cases of familial primary hyperparathyroidism. LOH on 11q13 was detected in 2 cases in 1 pedigree of familial pituitary adenoma, and 1 of them showed a heterozygous somatic mutation of the MEN1 gene. No LOH on 11q13 was detected in 3 cases of familial primary hyperparathyroidism. The authors concluded that the loss of function of MEN1 causes familial or sporadic MEN1, but does not cause familial primary hyperparathyroidism or most familial pituitary adenoma without MEN1. </p><p>Both alleles of the MEN1 gene at 11q13 are mutated in the majority of MEN1 tumors. Hessman et al. (2001) performed a genomewide LOH screening of 23 pancreatic lesions, 1 duodenal tumor, and 1 thymic carcinoid from 13 MEN1 patients. Multiple allelic deletions were found. Fractional allelic loss varied from 6 to 75% (mean 31%). All pancreatic tumors displayed LOH on chromosome 11, whereas the frequency of losses for chromosomes 3, 6, 8, 10, 18, and 21 was over 30%. Different lesions from individual patients had discrepant patterns of LOH. Intratumoral heterogeneity was revealed, with chromosome 6 and 11 deletions in most tumor cells, whereas other chromosomal loci were deleted in portions of the analyzed tumor. Chromosome 6 deletions were mainly found in lesions from patients with malignant features. Fractional allelic loss did not correlate to malignancy or to tumor size. The authors concluded that MEN1 pancreatic tumors fail to maintain DNA integrity and demonstrate signs of chromosomal instability. </p><p>Lipomatous tumors are known to occur in a relatively high proportion of patients with MEN1. By fluorescence in situ hybridization analysis of lipomas from 2 patients with MEN1, Vortmeyer et al. (1998) demonstrated deletion of 1 MEN1 allele in 53% of cells examined from case 1 and in 63% of cells examined from case 2. In both cases, both MEN1 gene copies were visualized in normal cellular constituents. </p><p>Giraud et al. (1998) studied a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors. They screened for MEN1 germline mutations by heteroduplex and sequence analysis of the gene-coding region of the MEN1 gene and its untranslated exon 1. Germline MEN1 alterations were identified in 47 of 54 (87%) MEN1 families, in 9 of 11 (82%) isolated MEN1 patients, and in only 6 of 19 (31.5%) atypical MEN1-related inherited cases. They characterized 52 distinct mutations in a total of 62 MEN1 germline alterations. Truncating mutations, frameshifts and nonsense mutations, accounted for 35 of the 52 alterations. No genotype/phenotype correlation could be made. Age-related penetrance was estimated to be more than 95% over age 30 years. No MEN1 germline mutations were found in 7 of 54 (13%) MEN1 families. </p><p>Teh et al. (1998) performed MEN1 mutation analysis in 55 MEN1 families from 7 countries, 13 isolated MEN1 cases without family history of the disease, 8 acromegaly families, and 4 familial isolated hyperparathyroidism (FIHP) families. Mutations were identified in samples from 27 MEN1 families and 9 isolated cases. The 22 different mutations were distributed across most of the 9 translated exons and included 11 frameshift, 6 nonsense, 2 splice site, and 2 missense mutations, and 1 in-frame deletion. Among the 19 Finnish MEN1 probands, a 1466del12 (613733.0032) mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases, indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was identified in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common 'warm' spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case, 1 mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved, and that additional families of these types need to be analyzed. </p><p>Sato et al. (1998) studied 8 unrelated Japanese families. These included 5 with familial MEN1, 2 with sporadic MEN1, and 1 with familial hyperparathyroidism. Six different mutations were identified, including 1 missense mutation, 3 deletions, and 2 nonsense mutations. In 1 proband with familial MEN1, no mutation was identified. </p><p>In Spain, Cebrian et al. (1999) studied 10 unrelated MEN1 kindreds by a complete sequencing analysis of the entire MEN1 gene. Mutations were identified in 9 of them: 5 deletions, 1 insertion, 2 nonsense mutations, and a complex alteration consisting of a deletion and an insertion that can be explained by a hairpin loop model. Two of the mutations had been described; the other 7 were novel, and they were scattered throughout the coding sequence of the gene. As in previous series, no correlation was found between