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<title>
Entry
- #244200 - HYPOGONADOTROPIC HYPOGONADISM 3 WITH OR WITHOUT ANOSMIA; HH3
- OMIM
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<span class="h4">#244200</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/244200"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS147950"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=HYPOGONADOTROPIC HYPOGONADISM 3 WITH OR WITHOUT ANOSMIA" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=8668&Typ=Pat" title="Normosmic congenital hypogonadotropic hypogonadism" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Normosmic congenital hypog…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3249&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Kallmann syndrome&nbsp;</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=432" title="Normosmic congenital hypogonadotropic hypogonadism" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Normosmic congenital hypog…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=478" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Kallmann syndrome</a></div>
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<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:0090092" 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/244200" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:244200" 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>ORPHA:</strong> 432, 478<br />
<strong>DO:</strong> 0090092<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>
244200
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
HYPOGONADOTROPIC HYPOGONADISM 3 WITH OR WITHOUT ANOSMIA; HH3
</span>
</h3>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/80?start=-3&limit=10&highlight=80">
20p12.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Hypogonadotropic hypogonadism 3 with or without anosmia
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/244200"> 244200 </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">
PROKR2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607123"> 607123 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/244200" 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/PS147950" 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/244200" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/244200" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hearing loss (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103276001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103276001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/343087000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">343087000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15188001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15188001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H91.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011053&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011053</a>, <a href="https://bioportal.bioontology.org/search?q=C0018772&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018772</a>, <a href="https://bioportal.bioontology.org/search?q=C1384666&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1384666</a>, <a href="https://bioportal.bioontology.org/search?q=C3887873&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887873</a>, <a href="https://bioportal.bioontology.org/search?q=C2029884&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2029884</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Nose </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hyposmia/anosmia (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3554023&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3554023</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CHEST </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Features </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pectus excavatum <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/391987005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">391987005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/391982004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">391982004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/754.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.81</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0016842&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0016842</a>, <a href="https://bioportal.bioontology.org/search?q=C2051831&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2051831</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000767" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000767</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000767" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000767</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Breasts </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Delayed or absent thelarche <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3553927&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3553927</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025515" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025515</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Genitalia (Male) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Micropenis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/34911001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">34911001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q55.62" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q55.62</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/752.64" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">752.64</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0266435&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0266435</a>, <a href="https://bioportal.bioontology.org/search?q=C4551492&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551492</a>, <a href="https://bioportal.bioontology.org/search?q=C1387005&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1387005</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008736" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008736</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000054" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000054</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000054" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000054</a>]</span><br /> -
Cryptorchidism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204878001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204878001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q53.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q53.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/752.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">752.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0010417&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010417</a>, <a href="https://bioportal.bioontology.org/search?q=C5441920&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5441920</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000028</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000028</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Internal Genitalia (Female) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Primary amenorrhea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/156035004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">156035004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/8913004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">8913004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N91.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N91.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0232939&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232939</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000786" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000786</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000786" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000786</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Hands </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hyperlaxity of digits (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4478866&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4478866</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Feet </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pes planus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/23407003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">23407003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/203534009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">203534009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/53226007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">53226007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q66.