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<title>
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Entry
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- #176400 - PRECOCIOUS PUBERTY, CENTRAL, 1; CPPB1
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- OMIM
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<span class="h4">#176400</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/phenotypicSeries/PS176400"> <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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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=(PRECOCIOUS PUBERTY, CENTRAL) OR (KISS1R)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=31887&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.diseaseinfosearch.org/x/7933" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=176400[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=650097" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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</span>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0112310" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/176400" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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<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">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 650097<br />
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<strong>DO:</strong> 0112310<br />
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">ICD+</a>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
|
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176400
|
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</span>
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</span>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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PRECOCIOUS PUBERTY, CENTRAL, 1; CPPB1
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</h3>
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</div>
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<div>
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<br />
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</div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
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<th>
|
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Inheritance
|
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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<th>
|
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Gene/Locus
|
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</th>
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<th>
|
|
Gene/Locus <br /> MIM number
|
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</th>
|
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<span class="mim-font">
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<a href="/geneMap/19/35?start=-3&limit=10&highlight=35">
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19p13.3
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<span class="mim-font">
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?Precocious puberty, central, 1
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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<span class="mim-font">
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<a href="/entry/176400"> 176400 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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KISS1R
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</span>
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</td>
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<span class="mim-font">
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<a href="/entry/604161"> 604161 </a>
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/176400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/176400" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<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>
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<strong> Endocrine </strong>
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<span class="mim-font">
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- Isosexual precocious puberty <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/4294006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">4294006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0271528&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0271528</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008236" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008236</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008236" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008236</a>]</span><br /> - Occasional hypothyroidism<br />
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<span class="h5 mim-font">
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<strong> Growth </strong>
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- Reduced adult height<br />
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<span class="h5 mim-font">
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<strong> Misc </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Onset of menarche before age 8.5 years or male pubertal changes before age 10 years<br />
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</span>
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<div>
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<span class="h5 mim-font">
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<strong> Lab </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Increased secretion of LH and FSH<br />
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<span class="h5 mim-font">
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<strong> Inheritance </strong>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- 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 />
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
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<h5>
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Precocious puberty, central
|
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- <a href="/phenotypicSeries/PS176400">PS176400</a>
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- 2 Entries
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</h5>
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</div>
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</div>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
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<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<thead>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Location</strong>
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
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<strong>Phenotype</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Inheritance</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />mapping key</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />MIM number</strong>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus<br />MIM number</strong>
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</th>
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<span class="mim-font">