phenotype and genotype. </p><p>The observation of LOH involving 11q13 in MEN1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the '2-hit' model of hereditary cancer. The second hit in MEN1 tumors typically involves large chromosomal deletions that include 11q13. However, this only represents one mechanism by which the second hit may occur. Pannett and Thakker (2001) searched for other mechanisms, such as intragenic deletions or point mutations that inactivate the MEN1 gene, in 6 MEN1 tumors (4 parathyroid tumors, 1 insulinoma, and 1 lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883, and PYGM centromerically and D11S449 and D11S913 telomerically. They found 4 somatic mutations, which consisted of 2 missense mutations and 2 frameshift mutations, in 2 parathyroid tumors, 1 insulinoma, and 1 lipoma. The authors concluded that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by the Knudson '2-hit' hypothesis. </p><p>Perren et al. (2007) hypothesized that monohormonal endocrine cell clusters observed in MEN1 patients are small neoplasms with loss of heterozygosity of the MEN1 locus. Loss of one MEN1 allele was found in all 27 microadenomas and 19 of 20 (95%) monohormonal endocrine cell clusters. By contrast, it was absent in islets and ductal or acinar structures. Perren et al. (2007) concluded that the frequent presence of single nonneoplastic insulin cells in microadenomas and the occurrence of microadenomas in islets suggest an islet origin of microadenomas. Islet hyperplasia does not seem to be an obligatory stage in pancreatic MEN1-associated tumor development. </p><p>By exhaustive sequence analysis of probands belonging to 170 unrelated MEN1 families collected through a French clinical network, Wautot et al. (2002) identified 165 mutations located in coding parts of the MEN1 gene, which represented 114 distinct MEN1 germline alterations. The mutations, which were spread over the entire coding sequence, included 56 frameshifts, 23 nonsense, 27 missense, and 8 deletion or insertion in-frame mutations. These mutations were included in a MEN1 locus-specific database available on the Internet together with approximately 240 germline and somatic MEN1 mutations listed from international published data. Taken together, most missense and in-frame MEN1 genomic alterations affected 1 or all domains of menin interacting with JUND (165162), SMAD3, and nuclear factor kappa-B (NFKB1; 164011), 3 major effectors in transcription and cell growth regulation. No correlation was observed between genotype and MEN1 phenotype. </p><p>Turner et al. (2002) ascertained 34 unrelated MEN1 probands and performed DNA sequence analysis. They identified 17 different mutations in 24 probands: 2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletion-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a G-to-A transition that resulted in a novel acceptor splice site in IVS4 (613733.0024). The IVS4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this IVS4 mutation is the most frequently occurring germline MEN1 mutation, accounting for approximately 10% of all mutations, and together with 5 others at codons 83-84, 118-119 (613733.0025), 209-211 (613733.0026), 418 (613733.0027), and 516 (613733.0028) accounts for 36.6% of all mutations. </p><p>In 3 members of a Japanese family with MEN1 and a predisposition to insulinoma, Okamoto et al. (2002) identified a heterozygous germline mutation in exon 4 of the MEN1 gene (613733.0030). Chi square analysis of 72 MEN1 patients with or without germline mutations in exon 4 and with or without insulinomas showed a significant difference (p = 0.0022), suggesting a possible correlation between insulinoma development and mutations in exon 4 where JunD binding occurs. </p><p>Park et al. (2003) investigated 5 Korean families with MEN1, 1 family with familial isolated hyperparathyroidism and 1 family with familial pituitary adenoma. Four germline mutations were identified in 5 typical MEN1 families. All of these mutations led to truncated proteins or a change in the amino acids of the functional domains. No MEN1 germline mutations were detected in the 2 families with FIHP or familial pituitary adenoma. </p><p>Using church records and MEN1 family information for the 2 founder MEN1 mutations in Northern Finland, 1466del12 (613733.0032) and 1657insC (613733.0033), Ebeling et al. (2004) traced back common ancestors born in the beginning of the 1700s (1466del12) and approximately 1850 (1657insC) and found 67 probable carriers born between 1728 