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q66.5</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M21.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M21.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/754.61" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.61</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/734" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">734</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0016202&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0016202</a>, <a href="https://bioportal.bioontology.org/search?q=C0392477&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0392477</a>, <a href="https://bioportal.bioontology.org/search?q=C0264133&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0264133</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001763</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001763</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=1f893093d35c2d1df583eed57a47b6cb" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Pes_Planus-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=1f893093d35c2d1df583eed57a47b6cb&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MUSCLE, SOFT TISSUES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Fibrous dysplasia (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/789439000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">789439000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/10623005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">10623005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M27.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M27.8</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0259779&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0259779</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010734" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010734</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Synkinesia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/54685005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">54685005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0234362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0234362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0034980" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0034980</a>]</span><br /> -
Seizures (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br />
</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">
- Hypogonadotropic hypogonadism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22053006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22053006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/33927004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">33927004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405769009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405769009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E23.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E23.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q98.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q98.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q98.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q98.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/758.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">758.7</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0271623&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0271623</a>, <a href="https://bioportal.bioontology.org/search?q=C0022735&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022735</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000044" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000044</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000044" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000044</a>]</span><br /> -
Delayed or absent puberty <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2677536&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2677536</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000823" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000823</a>]</span><br /> -
Low to undetectable gonadotropin levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4011624&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4011624</a>]</span><br /> -
Low testosterone level <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4011625&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4011625</a>]</span><br /> -
Low estradiol level <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4011626&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4011626</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Incomplete penetrance <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836598&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836598</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span><br /> -
Some patients experience later reversal of hypogonadotropic hypogonadism<br /> -
Phenotype may be oligogenic in some patients who carry mutations in more than one HH-associated gene<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the prokineticin receptor-2 gene (PROKR2, <a href="/entry/607123#0001">607123.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Hypogonadotropic hypogonadism with or without anosmia
- <a href="/phenotypicSeries/PS147950">PS147950</a>
- 27 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/952?start=-3&limit=10&highlight=952"> 1p13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619755"> ?Hypogonadotropic hypogonadism 27 without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619755"> 619755 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162361"> NHLH2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162361"> 162361 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/1607?start=-3&limit=10&highlight=1607"> 1q32.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614842"> ?Hypogonadotropic hypogonadism 13 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614842"> 614842 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603286"> KISS1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603286"> 603286 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/631?start=-3&limit=10&highlight=631"> 2q14.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614880"> {Hypogonadotropic hypogonadism 15 with or without anosmia} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614880"> 614880 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604846"> HS6ST1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604846"> 604846 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/410?start=-3&limit=10&highlight=410"> 3p14.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615267"> Hypogonadotropic hypogonadism 18 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>, <abbr class="mim-tip-hint" title="Digenic dominant">DD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615267"> 615267 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606807"> IL17RD </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606807"> 606807 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/459?start=-3&limit=10&highlight=459"> 3p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610628"> Hypogonadotropic hypogonadism 4 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610628"> 610628 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607002"> PROK2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607002"> 607002 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/255?start=-3&limit=10&highlight=255"> 4q13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/146110"> Hypogonadotropic hypogonadism 7 without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/146110"> 146110 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/138850"> GNRHR </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/138850"> 138850 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/456?start=-3&limit=10&highlight=456"> 4q24 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614840"> Hypogonadotropic hypogonadism 11 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614840"> 614840 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162332"> TACR3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162332"> 162332 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/524?start=-3&limit=10&highlight=524"> 4q27 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618841"> Hypogonadotropic hypogonadism 25 with anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618841"> 618841 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616506"> NDNF </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616506"> 616506 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/5/616?start=-3&limit=10&highlight=616"> 5q31.