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<a href="/geneMap/15/19?start=-3&limit=10&highlight=19"> 15q11.2 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/615346"> Precocious puberty, central, 2 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/615346"> 615346 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/603856"> MKRN3 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/603856"> 603856 </a>
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/19/35?start=-3&limit=10&highlight=35"> 19p13.3 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/176400"> ?Precocious puberty, central, 1 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/176400"> 176400 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/604161"> KISS1R </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/604161"> 604161 </a>
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</span>
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</td>
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</table>
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<div class="text-right small">
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
|
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that central precocious puberty-1 (CPPB1) is caused by heterozygous mutation in the GPR54 gene (KISS1R; <a href="/entry/604161">604161</a>) on chromosome 19p13. One such family has been reported.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>Early activation of the hypothalamic-pituitary-gonadal axis results in gonadotropin-dependent precocious puberty, also known as central precocious puberty, which is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. The timing of puberty is associated with risks of subsequent disease: earlier age of menarche in girls is associated with increased risk of breast cancer, endometrial cancer, obesity, type 2 diabetes, and cardiovascular disease. Central precocious puberty has also been associated with an increased incidence of conduct and behavior disorders during adolescence (summary by <a href="#1" class="mim-tip-reference" title="Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others. <strong>Central precocious puberty caused by mutations in the imprinted gene MKRN3.</strong> New Eng. J. Med. 368: 2467-2475, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23738509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23738509</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23738509[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa1302160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23738509">Abreu et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23738509" 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 Central Precocious Puberty</em></strong></p><p>
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Central precocious puberty-2 (CPPB2; <a href="/entry/615346">615346</a>) is caused by mutation in the MKRN3 gene (<a href="/entry/603856">603856</a>) on chromosome 15q11.</p>
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<br />
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</h4>
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</div>
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<p>So-called isosexual precocious puberty is usually defined as onset of menarche in the female before age 8.5 years or pubertal changes in the male before age 10 years. Puberty may occur before 3 years of age. Adult height is reduced. These cases are often misdiagnosed as adrenogenital syndrome. Male-to-male transmission has been observed. Central precocious puberty refers to a gonadotropin-dependent type which results from premature activation of the hypothalamic-pituitary-gonadal axis (<a href="#17" class="mim-tip-reference" title="Teles, M. G., Bianco, S. D. C., Brito, V. N., Trarbach, E. B., Kuohung, W., Xu, S., Seminara, S. B., Mendonca, B. B., Kaiser, U. B., Latronico, A. C. <strong>A GPR54-activating mutation in a patient with central precocious puberty.</strong> New Eng. J. Med. 358: 709-715, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18272894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18272894</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18272894[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa073443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18272894">Teles et al., 2008</a>). <a href="#15" class="mim-tip-reference" title="Rush, H. P., Bilderback, J. B., Slocum, D., Rogers, A. <strong>Pubertas praecox (macrogenitosomia).</strong> Endocrinology 21: 404-411, 1937."None>Rush et al. (1937)</a> and <a href="#7" class="mim-tip-reference" title="Jacobsen, A. W., Macklin, M. T. <strong>Hereditary sexual precocity: report of a family with 27 affected members.</strong> Pediatrics 9: 682-694, 1952.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14929627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14929627</a>]" pmid="14929627">Jacobsen and Macklin (1952)</a> reported a family in which 27 males (but no females) in 4 generations showed sexual precocity. <a href="#6" class="mim-tip-reference" title="Hampson, J. G., Money, J. <strong>Idiopathic sexual precocity in the female: report of three cases.</strong> Psychosom. Med. 17: 16-35, 1955.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13237387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13237387</a>] [<a href="https://doi.org/10.1097/00006842-195501000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13237387">Hampson and Money (1955)</a> suggested that female sexual precocity may be transmitted through the male. <a href="#8" class="mim-tip-reference" title="Jungck, E. C., Thrash, A. M., Ohlmacher, A. P., Knight, A. M., Jr., Dyrenforth, L. Y. <strong>Sexual precocity due to interstitial-cell tumor of the testis: report of 2 cases.</strong> J. Clin. Endocr. Metab. 17: 291-295, 1957.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13398469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13398469</a>] [<a href="https://doi.org/10.1210/jcem-17-2-291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13398469">Jungck et al. (1957)</a> observed transmission of male precocity through females. <a href="#4" class="mim-tip-reference" title="Ferrier, P., Shepard, T. H., Smith, E. K. <strong>Growth disturbances and values for hormone excretion in various forms of precocious sexual development.</strong> Pediatrics 28: 258-275, 1961.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13699158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13699158</a>]" pmid="13699158">Ferrier et al. (1961)</a> and <a href="#2" class="mim-tip-reference" title="Beas, F., Zurbrugg, R. P., Leibow, S. G., Patton, R. G., Gardner, L. I. <strong>Familial male sexual precocity: report of the eleventh kindred found, with observations on blood group linkage and urinary C-19-steroid excretion.</strong> J. Clin. Endocr. 22: 1095-1102, 1962.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13969962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13969962</a>] [<a href="https://doi.org/10.1210/jcem-22-11-1095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13969962">Beas et al. (1962)</a> reported families with affected brother and sister. <a href="#19" class="mim-tip-reference" title="Wilkins, L. <strong>Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. (3rd ed.)