and 1929, among their offspring. Information was gathered from 34 obligatory MEN1 gene carriers and 31 spouses. The mean age of death of affected males was 61.1 years versus 65.8 years for unaffected males, and for affected females was 67.2 years versus 67.7 years for unaffected females. The ages of death of the obligatory heterozygotes did not differ from that of the spouses in sex groups or from the sex matched life expectancy estimates derived from Finnish national statistics. The authors concluded that obligatory MEN1 gene carrier status did not show a harmful effect on survival in this retrospective analysis tracing back to almost 300 years. </p><p>Lemos and Thakker (2008) provided a detailed review of the clinical aspects and molecular genetics of MEN1. The majority of the 1,336 mutations reported to date are predicted to result in truncated forms of menin and are scattered throughout the gene. There were no apparent genotype/phenotype correlations. </p><p><strong><em>Familial Primary Isolated Hyperparathyroidism, MEN1 Variant</em></strong></p><p>
In a Caucasian English family in which 7 family members from 2 generations had primary isolated hyperparathyroidism (see 145000), Teh et al. (1998) found that affected members had a germline missense mutation in the MEN1 gene (613733.0020). This appeared to be the first study to demonstrate that familial isolated primary hyperparathyroidism can occur as a variant of MEN1. The pattern of transmission was autosomal dominant with high penetrance. Clinically, the hyperparathyroidism ran a rather mild course, as evidenced by 2 affected subjects who declined surgery and yet developed no obvious complications. Pathologically, the multiglandular parathyroid disease was consistent with that of MEN1. In 2 individuals, Teh et al. (1998) demonstrated loss of heterozygosity (LOH) in the parathyroid tumors, consistent with the Knudson 2-hit model. </p><p>In a 61-year-old Japanese woman and 2 of her sons, aged 38 and 33 years, all with hyperparathyroidism due to parathyroid adenomas. Fujimori et al. (1998) identified a missense mutation in the MEN1 gene (613733.0021). </p><p>Warner et al. (2004) screened 22 unrelated patients with FIHP for mutations in the MEN1, CASR (601199) and HRPT2 (CDC73; 607393) genes. They identified 5 patients with MEN1 mutations, 4 with CASR mutations, and none with HRPT2 mutations. All 9 patients in whom mutations were found had multiglandular hyperparathyroidism. The patients with CASR mutations did not have biochemical findings of hypocalciuric hypercalcemia. Warner et al. (2004) recommended MEN1 and CASR genotyping in patients with multiglandular FIHP, regardless of urinary calcium excretion. </p><p><strong><em>MEN1 Somatic Mutations</em></strong></p><p>
Heppner et al. (1997) found somatic mutation of the MEN1 gene in 21% of parathyroid tumors not associated with MEN1, representing 54% of parathyroid tumors with 11q13 LOH. The authors suggested that parathyroid tumor formation in kindreds with somatic mutation of MEN1 may be initiated by germline mutation of an unidentified tumor suppressor gene or oncogene. The finding of somatic mutation (613733.0013) in a single tumor from a member of such a kindred indicated that somatic MEN1 gene mutation may also contribute to tumorigenesis in such individuals. Previous studies had found frequent 11q13 LOH in sporadic tumors as follows: gastrinoma (45%), insulinoma (19%), anterior pituitary gland tumors (3 to 30%), carcinoid tumors (78%), thyroid follicular tumors (15%), and aldosteronomas (36%). Heppner et al. (1997) suggested that many of these tumors likewise may have MEN1 somatic mutations. </p><p>Carling et al. (1998) used microsatellite analysis for LOH at 11q13 and DNA sequencing of the coding exons to study the MEN1 gene in 49 parathyroid lesions of patients with nonfamilial primary hyperparathyroidism. Allelic loss at 11q13 was detected in 13 tumors, 6 of which had previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of these mutations were predicted to encode a nonfunctional menin protein, consistent with a tumor suppressor mechanism. While the clinical and biochemical characteristics of hyperparathyroidism were apparently unrelated to LOH at 11q13 and the MEN1 gene mutations, the demonstration of LOH and MEN1 gene mutations in small parathyroid adenomas of patients who had slight hypercalcemia and normal serum parathyroid hormone (168450) levels suggested that altered MEN1 gene function may also be important for the development of mild