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615266"> Hypogonadotropic hypogonadism 17 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615266"> 615266 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607984"> SPRY4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607984"> 607984 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/380?start=-3&limit=10&highlight=380"> 7q21.11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614897"> {Hypogonadotropic hypogonadism 16 with or without anosmia} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614897"> 614897 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603961"> SEMA3A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603961"> 603961 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/622?start=-3&limit=10&highlight=622"> 7q31.32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616030"> Hypogonadotropic hypogonadism 22, with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616030"> 616030 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613301"> FEZF1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613301"> 613301 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/99?start=-3&limit=10&highlight=99"> 8p21.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615270"> Hypogonadotropic hypogonadism 20 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615270"> 615270 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603725"> FGF17 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603725"> 603725 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/139?start=-3&limit=10&highlight=139"> 8p21.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614841"> ?Hypogonadotropic hypogonadism 12 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614841"> 614841 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/152760"> GNRH1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/152760"> 152760 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/211?start=-3&limit=10&highlight=211"> 8p11.23 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147950"> Hypogonadotropic hypogonadism 2 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147950"> 147950 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/136350"> FGFR1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/136350"> 136350 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/295?start=-3&limit=10&highlight=295"> 8q12.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612370"> Hypogonadotropic hypogonadism 5 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612370"> 612370 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608892"> CHD7 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608892"> 608892 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/698?start=-3&limit=10&highlight=698"> 9q34.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614838"> Hypogonadotropic hypogonadism 9 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614838"> 614838 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608137"> NSMF </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608137"> 608137 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/502?start=-3&limit=10&highlight=502"> 10q24.32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612702"> Hypogonadotropic hypogonadism 6 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612702"> 612702 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600483"> FGF8 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600483"> 600483 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/617?start=-3&limit=10&highlight=617"> 10q26.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614858"> Hypogonadotropic hypogonadism 14 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614858"> 614858 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606417"> WDR11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606417"> 606417 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/266?start=-3&limit=10&highlight=266"> 11p14.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/229070"> Hypogonadotropic hypogonadism 24 without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/229070"> 229070 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/136530"> FSHB </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/136530"> 136530 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/528?start=-3&limit=10&highlight=528"> 12q13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614839"> Hypogonadotropic hypogonadism 10 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614839"> 614839 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162330"> TAC3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162330"> 162330 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/669?start=-3&limit=10&highlight=669"> 12q21.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615269"> Hypogonadotropic hypogonadism 19 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615269"> 615269 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602748"> DUSP6 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602748"> 602748 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/242?start=-3&limit=10&highlight=242"> 15q21.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619718"> Hypogonadotropic hypogonadism 26 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619718"> 619718 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600480"> TCF12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600480"> 600480 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/35?start=-3&limit=10&highlight=35"> 19p13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614837"> Hypogonadotropic hypogonadism 8 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614837"> 614837 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604161"> KISS1R </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604161"> 604161 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/923?start=-3&limit=10&highlight=923"> 19q13.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/228300"> Hypogonadotropic hypogonadism 23 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/228300"> 228300 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/152780"> LHB </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/152780"> 152780 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/80?start=-3&limit=10&highlight=80"> 20p12.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/244200"> Hypogonadotropic hypogonadism 3 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/244200"> 244200 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607123"> PROKR2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607123"> 607123 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/108?start=-3&limit=10&highlight=108"> 20p12.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615271"> Hypogonadotropic hypogonadism 21 with anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615271"> 615271 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604808"> FLRT3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604808"> 604808 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/X/43?start=-3&limit=10&highlight=43"> Xp22.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/308700"> Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/308700"> 308700 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300836"> ANOS1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300836"> 300836 </a>
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<p>A number sign (#) is used with this entry because hypogonadotropic hypogonadism-3 with or without anosmia (HH3) is caused by heterozygous mutation in the G protein-coupled prokineticin receptor-2 gene (PROKR2; <a href="/entry/607123">607123</a>) on chromosome 20p12, sometimes in association with mutation in another gene, e.g., KAL1 (<a href="/entry/300836">300836</a>).</p>