</strong> Springfield, Ill.: Charles C Thomas (pub.) 1965."None>Wilkins (1965)</a> stated that 'among girls we also have seen a familial tendency to sexual precocity and have had one family in which both sexes were affected.' Precocious puberty is a more frequent occurrence in females than in males, but familial occurrence seems rarer in females. X-linked recessive inheritance was postulated by <a href="#18" class="mim-tip-reference" title="Vasquez, S. B., Friedman, C. I., Kim, M., Sotos, J. F. <strong>Endocrine studies in X-linked familial precocious puberty. (Abstract)</strong> Pediat. Res. 12: 518 only, 1978."None>Vasquez et al. (1978)</a>, who observed 2 male cousins. Commenting on the rarity of familial precocious puberty in girls, <a href="#14" class="mim-tip-reference" title="Rangasami, J. J., Grant, D. B. <strong>Familial precocious puberty in girls.</strong> J. Roy. Soc. Med. 85: 497-498, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1404207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1404207</a>] [<a href="https://doi.org/10.1177/014107689208500826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1404207">Rangasami and Grant (1992)</a> reported its occurrence in sisters at which puberty began with breast development at the age of 4 years and 5 years and three months, respectively. There appeared to be a premature activation of the hypothalamic-pituitary-gonadal axis as shown by increased secretion of LH and FSH. <a href="#13" class="mim-tip-reference" title="Prasher, V. P. <strong>Familial precocious puberty in girls. (Letter)</strong> J. Roy. Soc. Med. 86: 61 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8423588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8423588</a>]" pmid="8423588">Prasher (1993)</a> pointed out that hypothyroidism is occasionally accompanied by precocious puberty rather than delay of sexual maturation and that thyroid function should be checked in patients such as those reported by <a href="#14" class="mim-tip-reference" title="Rangasami, J. J., Grant, D. B. <strong>Familial precocious puberty in girls.</strong> J. Roy. Soc. Med. 85: 497-498, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1404207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1404207</a>] [<a href="https://doi.org/10.1177/014107689208500826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1404207">Rangasami and Grant (1992)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13969962+14929627+8423588+1404207+13237387+13398469+18272894+13699158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Kalantaridou, S. N., Chrousos, G. P. <strong>Monogenic disorders of puberty.</strong> J. Clin. Endocr. Metab. 87: 2481-2494, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050203</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050203">Kalantaridou and Chrousos (2002)</a> reviewed monogenic disorders of puberty. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050203" 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="de Vries, L., Kauschansky, A., Shohat, M., Phillip, M. <strong>Familial central precocious puberty suggests autosomal dominant inheritance.</strong> J. Clin. Endocr. Metab. 89: 1794-1800, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15070947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15070947</a>] [<a href="https://doi.org/10.1210/jc.2003-030361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15070947">De Vries et al. (2004)</a> investigated the mode of inheritance of familial precocious puberty and sought to identify characteristics that distinguish familial from isolated precocious puberty. Of the 453 children referred to their center for suspected precocious puberty, 156 (147 girls and 9 boys) were found to have idiopathic central precocious puberty, which was familial in 43 (42 girls and 1 boy; 27.5%). The familial group was characterized by a significantly lower age of maternal menarche than the sporadic group (mean, 11.47 +/- 1.96 vs 12.66 +/- 1.18 years, P = 0.0001) and more advanced puberty at admission (Tanner stage 2, 56.5% vs 78.1%, P = 0.006). Segregation analysis was used to study the mode of inheritance. The segregation ratio for precocious puberty was 0.38 (0.45 after exclusion of young sibs) assuming incomplete penetrance and 0.58 (0.65 after exclusion of young sibs) assuming complete ascertainment. The authors concluded that these results suggest autosomal dominant transmission with incomplete, sex-dependent penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15070947" 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="Teles, M. G., Bianco, S. D. C., Brito, V. N., Trarbach, E. B., Kuohung, W., Xu, S., Seminara, S. B., Mendonca, B. B., Kaiser, U. B., Latronico, A. C. <strong>A GPR54-activating mutation in a patient with central precocious puberty.</strong> New Eng. J. Med. 358: 709-715, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18272894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18272894</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18272894[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa073443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18272894">Teles et al. (2008)</a> described an 8-year-old girl referred for evaluation of precocious puberty. Premature breast development with slow progression had been observed since birth. At 7 years of age breast growth accelerated and pubic hair was noted. Additional pubertal signs such as acne, oily skin, axillary hair, and menstrual bleeding were absent. There were no cafe-au-lait spots. At 8 years of age height was 131.5 cm and weight was 26.7 kg, with a bone age of 11 years; breast development was Tanner stage 4, and pubic hair Tanner stage 2. Treatment with an analog of gonadotropin-releasing hormone receptor (GNRHR; <a href="/entry/138850">138850</a>) was initiated and maintained for 4 years. The diagnosis of central precocious puberty was confirmed by a satisfactory response to the treatment, including partial regression of breast development, decrease in growth velocity, arrest of bone maturation, reduction of ovarian size, and gonadotropin suppression along with the returned prepubertal estradiol levels. Spontaneous menarche occurred at age 12 and was followed by regular menses. The patient's adult height was 152.2 cm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18272894" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N. <strong>Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.</strong> Europ. J. Endocr. 174: 1-8, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26431553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26431553</a>] [<a href="https://doi.org/10.1530/EJE-15-0488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26431553">Simon et al. (2016)</a> described 21 girls with central precocious puberty from 14 families with mutations in the MKRN3 gene. Median age at puberty onset was 6 years, at which time the patients displayed typical features of precocious puberty, including Tanner stage 3, high height velocity, and advanced bone age. The authors noted that 34 girls with CPPB who did not have MKRN3 mutations showed a later onset of puberty, at age 7 years, but no differences in hormone levels or in ultrasound evidence of estrogen exposure were found between girls with and those without MKRN3 mutations. A history of precocious puberty was self-reported in only 1 of 8 fathers carrying MKRN3 mutations, and in 2 families there was an apparently unaffected brother who also carried the mutation, inherited from their fathers. <a href="#16" class="mim-tip-reference" title="Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N. <strong>Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.