sporadic primary hyperparathyroidism. </p><p>Farnebo et al. (1998) screened 45 sporadic tumors from 40 patients for alterations involving the MEN1 gene. Thirteen tumors showed LOH at 11q13, and in 6 of these cases, a somatic mutation of the MEN1 gene was detected. In tumors without LOH, no mutations were detected. The mutations consisted of 3 small deletions, 1 insertion, and 2 missense mutations that had not been reported in MEN1 patients or parathyroid tumors previously. Using mRNA in situ hybridization, the expression of the MEN1 gene was studied. The authors concluded that there was no difference in MEN1 expression between normal and tumor tissue, and that their findings of inactivating mutations in tumors with LOH at 11q13 confirmed the role of the MEN1 tumor suppressor gene in a subset of sporadic parathyroid tumors. </p><p>By comparative genomic hybridization, Farnebo et al. (1999) screened DNAs from 44 parathyroid tumors from 26 sporadic cases, 10 cases previously given irradiation to the neck, and 8 familial cases for sequence copy number alterations. In the sporadic adenomas, commonly occurring minimal regions of loss could be defined to chromosome 11 (38%), 15q15-qter (27%), and 1p34-pter (19%), whereas gains preferentially involved 19p13.2-pter (15%) and 7pter-qter (12%). Multiple aberrations were found in sporadic tumors with a somatic mutation and/or LOH of the MEN1 gene. The irradiation-associated tumors also showed multiple comparative genomic hybridization alterations and frequent losses of 11q (50%), and subsequent analysis of the MEN1 gene demonstrated mutations in 4 of 8 cases (50%). The majority of these alterations were found in tumors with confirmed involvement of the MEN1 gene, in agreement with a role of the MEN1 gene in genomic stability. The authors concluded that the frequent occurrence of MEN1 mutations in irradiation-associated parathyroid tumors suggests that inactivation of the MEN1 gene is an important genetic alteration involved in the development of parathyroid tumors in post-irradiation patients. </p><p>Prezant et al. (1998) screened the complete coding sequence of the MEN1 gene for mutations in 45 sporadic anterior pituitary tumors, including 14 hormone-secreting tumors and 31 nonsecreting tumors, by dideoxy fingerprinting and sequence analysis. No pathogenic sequence changes were found in the MEN1 coding region. The MEN1 gene was expressed in 43 of these tumors with sufficient RNA, including 1 tumor with LOH for several polymorphic markers on chromosomal region 11q13. Also, both alleles were expressed in 19 tumors in which the constitutional DNA was heterozygous for intragenic polymorphisms. The authors concluded that inactivation of the MEN1 tumor suppressor gene, by mutation or by imprinting, does not appear to play a prominent role in sporadic pituitary adenoma pathogenesis. </p><p>Heppner et al. (1999) studied whether somatic inactivation of the MEN1 gene contributes to the pathogenesis of sporadic adrenocortical neoplasms. Thirty-three tumors and cell lines were screened for mutations throughout the MEN1 open reading frame and adjacent splice junctions. No mutations were detected within the MEN1 coding region. The authors concluded that somatic mutations within the MEN1 coding region do not occur commonly in sporadic adrenocortical tumors, although the majority of adrenocortical carcinomas exhibited 11q13 LOH. </p><p>To investigate the role of the MEN1 gene in sporadic lipomas, Vortmeyer et al. (1998) analyzed 6 sporadic tumors. In 1 case, SSCP analysis and subsequent sequencing revealed a 4-bp deletion in exon 2 (613733.0017). This deletion was present only in the tumor tissue, and not in the normal tissue from the same patient. </p><p>To identify chromosomal regions that may contain loci for tumor suppressor genes involved in adrenocortical tumor development, Kjellman et al. (1999) screened a panel of 60 tumors (39 carcinomas and 21 adenomas) for loss of heterozygosity. The vast majority of LOH detected was in the carcinomas involving chromosomes 2, 4, 11, and 18; little was found in the adenomas. The Carney complex (160980) and the MEN1 loci on 2p16 and 11q13, respectively, were further studied in 27 (13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of the 2p16 region mapped a minimal area of overlapping deletions to a 1-cM region that is separate from the Carney complex locus. LOH for PYGM was detected in all 8 informative carcinomas and in 2 of 14 adenomas. Of the cases analyzed in detail, 13 of 27 (11 