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<p>Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; <a href="/entry/152760">152760</a>) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by <a href="#4" class="mim-tip-reference" title="Raivio, T., Falardeau, J., Dwyer, A., Quinton, R., Hayes, F. J., Hughes, V. A., Cole, L. W., Pearce, S. H., Lee, H., Boepple, P., Crowley, W. F., Jr., Pitteloud, N. &lt;strong&gt;Reversal of idiopathic hypogonadotropic hypogonadism.&lt;/strong&gt; New Eng. J. Med. 357: 863-873, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17761590/&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;17761590&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa066494&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="17761590">Raivio et al., 2007</a>). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17761590" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of autosomal hypogonadotropic hypogonadism with or without anosmia, see <a href="/entry/147950">147950</a>.</p>
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<p><a href="#2" class="mim-tip-reference" title="Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. &lt;strong&gt;Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.&lt;/strong&gt; J. Clin. Endocr. Metab. 93: 3551-3559, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18559922/&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;18559922&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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/10.1210/jc.2007-2654&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="18559922">Cole et al. (2008)</a> confirmed autosomal dominant inheritance of HH3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18559922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a study of 192 patients with Kallmann syndrome, <a href="#3" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. &lt;strong&gt;Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.&lt;/strong&gt; PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17054399/&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;17054399&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1371/journal.pgen.0020175&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="17054399">Dode et al. (2006)</a> identified 10 and 4 different point mutations in the PROKR2 gene (e.g., <a href="/entry/607123#0001">607123.0001</a>-<a href="/entry/607123#0005">607123.0005</a>) and in one of its ligands, prokineticin-2 (PROK2; <a href="/entry/607002">607002</a>), respectively. One of the patients was heterozygous for a PROKR2 mutation (<a href="/entry/607123#0001">607123.0001</a>) and a missense mutation in KAL1 (<a href="/entry/300836#0012">300836.0012</a>), indicating possible digenic inheritance of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" 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 cohort of 324 IHH patients, 170 of whom were anosmic and 154 normosmic, <a href="#2" class="mim-tip-reference" title="Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. &lt;strong&gt;Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.&lt;/strong&gt; J. Clin. Endocr. Metab. 93: 3551-3559, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18559922/&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;18559922&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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/10.1210/jc.2007-2654&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="18559922">Cole et al. (2008)</a> analyzed the PROKR2 and PROK2 genes and identified 10 and 5 different point mutations, respectively. All 10 mutations in PROKR2 were heterozygous (see, e.g., <a href="/entry/607123#0001">607123.0001</a> and <a href="/entry/607123#0006">607123.0006</a>-<a href="/entry/607123#0009">607123.0009</a>); 1 of the probands (see <a href="/entry/607123#0007">607123.0007</a>) also carried a heterozygous mutation in PROK2 (<a href="/entry/607002#0005">607002.0005</a>). Of the 11 probands with a mutation in PROKR2, 7 had Kallmann syndrome and 4 had normosmic IHH. Two of the probands underwent partial puberty, 1 of whom experienced reversal of his hypogonadism later in life after discontinuation of sex steroid therapy (see <a href="/entry/607123#0009">607123.0009</a>). The mutation-positive probands were screened for mutations in other HH-associated genes, including KAL1 (<a href="/entry/300836">300836</a>), FGFR1 (<a href="/entry/136350">136350</a>), KISS1R (<a href="/entry/604161">604161</a>), NELF (<a href="/entry/608137">608137</a>), and GNRHR (<a href="/entry/138850">138850</a>), but no additional mutations were detected. All mutant alleles appeared to decrease intracellular calcium mobilization; some also exhibited decreased MAPK signaling and decreased receptor expression. <a href="#2" class="mim-tip-reference" title="Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. &lt;strong&gt;Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.&lt;/strong&gt; J. Clin. Endocr. Metab. 93: 3551-3559, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18559922/&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;18559922&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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/10.1210/jc.2007-2654&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="18559922">Cole et al. (2008)</a> concluded that loss-of-function mutations in PROKR2 can cause both Kallmann syndrome and normosmic IHH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18559922" 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>Possible Association with Functional Hypothalamic Amenorrhea in Carrier Females</em></strong></p><p>
<a href="#1" class="mim-tip-reference" title="Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., Seminara, S. B., Boepple, P. A., Sidis, Y., Crowley, W. F., Jr., Martin, K. A., Hall, J. E., Pitteloud, N. &lt;strong&gt;A genetic basis for functional hypothalamic amenorrhea.&lt;/strong&gt; New Eng. J. Med. 364: 215-225, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21247312/&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;21247312&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21247312[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/10.1056/NEJMoa0911064&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="21247312">Caronia et al. (2011)</a> studied 55 women with functional hypothalamic amenorrhea, who had all completed puberty spontaneously and had a history of secondary amenorrhea for 6 months or more, with low or normal gonadotropin levels and low serum estradiol levels. All had 1 or more predisposing factors, including excessive exercise, loss of more than 15% of body weight, and/or a subclinical eating disorder, and all had normal results on neuroimaging. The authors screened 7 HH-associated genes in the 55 affected women and identified 7 patients from 6 families who carried heterozygous mutations, including 1 in KAL1, 2 in FGFR1, 2 in PROKR2, and 1 in the GNRHR gene. Since these women with mutations resumed regular menses after discontinuing hormone-replacement therapy, <a href="#1" class="mim-tip-reference" title="Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., Seminara, S. B., Boepple, P. A., Sidis, Y., Crowley, W. F., Jr., Martin, K. A., Hall, J. E., Pitteloud, N. &lt;strong&gt;A genetic basis for functional hypothalamic amenorrhea.&lt;/strong&gt; New Eng. J. Med. 364: 215-225, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21247312/&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;21247312&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21247312[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/10.1056/NEJMoa0911064&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="21247312">Caronia et al. (2011)</a> concluded that the genetic component of hypothalamic amenorrhea predisposes patients to, but is not sufficient to cause, GnRH deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21247312" 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="#3" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. &lt;strong&gt;Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.&lt;/strong&gt; PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17054399/&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;17054399&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1371/journal.pgen.0020175&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="17054399">Dode et al. (2006)</a> noted that Kallmann syndrome patients with mutations in PROKR2 or PROK2 had variable degrees of olfactory and reproductive dysfunction and did not seem to have any of the occasional clinical anomalies that had been reported in previously characterized genetic forms of the disease, i.e., bimanual synkinesis, renal agenesis, dental agenesis, and cleft lip or palate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" 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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Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., Seminara, S. B., Boepple, P. A., Sidis, Y., Crowley, W. F., Jr., Martin, K. A., Hall, J. E., Pitteloud, N.