</strong> Europ. J. Endocr. 174: 1-8, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26431553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26431553</a>] [<a href="https://doi.org/10.1530/EJE-15-0488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26431553">Simon et al. (2016)</a> commented that puberty onset is harder to recognize in boys than in girls, and that cases of precocious puberty may have been missed. The authors also noted a deficit of boys in the offspring of fathers with MKRN3 mutations, both in the current study and in previous reports (41 girls vs 10 boys), and suggested that Y-bearing sperm cells carrying MKRN3 mutations may be defective. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26431553" 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="Grandone, A., Capristo, C., Cirillo, G., Sasso, M., Umano, G. R., Mariani, M., Del Giudice, E. M., Perrone, L. <strong>Molecular screening of MKRN3, DLK1, and KCNK9 genes in girls with idiopathic central precocious puberty.</strong> Horm. Res. Paediat. 88: 194-200, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28672280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28672280</a>] [<a href="https://doi.org/10.1159/000477441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28672280">Grandone et al. (2017)</a> reported 3 unrelated girls with CPPB and mutations in the MKRN3 gene. Puberty onset occurred at age 5.5 years in 1 girl and 6.0 years in the other 2; 2 of the patients were Tanner stage 3 and 1 was Tanner stage 2, and bone ages were 8.0, 10.3, and 11.2 years. In 1 family, an affected female cousin also carried the mutation, and in all cases, the mutation was inherited from an apparently unaffected father. The patients did not exhibit other dysmorphic features or pituitary alterations, and all responded well to GnRH analog treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28672280" 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="#10" class="mim-tip-reference" title="Klein, K. O., Barnes, K. M., Jones, J. V., Feuillan, P. P., Cutler, G. B., Jr. <strong>Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience.</strong> J. Clin. Endocr. Metab. 86: 4711-4716, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11600530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11600530</a>] [<a href="https://doi.org/10.1210/jcem.86.10.7915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11600530">Klein et al. (2001)</a> studied 98 children who had reached final adult height in a long-term trial of LHRH (<a href="/entry/152760">152760</a>) agonist treatment. These children were 5.3 +/- 2.1 years old at the start of treatment and were treated with either deslorelin or histrelin for an average of 6.1 +/- 2.5 years. The authors concluded that LHRH agonist treatment improves the final height for children with rapidly progressing precocious puberty treated before the age of 8 years for girls or 9 years for boys. Less delay in the onset of treatment, longer duration of treatment, and lower chronologic and bone age at the onset of treatment all lead to greater final height. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11600530" 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="#17" class="mim-tip-reference" title="Teles, M. G., Bianco, S. D. C., Brito, V. N., Trarbach, E. B., Kuohung, W., Xu, S., Seminara, S. B., Mendonca, B. B., Kaiser, U. B., Latronico, A. C. <strong>A GPR54-activating mutation in a patient with central precocious puberty.</strong> New Eng. J. Med. 358: 709-715, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18272894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18272894</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18272894[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1056/NEJMoa073443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18272894">Teles et al. (2008)</a> identified a heterozygous activating mutation in the GPR54 gene (<a href="/entry/604161#0006">604161.0006</a>) in an adopted girl with central precocious puberty. The patient had had thelarche from birth, but with slow progression, suggesting an early, persistent, and mild increase in estrogen secretion. Isolated thelarche was ruled out on the basis of progressive secondary sexual development and accelerated growth and skeletal maturation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18272894" 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 1 male and 45 female probands from France and Italy with central precocious puberty, who were negative for mutation in the KISS1 (<a href="/entry/603286">603286</a>) and KISS1R (<a href="/entry/604161">604161</a>) genes, <a href="#16" class="mim-tip-reference" title="Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N. <strong>Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.</strong> Europ. J. Endocr. 174: 1-8, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26431553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26431553</a>] [<a href="https://doi.org/10.1530/EJE-15-0488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26431553">Simon et al. (2016)</a> analyzed the MKRN3 gene and identified heterozygosity for 2 frameshift and 5 missense mutations (see, e.g., <a href="/entry/603856#0005">603856.0005</a>) in 14 (30%) of the probands. One of the frameshift mutations was a previously reported 1-bp insertion (c.482insC; <a href="/entry/603856#0004">603856.0004</a>) that was detected in 8 of the families, and the remaining mutations were found in 1 family each. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26431553" 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="Grandone, A., Capristo, C., Cirillo, G., Sasso, M., Umano, G. R., Mariani, M., Del Giudice, E. M., Perrone, L. <strong>Molecular screening of MKRN3, DLK1, and KCNK9 genes in girls with idiopathic central precocious puberty.</strong> Horm. Res. Paediat. 88: 194-200, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28672280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28672280</a>] [<a href="https://doi.org/10.1159/000477441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28672280">Grandone et al. (2017)</a> sequenced the MKRN3, DLK1 (<a href="/entry/176290">176290</a>), and KCNK9 (<a href="/entry/605874">605874</a>) genes in 60 girls with central precocious puberty and identified 3 heterozygous mutations in MKRN3 in 3 of the probands (see, e.g., <a href="/entry/603856#0005">603856.0005</a>), for an overall prevalence of 5%. No mutations were detected in the DLK1 or KCNK9 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28672280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between central precocious puberty and a chromosome 14q32 rearrangement involving the DLK1 gene, see <a href="/entry/176290">176290</a>.</p>
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<a href="#Mortimer1954" class="mim-tip-reference" title="Mortimer, E. A. <strong>Familial constitutional precocious puberty in a boy three years of age: report of a case.</strong> Pediatrics 13: 174-177, 1954.">Mortimer (1954)</a>; <a href="#Novak1944" class="mim-tip-reference" title="Novak, E. <strong>Constitutional type of female precocious puberty with a report of 9 cases.</strong> Am. J. Obstet. Gynec. 47: 20-42, 1944.">Novak (1944)</a>
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Grandone, A., Capristo, C., Cirillo, G., Sasso, M., Umano, G. R., Mariani, M., Del Giudice, E. M., Perrone, L.