carcinomas and 2 adenomas) showed LOH on chromosome 11, and these were selected for MEN1 mutation analysis. In 6 cases a common polymorphism was found, but no mutation was detected. The authors concluded that LOH in 2p16 was strongly associated with the malignant phenotype, and LOH in 11q13 occurred frequently in carcinomas, but was not associated with a MEN1 mutation, suggesting the involvement of a different tumor suppressor gene on this chromosome. </p><p>Hibernomas are benign tumors of brown fat, frequently characterized by aberrations of chromosome band 11q13. Gisselsson et al. (1999) analyzed chromosome 11 changes in 5 hibernomas in detail by metaphase fluorescence in situ hybridization. In all cases, complex rearrangements leading to loss of chromosome 11 material were found. Deletions were present not only in those chromosomes that were shown to be rearranged by G-banding, but in 4 cases also in the ostensibly normal homologs, resulting in homozygous loss of several loci. Among these, the MEN1 gene was most frequently deleted. In addition to the MEN1 deletions, heterozygous loss of a second region, approximately 3 Mb distal to MEN1, was found in all 5 cases, adding to previous evidence for a second tumor suppressor locus in 11q13. </p><p>Tahara et al. (2000) analyzed 81 parathyroid glands from 22 Japanese uremic patients for allelic loss on chromosomal arm 11q13 DNA using 3 flanking markers (PYGM, 608455; D11S4946; and D11S449), and for mutations of the MEN1-coding exons by PCR-based SSCP analysis and sequencing. Allelic loss on 11q13 was observed in 6 glands (7%), and 1 of 6 demonstrated a previously unrecognized somatic frameshift deletion in MEN1. They inferred that this mutation would result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and pathologic characteristics of hyperparathyroidism were unrelated to the presence or absence of loss of heterozygosity on 11q13 and MEN1 gene mutations. The authors concluded that somatic inactivation of the MEN1 gene contributes to the pathogenesis of uremia-associated parathyroid tumors, but its role in this disease appears to be very limited. </p><p>Sato et al. (2001) reported a male patient with adult-onset, hypophosphatemic osteomalacia who had been treated with 1-alpha-hydroxyvitamin D3 and oral phosphate for 13 years when tertiary hyperparathyroidism developed. Sequence analysis of the coding exons of the MEN1 gene revealed somatic MEN1 mutations in 2 of the 4 hyperplastic parathyroid glands, accompanied by loss of heterozygosity at the 11q13 locus in 1 gland. These findings suggested that the repeated increase in serum phosphate concentrations for a prolonged period may be related to tumorigenesis of the parathyroid gland. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Chedid et al. (1988) described hereditary pituitary prolactinomas in the rat. It was thought to be an autosomal dominant characteristic with incomplete penetrance and a greater incidence in males. </p><p>To examine the role of MEN1 in tumor formation, Crabtree et al. (2001) generated a mouse model through homologous recombination of the mouse homolog Men1. Homozygous null mice died in utero at embryonic days 11.5 to 12.5, whereas heterozygous mice developed features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets showed a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas were frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary were seen by 16 months. All of the tumors tested showed loss of the wildtype Men1 allele, further supporting the role of MEN1 as a tumor suppressor gene. </p><p>Most tumor suppressor genes show a widespread pattern of expression, yet individuals with germline, heterozygous loss of function of such genes develop tumors in a restricted set of tissues. To investigate the paradox of tissue-specific tumor phenotype in MEN1, Scacheri et al. (2004) bred mice homozygous for an Men1 gene with exons 3-8 flanked by loxP sites to transgenic mice expressing cre from the albumin promoter. This strategy allowed them to generate mice with homozygous deletion of the Men1 gene in liver, a tissue not normally predisposed to developing tumors in humans or mice with heterozygous MEN1 loss-of-function mutations. Livers that were completely null for menin expression appeared entirely normal and remained tumor free until late adulthood. These results narrowed the possible mechanisms of tissue specificity in MEN1. </p><p>Busygina et al. (2004) generated a null allele of Mnn1, the Drosophila homolog of the MEN1 