<strong>A genetic basis for functional hypothalamic amenorrhea.</strong>
New Eng. J. Med. 364: 215-225, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21247312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21247312</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21247312[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=21247312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa0911064" target="_blank">Full Text</a>]
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Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N.
<strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong>
J. Clin. Endocr. Metab. 93: 3551-3559, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18559922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18559922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18559922[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=18559922" 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.2007-2654" target="_blank">Full Text</a>]
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<a id="Dode2006" class="mim-anchor"></a>
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Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P.
<strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong>
PLoS Genet. 2: e175, 2006. Note: Electronic Article.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank">Full Text</a>]
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Raivio, T., Falardeau, J., Dwyer, A., Quinton, R., Hayes, F. J., Hughes, V. A., Cole, L. W., Pearce, S. H., Lee, H., Boepple, P., Crowley, W. F., Jr., Pitteloud, N.
<strong>Reversal of idiopathic hypogonadotropic hypogonadism.</strong>
New Eng. J. Med. 357: 863-873, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761590</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17761590" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa066494" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 04/06/2017
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Marla J. F. O'Neill - updated : 02/09/2016<br>Marla J. F. O'Neill - updated : 10/23/2014<br>Marla J. F. O'Neill - updated : 9/27/2012<br>Victor A. McKusick - updated : 11/21/2006
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Victor A. McKusick : 6/3/1986
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carol : 07/18/2024
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<h3>
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<strong>#</strong> 244200
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<h3>
<span class="mim-font">
HYPOGONADOTROPIC HYPOGONADISM 3 WITH OR WITHOUT ANOSMIA; HH3
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<span class="mim-text-font">
<strong>ORPHA:</strong> 432, 478; &nbsp;
<strong>DO:</strong> 0090092; &nbsp;
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<h4>
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
20p12.3
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Hypogonadotropic hypogonadism 3 with or without anosmia
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244200
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Autosomal dominant
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3
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PROKR2
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607123
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because hypogonadotropic hypogonadism-3 with or without anosmia (HH3) is caused by heterozygous mutation in the G protein-coupled prokineticin receptor-2 gene (PROKR2; 607123) on chromosome 20p12, sometimes in association with mutation in another gene, e.g., KAL1 (300836).</p>
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<strong>Description</strong>
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<p>Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' </p><p>For a discussion of genetic heterogeneity of autosomal hypogonadotropic hypogonadism with or without anosmia, see 147950.</p>
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<strong>Inheritance</strong>
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<p>Cole et al. (2008) confirmed autosomal dominant inheritance of HH3. </p>
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<strong>Molecular Genetics</strong>