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<strong>Molecular screening of MKRN3, DLK1, and KCNK9 genes in girls with idiopathic central precocious puberty.</strong>
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Horm. Res. Paediat. 88: 194-200, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28672280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28672280</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28672280" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13398469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13398469</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13398469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11600530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11600530</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11600530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Mortimer, E. A.
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<strong>Familial constitutional precocious puberty in a boy three years of age: report of a case.</strong>
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Pediatrics 13: 174-177, 1954.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13133567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13133567</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13133567" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Novak, E.
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<strong>Constitutional type of female precocious puberty with a report of 9 cases.</strong>
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Am. J. Obstet. Gynec. 47: 20-42, 1944.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1404207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1404207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1404207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1177/014107689208500826" target="_blank">Full Text</a>]
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<a id="15" class="mim-anchor"></a>
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<a id="Rush1937" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rush, H. P., Bilderback, J. B., Slocum, D., Rogers, A.
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<strong>Pubertas praecox (macrogenitosomia).</strong>
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Endocrinology 21: 404-411, 1937.
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<a id="Simon2016" class="mim-anchor"></a>
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Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N.
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<strong>Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.</strong>
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Europ. J. Endocr. 174: 1-8, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26431553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26431553</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26431553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1530/EJE-15-0488" target="_blank">Full Text</a>]
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<a id="Teles2008" class="mim-anchor"></a>
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Teles, M. G., Bianco, S. D. C., Brito, V. N., Trarbach, E. B., Kuohung, W., Xu, S., Seminara, S. B., Mendonca, B. B., Kaiser, U. B., Latronico, A. C.
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<strong>A GPR54-activating mutation in a patient with central precocious puberty.</strong>
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New Eng. J. Med. 358: 709-715, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18272894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18272894</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18272894[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18272894" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJMoa073443" target="_blank">Full Text</a>]
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<a id="18" class="mim-anchor"></a>
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<a id="Vasquez1978" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vasquez, S. B., Friedman, C. I., Kim, M., Sotos, J. F.
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<strong>Endocrine studies in X-linked familial precocious puberty. (Abstract)</strong>
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Pediat. Res. 12: 518 only, 1978.
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<a id="Wilkins1965" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilkins, L.
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<strong>Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. (3rd ed.)</strong>
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Springfield, Ill.: Charles C Thomas (pub.) 1965.
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 09/07/2017
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 7/29/2013<br>Victor A. McKusick - updated : 3/19/2008<br>John A. Phillips, III - updated : 7/25/2005<br>John A. Phillips, III - updated : 4/8/2003<br>John A. Phillips, III - updated : 3/22/2002
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Victor A. McKusick : 6/2/1986
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carol : 06/06/2018
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carol : 10/03/2017<br>carol : 10/02/2017<br>carol : 09/07/2017<br>carol : 07/09/2016<br>carol : 10/24/2014<br>carol : 10/15/2014<br>carol : 10/15/2014<br>mcolton : 10/14/2014<br>carol : 7/29/2013<br>carol : 7/29/2013<br>terry : 9/9/2010<br>carol : 6/3/2009<br>alopez : 3/25/2008<br>terry : 3/19/2008<br>alopez : 7/25/2005<br>joanna : 3/18/2004<br>tkritzer : 4/14/2003<br>tkritzer : 4/8/2003<br>terry : 4/8/2003<br>alopez : 3/22/2002<br>carol : 3/5/2001<br>yemi : 2/11/2000<br>mimadm : 2/25/1995<br>davew : 8/1/1994<br>carol : 3/9/1993<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989
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<strong>#</strong> 176400
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PRECOCIOUS PUBERTY, CENTRAL, 1; CPPB1
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<strong>ORPHA:</strong> 650097;
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<strong>DO:</strong> 0112310;
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<strong>Phenotype-Gene Relationships</strong>
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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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<span class="mim-font">
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19p13.3
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<span class="mim-font">
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?Precocious puberty, central, 1
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<span class="mim-font">
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176400