gene, and showed that homozygous inactivation resulted in morphologically normal flies that are hypersensitive to ionizing radiation and 2 DNA crosslinking agents (nitrogen mustard and cisplatinum). The spectrum of agents to which mutant flies were sensitive and analysis of the molecular mechanisms of this sensitivity suggested a defect in nucleotide excision repair. Drosophila Mnn1 mutants had an elevated rate of both sporadic and DNA damage-induced mutations. In a genetic background heterozygous for lats (LATS1; 603473), which is a Drosophila and vertebrate tumor suppressor gene, homozygous inactivation of Mnn1 enhanced somatic mutation of the second allele of lats and formation of multiple primary tumors. Busygina et al. (2004) concluded that Mnn1 is a novel member of the class of autosomal dominant cancer genes that function in maintenance of genomic integrity, similar to the BRCA1 (113705) and MSH2 (609309) genes. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Wermer first reported 'his' syndrome in 1954, and Zollinger and Ellison 'theirs' in 1955 (see Wermer, 1954; Zollinger and Ellison, 1955). The Zollinger-Ellison syndrome of intractable peptic ulcer with pancreatic islet adenoma is a facet of multiple endocrine adenomatosis. Recognition that the 2 eponymic syndromes are one subsequently occurred (Lulu et al., 1968), with multiple endocrine neoplasia type I (MEN1) as the preferred designation. </p><p>On the basis of studies of 8 affected members of a family, Vance et al. (1972) suggested that the primary genetic lesion in endocrine adenomatosis is one that leads to neoplasia and hyperfunction of the islets of Langerhans and that the other endocrine tumors arise as secondary effects of hypersecretion of islet hormones. </p><p>Brandi et al. (1986) concluded that primary hyperparathyroidism in familial MEN type I may have a humoral cause. Since the mitogenic factor persists after parathyroidectomy, it evidently is not secreted by the hyperplastic glands themselves. It did not seem to be identical to any of the well-recognized circulating growth factors, nor did it have similar mitogenic effects on pancreatic or pituitary cells in vitro, despite the presence of islet cell and pituitary tumors in some of the same patients. Curiously, Brandi et al. (1986) did not detect a parathyroid mitogenic factor in patients with MEN II who also had hyperparathyroidism. Schimke (1986) suggested: 'Considered within the framework of a 2-step model, the general event in the multiple endocrine neoplasia syndromes may be an abnormality of a plasma-membrane receptor in the affected endocrine glands. The somatic mutation may involve derepression of a primitive gene coding for a protein that promotes the growth of endocrine glands.' The 'primitive gene' might be an oncogene. This would represent a rather different 2-mutation theory than the one that applies to retinoblastoma (180200) and Wilms tumor (194070). In this case the mutations are presumably at different loci. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Aach and Kissane (1969); Bale et al. (1989); Bale et al. (1989);
Betts et al. (1980); Buchta and Kaplan (1971); Cocco and Conway
(1975); Deveney et al. (1978); Ellison and Wilson (1964); Ellison and
Wilson (1967); Friesen et al. (1972); Groussin et al. (1980); Guru et
al. (1998); Jones et al. (1970); Koch and Tiwisina (1959); Koch
(1949); Lamers and Froeling (1979); Lamers et al. (1978); Mallette et
al. (1974); McCarthy et al. (1977); Mee et al. (1983); Regan and
Malagelada (1978); Reimer and Singh (1981); Schimke (1976); Schimke
(1984); Snyder et al. (1974); Stadil et al. (1976); Straus et al.
(1977); Vance et al. (1969); Way et al. (1968)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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</h4>
<div>
<p />
</div>
<div>
<ol>
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<strong>Mapping of multiple endocrine neoplasia type 1 with markers on chromosome 11q. (Abstract)</strong>
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Bale, S. J., Bale, A. E., Stewart, K., Dachowski, L., McBride, O. W., Glaser, T., Green, J. E., III, Mulvihill, J. J., Brandi, M. L., Sakaguchi, K., Aurbach, G. D., Marx, S. J.
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<p class="mim-text-font">
Bale, S. J., Marx, S. J., Langfield, D., Bale, A. E., Mulvihill, J., Green, J., III.
<strong>Multiple endocrine neoplasia type 1 (MEN1): genetic linkage studies. (Abstract)</strong>
Cytogenet. Cell Genet. 46: 575, 1987.