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<p>In a study of 192 patients with Kallmann syndrome, Dode et al. (2006) identified 10 and 4 different point mutations in the PROKR2 gene (e.g., 607123.0001-607123.0005) and in one of its ligands, prokineticin-2 (PROK2; 607002), respectively. One of the patients was heterozygous for a PROKR2 mutation (607123.0001) and a missense mutation in KAL1 (300836.0012), indicating possible digenic inheritance of the disorder. </p><p>In a cohort of 324 IHH patients, 170 of whom were anosmic and 154 normosmic, Cole et al. (2008) analyzed the PROKR2 and PROK2 genes and identified 10 and 5 different point mutations, respectively. All 10 mutations in PROKR2 were heterozygous (see, e.g., 607123.0001 and 607123.0006-607123.0009); 1 of the probands (see 607123.0007) also carried a heterozygous mutation in PROK2 (607002.0005). Of the 11 probands with a mutation in PROKR2, 7 had Kallmann syndrome and 4 had normosmic IHH. Two of the probands underwent partial puberty, 1 of whom experienced reversal of his hypogonadism later in life after discontinuation of sex steroid therapy (see 607123.0009). The mutation-positive probands were screened for mutations in other HH-associated genes, including KAL1 (300836), FGFR1 (136350), KISS1R (604161), NELF (608137), and GNRHR (138850), but no additional mutations were detected. All mutant alleles appeared to decrease intracellular calcium mobilization; some also exhibited decreased MAPK signaling and decreased receptor expression. Cole et al. (2008) concluded that loss-of-function mutations in PROKR2 can cause both Kallmann syndrome and normosmic IHH. </p><p><strong><em>Possible Association with Functional Hypothalamic Amenorrhea in Carrier Females</em></strong></p><p>
Caronia et al. (2011) studied 55 women with functional hypothalamic amenorrhea, who had all completed puberty spontaneously and had a history of secondary amenorrhea for 6 months or more, with low or normal gonadotropin levels and low serum estradiol levels. All had 1 or more predisposing factors, including excessive exercise, loss of more than 15% of body weight, and/or a subclinical eating disorder, and all had normal results on neuroimaging. The authors screened 7 HH-associated genes in the 55 affected women and identified 7 patients from 6 families who carried heterozygous mutations, including 1 in KAL1, 2 in FGFR1, 2 in PROKR2, and 1 in the GNRHR gene. Since these women with mutations resumed regular menses after discontinuing hormone-replacement therapy, Caronia et al. (2011) concluded that the genetic component of hypothalamic amenorrhea predisposes patients to, but is not sufficient to cause, GnRH deficiency. </p>
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<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
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</h4>
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<p>Dode et al. (2006) noted that Kallmann syndrome patients with mutations in PROKR2 or PROK2 had variable degrees of olfactory and reproductive dysfunction and did not seem to have any of the occasional clinical anomalies that had been reported in previously characterized genetic forms of the disease, i.e., bimanual synkinesis, renal agenesis, dental agenesis, and cleft lip or palate. </p>
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<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., Seminara, S. B., Boepple, P. A., Sidis, Y., Crowley, W. F., Jr., Martin, K. A., Hall, J. E., Pitteloud, N.
<strong>A genetic basis for functional hypothalamic amenorrhea.</strong>
New Eng. J. Med. 364: 215-225, 2011.
[PubMed: 21247312]
[Full Text: https://doi.org/10.1056/NEJMoa0911064]
</p>
</li>
<li>
<p class="mim-text-font">
Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N.
<strong>Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum.</strong>
J. Clin. Endocr. Metab. 93: 3551-3559, 2008.
[PubMed: 18559922]
[Full Text: https://doi.org/10.1210/jc.2007-2654]
</p>
</li>
<li>
<p class="mim-text-font">
Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P.
<strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong>
PLoS Genet. 2: e175, 2006. Note: Electronic Article.
[PubMed: 17054399]
[Full Text: https://doi.org/10.1371/journal.pgen.0020175]
</p>
</li>
<li>
<p class="mim-text-font">
Raivio, T., Falardeau, J., Dwyer, A., Quinton, R., Hayes, F. J., Hughes, V. A., Cole, L. W., Pearce, S. H., Lee, H., Boepple, P., Crowley, W. F., Jr., Pitteloud, N.
<strong>Reversal of idiopathic hypogonadotropic hypogonadism.</strong>
New Eng. J. Med. 357: 863-873, 2007.
[PubMed: 17761590]
[Full Text: https://doi.org/10.1056/NEJMoa066494]
</p>
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Marla J. F. O&#x27;Neill - updated : 04/06/2017<br>Marla J. F. O&#x27;Neill - updated : 02/09/2016<br>Marla J. F. O&#x27;Neill - updated : 10/23/2014<br>Marla J. F. O&#x27;Neill - updated : 9/27/2012<br>Victor A. McKusick - updated : 11/21/2006
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Victor A. McKusick : 6/3/1986
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carol : 07/18/2024<br>carol : 04/18/2017<br>carol : 04/06/2017<br>carol : 02/09/2016<br>carol : 10/24/2014<br>mcolton : 10/23/2014<br>carol : 9/27/2012<br>carol : 9/27/2012<br>alopez : 3/10/2011<br>carol : 12/5/2006<br>terry : 11/21/2006<br>mgross : 3/17/2004<br>mark : 1/19/1996<br>mimadm : 4/17/1994<br>warfield : 3/9/1994<br>carol : 1/26/1994<br>carol : 7/23/1993<br>carol : 4/1/1992<br>supermim : 3/16/1992
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