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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KISS1R
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<span class="mim-font">
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604161
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<p>A number sign (#) is used with this entry because of evidence that central precocious puberty-1 (CPPB1) is caused by heterozygous mutation in the GPR54 gene (KISS1R; 604161) on chromosome 19p13. One such family has been reported.</p>
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<strong>Description</strong>
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<p>Early activation of the hypothalamic-pituitary-gonadal axis results in gonadotropin-dependent precocious puberty, also known as central precocious puberty, which is clinically defined by the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. The timing of puberty is associated with risks of subsequent disease: earlier age of menarche in girls is associated with increased risk of breast cancer, endometrial cancer, obesity, type 2 diabetes, and cardiovascular disease. Central precocious puberty has also been associated with an increased incidence of conduct and behavior disorders during adolescence (summary by Abreu et al., 2013). </p><p><strong><em>Genetic Heterogeneity of Central Precocious Puberty</em></strong></p><p>
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Central precocious puberty-2 (CPPB2; 615346) is caused by mutation in the MKRN3 gene (603856) on chromosome 15q11.</p>
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<p>So-called isosexual precocious puberty is usually defined as onset of menarche in the female before age 8.5 years or pubertal changes in the male before age 10 years. Puberty may occur before 3 years of age. Adult height is reduced. These cases are often misdiagnosed as adrenogenital syndrome. Male-to-male transmission has been observed. Central precocious puberty refers to a gonadotropin-dependent type which results from premature activation of the hypothalamic-pituitary-gonadal axis (Teles et al., 2008). Rush et al. (1937) and Jacobsen and Macklin (1952) reported a family in which 27 males (but no females) in 4 generations showed sexual precocity. Hampson and Money (1955) suggested that female sexual precocity may be transmitted through the male. Jungck et al. (1957) observed transmission of male precocity through females. Ferrier et al. (1961) and Beas et al. (1962) reported families with affected brother and sister. Wilkins (1965) stated that 'among girls we also have seen a familial tendency to sexual precocity and have had one family in which both sexes were affected.' Precocious puberty is a more frequent occurrence in females than in males, but familial occurrence seems rarer in females. X-linked recessive inheritance was postulated by Vasquez et al. (1978), who observed 2 male cousins. Commenting on the rarity of familial precocious puberty in girls, Rangasami and Grant (1992) reported its occurrence in sisters at which puberty began with breast development at the age of 4 years and 5 years and three months, respectively. There appeared to be a premature activation of the hypothalamic-pituitary-gonadal axis as shown by increased secretion of LH and FSH. Prasher (1993) pointed out that hypothyroidism is occasionally accompanied by precocious puberty rather than delay of sexual maturation and that thyroid function should be checked in patients such as those reported by Rangasami and Grant (1992). </p><p>Kalantaridou and Chrousos (2002) reviewed monogenic disorders of puberty. </p><p>De Vries et al. (2004) investigated the mode of inheritance of familial precocious puberty and sought to identify characteristics that distinguish familial from isolated precocious puberty. Of the 453 children referred to their center for suspected precocious puberty, 156 (147 girls and 9 boys) were found to have idiopathic central precocious puberty, which was familial in 43 (42 girls and 1 boy; 27.5%). The familial group was characterized by a significantly lower age of maternal menarche than the sporadic group (mean, 11.47 +/- 1.96 vs 12.66 +/- 1.18 years, P = 0.0001) and more advanced puberty at admission (Tanner stage 2, 56.5% vs 78.1%, P = 0.006). Segregation analysis was used to study the mode of inheritance. The segregation ratio for precocious puberty was 0.38 (0.45 after exclusion of young sibs) assuming incomplete penetrance and 0.58 (0.65 after exclusion of young sibs) assuming complete ascertainment. The authors concluded that these results suggest autosomal dominant transmission with incomplete, sex-dependent penetrance. </p><p>Teles et al. (2008) described an 8-year-old girl referred for evaluation of precocious puberty. Premature breast development with slow progression had been observed since birth. At 7 years of age breast growth accelerated and pubic hair was noted. Additional pubertal signs such as acne, oily skin, axillary hair, and menstrual bleeding were absent. There were no cafe-au-lait spots. At 8 years of age height was 131.5 cm and weight was 26.7 kg, with a bone age of 11 years; breast development was Tanner stage 4, and pubic hair Tanner stage 2. Treatment with an analog of gonadotropin-releasing hormone receptor (GNRHR; 138850) was initiated and maintained for 4 years. The diagnosis of central precocious puberty was confirmed by a satisfactory response to the treatment, including partial regression of breast development, decrease in growth velocity, arrest of bone maturation, reduction of ovarian size, and gonadotropin suppression along with the returned prepubertal estradiol levels. Spontaneous menarche occurred at age 12 and was followed by regular menses. The patient's adult height was 152.2 cm. </p><p>Simon et al. (2016) described 21 girls with central precocious puberty from 14 families with mutations in the MKRN3 gene. Median age at puberty onset was 6 years, at which time the patients displayed typical features of precocious puberty, including Tanner stage 3, high height velocity, and advanced bone age. The authors noted that 34 girls with CPPB who did not have MKRN3 mutations showed a later onset of puberty, at age 7 years, but no differences in hormone levels or in ultrasound evidence of estrogen exposure were found between girls with and those without MKRN3 mutations. A history of precocious puberty was self-reported in only 1 of 8 fathers carrying MKRN3 mutations, and in 2 families there was an apparently unaffected brother who also carried the mutation, inherited from their fathers. Simon et al. (2016) commented that puberty onset is harder to recognize in boys than in girls, and that cases of precocious puberty may have been missed. The authors also noted a deficit of boys in the offspring of fathers with MKRN3 mutations, both in the current study and in previous reports (41 girls vs 10 boys), and suggested that Y-bearing sperm cells carrying MKRN3 mutations may be defective. </p><p>Grandone et al. (2017) reported 3 unrelated girls with CPPB and mutations in the MKRN3 gene. Puberty onset occurred at age 5.5 years in 1 girl and 6.0 years in the other 2; 2 of the patients were Tanner stage 3 and 1 was Tanner stage 2, and bone ages were 8.0, 10.3, and 11.2 years. In 1 family, an affected female cousin also carried the mutation, and in all cases, the mutation was inherited from an apparently unaffected father. The patients did not exhibit other dysmorphic features or pituitary alterations, and all responded well to GnRH analog treatment. </p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Management</strong>