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<p class="mim-text-font">
Ballard, H. S., Frame, B., Hartsock, R. J.
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Bear, J. C., Briones-Urbina, R., Fahey, J. F., Farid, N. R.
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Hum. Hered. 35: 15-20, 1985.
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Bystrom, C., Larsson, C., Blomberg, C., Sandelin, K., Falkmer, U., Skogseid, B., Oberg, K., Werner, S., Nordenskjold, M.
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Ebeling, T., Vierimaa, O., Kytola, S., Leisti, J., Salmela, P. I.
<strong>Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations.</strong>
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Contributors:
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Cassandra L. Kniffin - updated : 3/6/2008<br>John A. Phillips, III - updated : 2/13/2008<br>Patricia A. Hartz - updated : 8/10/2007<br>George E. Tiller - updated : 6/21/2007<br>John A. Phillips, III - updated : 5/23/2007<br>Marla J. F. O&#x27;Neill - updated : 2/12/2007<br>John A. Phillips, III - updated : 10/20/2006<br>Patricia A. Hartz - updated : 3/16/2006<br>John A. Phillips, III - updated : 8/2/2005<br>John A. Phillips, III - updated : 8/1/2005<br>John A. Phillips, III - updated : 4/13/2005<br>Victor A. McKusick - updated : 1/31/2005<br>Stylianos E. Antonarakis - updated : 11/24/2004<br>John A. Phillips, III - updated : 10/13/2004<br>Marla J. F. O&#x27;Neill - updated : 9/1/2004<br>Victor A. McKusick - updated : 8/20/2004<br>Gary A. Bellus - updated : 9/3/2003<br>Victor A. McKusick - updated : 7/18/2003<br>John A. Phillips, III - updated : 1/13/2003<br>John A. Phillips, III - updated : 10/29/2002<br>Victor A. McKusick - updated : 8/27/2002<br>John A. Phillips, III - updated : 7/30/2002<br>John A. Phillips, III - updated : 7/25/2002<br>John A. Phillips, III - updated : 6/7/2002<br>John A. Phillips, III - updated : 5/22/2002<br>John A. Phillips, III - updated : 2/26/2002<br>John A. Phillips, III - updated : 10/10/2001<br>John A. Phillips, III - updated : 9/19/2001<br>John A. Phillips, III - updated : 7/27/2001<br>John A. Phillips, III - updated : 7/10/2001<br>Victor A. McKusick - updated : 4/17/2001<br>Victor A. McKusick - updated : 3/5/2001<br>Victor A. McKusick - updated : 1/13/2000<br>John A. Phillips, III - updated : 10/3/1999<br>Victor A. McKusick - updated : 9/29/1999<br>Victor A. McKusick - updated : 9/8/1999<br>Carol A. Bocchini - updated : 7/12/1999<br>Victor A. McKusick - updated : 4/16/1999<br>John A. Phillips, III - updated : 3/26/1999<br>John A. Phillips, III - updated : 3/3/1999<br>Michael J. Wright - updated : 2/12/1999<br>Victor A. McKusick - updated : 2/3/1999<br>Stylianos E. Antonarakis - updated : 2/2/1999<br>Sheryl A. Jankowski - updated : 1/12/1999<br>Victor A. McKusick - updated : 12/29/1998<br>Victor A. McKusick - updated : 12/8/1998<br>Jennifer P. Macke - updated : 10/22/1998<br>Victor A. McKusick - updated : 10/14/1998<br>John A. Phillips, III - updated : 10/1/1998<br>Victor A. McKusick - updated : 9/11/1998<br>Victor A. McKusick - updated : 5/19/1998<br>Victor A. McKusick - updated : 4/29/1998<br>Victor A. McKusick - updated : 4/10/1998<br>Victor A. McKusick - updated : 3/27/1998<br>Victor A. McKusick - updated : 3/5/1998<br>Victor A. McKusick - updated : 12/19/1997<br>Victor A. McKusick - updated : 9/8/1997<br>Alan F. Scott - updated : 8/5/1997<br>Victor A. McKusick - updated : 7/31/1997<br>Victor A. McKusick - updated : 4/17/1997
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Creation Date:
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Victor A. McKusick : 6/4/1986
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