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<span class="mim-text-font">
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<p>Klein et al. (2001) studied 98 children who had reached final adult height in a long-term trial of LHRH (152760) agonist treatment. These children were 5.3 +/- 2.1 years old at the start of treatment and were treated with either deslorelin or histrelin for an average of 6.1 +/- 2.5 years. The authors concluded that LHRH agonist treatment improves the final height for children with rapidly progressing precocious puberty treated before the age of 8 years for girls or 9 years for boys. Less delay in the onset of treatment, longer duration of treatment, and lower chronologic and bone age at the onset of treatment all lead to greater final height. </p>
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<strong>Molecular Genetics</strong>
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<p>Teles et al. (2008) identified a heterozygous activating mutation in the GPR54 gene (604161.0006) in an adopted girl with central precocious puberty. The patient had had thelarche from birth, but with slow progression, suggesting an early, persistent, and mild increase in estrogen secretion. Isolated thelarche was ruled out on the basis of progressive secondary sexual development and accelerated growth and skeletal maturation. </p><p>In 1 male and 45 female probands from France and Italy with central precocious puberty, who were negative for mutation in the KISS1 (603286) and KISS1R (604161) genes, Simon et al. (2016) analyzed the MKRN3 gene and identified heterozygosity for 2 frameshift and 5 missense mutations (see, e.g., 603856.0005) in 14 (30%) of the probands. One of the frameshift mutations was a previously reported 1-bp insertion (c.482insC; 603856.0004) that was detected in 8 of the families, and the remaining mutations were found in 1 family each. </p><p>Grandone et al. (2017) sequenced the MKRN3, DLK1 (176290), and KCNK9 (605874) genes in 60 girls with central precocious puberty and identified 3 heterozygous mutations in MKRN3 in 3 of the probands (see, e.g., 603856.0005), for an overall prevalence of 5%. No mutations were detected in the DLK1 or KCNK9 genes. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between central precocious puberty and a chromosome 14q32 rearrangement involving the DLK1 gene, see 176290.</p>
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Mortimer (1954); Novak (1944)
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<strong>REFERENCES</strong>
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Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others.
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<strong>Central precocious puberty caused by mutations in the imprinted gene MKRN3.</strong>
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New Eng. J. Med. 368: 2467-2475, 2013.
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[PubMed: 23738509]
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[Full Text: https://doi.org/10.1056/NEJMoa1302160]
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Beas, F., Zurbrugg, R. P., Leibow, S. G., Patton, R. G., Gardner, L. I.
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<strong>Familial male sexual precocity: report of the eleventh kindred found, with observations on blood group linkage and urinary C-19-steroid excretion.</strong>
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J. Clin. Endocr. 22: 1095-1102, 1962.
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[PubMed: 13969962]
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de Vries, L., Kauschansky, A., Shohat, M., Phillip, M.
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<strong>Familial central precocious puberty suggests autosomal dominant inheritance.</strong>
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J. Clin. Endocr. Metab. 89: 1794-1800, 2004.
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[PubMed: 15070947]
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[Full Text: https://doi.org/10.1210/jc.2003-030361]
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<p class="mim-text-font">
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Ferrier, P., Shepard, T. H., Smith, E. K.
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<strong>Growth disturbances and values for hormone excretion in various forms of precocious sexual development.</strong>
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Pediatrics 28: 258-275, 1961.
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[PubMed: 13699158]
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</p>
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<li>
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<p class="mim-text-font">
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Grandone, A., Capristo, C., Cirillo, G., Sasso, M., Umano, G. R., Mariani, M., Del Giudice, E. M., Perrone, L.
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<strong>Molecular screening of MKRN3, DLK1, and KCNK9 genes in girls with idiopathic central precocious puberty.</strong>
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Horm. Res. Paediat. 88: 194-200, 2017.
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[PubMed: 28672280]
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[Full Text: https://doi.org/10.1159/000477441]
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<p class="mim-text-font">
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Hampson, J. G., Money, J.
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<strong>Idiopathic sexual precocity in the female: report of three cases.</strong>
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Psychosom. Med. 17: 16-35, 1955.
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[PubMed: 13237387]
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[Full Text: https://doi.org/10.1097/00006842-195501000-00002]
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<p class="mim-text-font">
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Jacobsen, A. W., Macklin, M. T.
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<strong>Hereditary sexual precocity: report of a family with 27 affected members.</strong>
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Pediatrics 9: 682-694, 1952.
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[PubMed: 14929627]
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Jungck, E. C., Thrash, A. M., Ohlmacher, A. P., Knight, A. M., Jr., Dyrenforth, L. Y.
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<strong>Sexual precocity due to interstitial-cell tumor of the testis: report of 2 cases.</strong>
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J. Clin. Endocr. Metab. 17: 291-295, 1957.
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[PubMed: 13398469]
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[Full Text: https://doi.org/10.1210/jcem-17-2-291]
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Kalantaridou, S. N., Chrousos, G. P.
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<strong>Monogenic disorders of puberty.</strong>
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J. Clin. Endocr. Metab. 87: 2481-2494, 2002.
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[PubMed: 12050203]
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[Full Text: https://doi.org/10.1210/jcem.87.6.8668]
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Klein, K. O., Barnes, K. M., Jones, J. V., Feuillan, P. P., Cutler, G. B., Jr.
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<strong>Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience.</strong>
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J. Clin. Endocr. Metab. 86: 4711-4716, 2001.
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[PubMed: 11600530]
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[Full Text: https://doi.org/10.1210/jcem.86.10.7915]
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<p class="mim-text-font">
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Mortimer, E. A.
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<strong>Familial constitutional precocious puberty in a boy three years of age: report of a case.</strong>
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Pediatrics 13: 174-177, 1954.
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[PubMed: 13133567]
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<p class="mim-text-font">
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Novak, E.
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<strong>Constitutional type of female precocious puberty with a report of 9 cases.</strong>
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Am. J. Obstet. Gynec. 47: 20-42, 1944.
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</p>
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<li>
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<p class="mim-text-font">
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Prasher, V. P.
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<strong>Familial precocious puberty in girls. (Letter)</strong>
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J. Roy. Soc. Med. 86: 61 only, 1993.
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[PubMed: 8423588]
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<p class="mim-text-font">
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Rangasami, J. J., Grant, D. B.
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<strong>Familial precocious puberty in girls.</strong>
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J. Roy. Soc. Med. 85: 497-498, 1992.
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[PubMed: 1404207]
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[Full Text: https://doi.org/10.1177/014107689208500826]
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<p class="mim-text-font">
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Rush, H. P., Bilderback, J. B., Slocum, D., Rogers, A.
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<strong>Pubertas praecox (macrogenitosomia).</strong>
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Endocrinology 21: 404-411, 1937.
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Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N.
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<strong>Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.</strong>
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Europ. J. Endocr. 174: 1-8, 2016.
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[PubMed: 26431553]
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[Full Text: https://doi.org/10.1530/EJE-15-0488]
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Teles, M. G., Bianco, S. D. C., Brito, V. N., Trarbach, E. B., Kuohung, W., Xu, S., Seminara, S. B., Mendonca, B. B., Kaiser, U. B., Latronico, A. C.
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<strong>A GPR54-activating mutation in a patient with central precocious puberty.</strong>
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New Eng. J. Med. 358: 709-715, 2008.
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[PubMed: 18272894]
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[Full Text: https://doi.org/10.1056/NEJMoa073443]
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<p class="mim-text-font">
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Vasquez, S. B., Friedman, C. I., Kim, M., Sotos, J. F.
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<strong>Endocrine studies in X-linked familial precocious puberty. (Abstract)</strong>
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Pediat. Res. 12: 518 only, 1978.
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<li>
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<p class="mim-text-font">
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Wilkins, L.
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<strong>Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. (3rd ed.)</strong>
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Springfield, Ill.: Charles C Thomas (pub.) 1965.
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Marla J. F. O'Neill - updated : 09/07/2017<br>Marla J. F. O'Neill - updated : 7/29/2013<br>Victor A. McKusick - updated : 3/19/2008<br>John A. Phillips, III - updated : 7/25/2005<br>John A. Phillips, III - updated : 4/8/2003<br>John A. Phillips, III - updated : 3/22/2002
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Victor A. McKusick : 6/2/1986
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carol : 06/06/2018<br>carol : 10/03/2017<br>carol : 10/02/2017<br>carol : 09/07/2017<br>carol : 07/09/2016<br>carol : 10/24/2014<br>carol : 10/15/2014<br>carol : 10/15/2014<br>mcolton : 10/14/2014<br>carol : 7/29/2013<br>carol : 7/29/2013<br>terry : 9/9/2010<br>carol : 6/3/2009<br>alopez : 3/25/2008<br>terry : 3/19/2008<br>alopez : 7/25/2005<br>joanna : 3/18/2004<br>tkritzer : 4/14/2003<br>tkritzer : 4/8/2003<br>terry : 4/8/2003<br>alopez : 3/22/2002<br>carol : 3/5/2001<br>yemi : 2/11/2000<br>mimadm : 2/25/1995<br>davew : 8/1/1994<br>carol : 3/9/1993<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989
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