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Entry
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- #147950 - HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA; HH2
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- OMIM
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<span class="h4">#147950</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/147950"><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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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#history">History</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=HYPOGONADOTROPIC HYPOGONADISM 2 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><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=8668&Typ=Pat" title="Normosmic congenital hypogonadotropic hypogonadism" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Normosmic congenital hypog… </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 </a></div>
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</div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1334/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/3947" 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=147950[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=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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</div>
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0090083" 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/147950" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0090083" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:147950" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<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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<a id="title" class="mim-anchor"></a>
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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> 432, 478<br />
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<strong>DO:</strong> 0090083<br />
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">ICD+</a>
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</div>
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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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147950
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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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HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA; HH2
|
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</span>
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</h3>
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</div>
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<div>
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<br />
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<p>
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|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
KALLMANN SYNDROME 2; KAL2
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="phenotypeMap" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/8/211?start=-3&limit=10&highlight=211">
|
|
8p11.23
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hypogonadotropic hypogonadism 2 with or without anosmia
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/147950"> 147950 </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">
|
|
FGFR1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/136350"> 136350 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/147950" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<a href="/phenotypicSeries/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>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<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/147950" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/147950" 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, unilateral (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0521785&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0521785</a>]</span> <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">[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> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Iris coloboma (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/51485001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">51485001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q13.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q13.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240063&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240063</a>, <a href="https://bioportal.bioontology.org/search?q=C0266551&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0266551</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000612" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000612</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000612" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000612</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 /> -
|
|
Absence of nasal cartilage, unilateral (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4011634&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4011634</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Mouth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Cleft lip <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/80281008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">80281008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q36" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q36</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q36.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q36.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/749.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">749.1</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/749.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">749.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0008924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008924</a>, <a href="https://bioportal.bioontology.org/search?q=C4321245&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4321245</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000204" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000204</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0410030" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0410030</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0410030" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0410030</a>]</span><br /> -
|
|
Cleft palate <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/63567004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">63567004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/87979003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">87979003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q35.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q35.5</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q35" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q35</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q35.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q35.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/749.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">749.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/749.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">749.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837218&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837218</a>, <a href="https://bioportal.bioontology.org/search?q=C2981150&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2981150</a>, <a href="https://bioportal.bioontology.org/search?q=C2240378&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2240378</a>, <a href="https://bioportal.bioontology.org/search?q=C0008925&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008925</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000175" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000175</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000175" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000175</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Teeth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Tooth agenesis, variable in number (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4011635&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4011635</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009804" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009804</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;">
|
|
|
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<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 /> -
|
|
Gynecomastia (in untreated males) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4011629&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4011629</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/4754008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">4754008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N62" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N62</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000771" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000771</a>]</span><br />
|
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|
</span>
|
|
</div>
|
|
</div>
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|
|
</div>
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</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GENITOURINARY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
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|
|
<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>
|
|
<span class="mim-font">
|
|
|
|
- Osteopenia (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/312894000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">312894000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029453&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029453</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000938" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000938</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000938" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000938</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Hands </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Clinodactyly (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/17268007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">17268007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551485&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551485</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030084" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030084</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030084" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030084</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=6c6553591f42fb5585fec835d3e3bab3" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Clinodactyly-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=6c6553591f42fb5585fec835d3e3bab3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
|
|
Fusion of fourth and fifth metacarpal bones (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4011628&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4011628</a>]</span><br /> -
|
|
Ectrodactyly (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13624003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13624003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81208006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81208006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q71.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q71.6</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q71.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q71.60</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/755.58" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">755.58</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2931019&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2931019</a>, <a href="https://bioportal.bioontology.org/search?q=C0265554&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265554</a>, <a href="https://bioportal.bioontology.org/search?q=C2699510&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2699510</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001171" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001171</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0100257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100257</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=55c8d7d8f005af0ba3e1fd0632b2418a" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Foot,Split-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=55c8d7d8f005af0ba3e1fd0632b2418a" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><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">
|
|
|
|
- Ectrodactyly (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13624003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13624003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/81208006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">81208006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q71.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q71.6</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q71.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q71.60</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/755.58" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">755.58</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2931019&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2931019</a>, <a href="https://bioportal.bioontology.org/search?q=C0265554&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265554</a>, <a href="https://bioportal.bioontology.org/search?q=C2699510&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2699510</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001171" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001171</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0100257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100257</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=55c8d7d8f005af0ba3e1fd0632b2418a" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Foot,Split-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=55c8d7d8f005af0ba3e1fd0632b2418a" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
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|
|
</div>
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<div>
|
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<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">
|
|
|
|
- Mirror hand movements (bimanual synkinesis, in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/229247004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">229247004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0454455&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0454455</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001335" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001335</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001335" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001335</a>]</span><br /> -
|
|
Corpus callosum agenesis (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/5102002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">5102002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q04.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q04.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0175754&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0175754</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001274" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001274</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001274" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001274</a>]</span><br />
|
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|
|
</span>
|
|
</div>
|
|
</div>
|
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|
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|
|
</div>
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</div>
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|
|
<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 />
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|
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</span>
|
|
</div>
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</div>
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</div>
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<div>
|
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<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>
|
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|
|
</div>
|
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<div>
|
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<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 fibroblast growth factor receptor-1 gene (FGFR1, <a href="/entry/136350#0002">136350.0002</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
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|
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</div>
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|
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</div>
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|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
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|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
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|
|
|
|
|
|
|
|
|
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|
|
<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>
|
|
|
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</span>
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<a href="/entry/614839"> Hypogonadotropic hypogonadism 10 with or without anosmia </a>
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<a href="/entry/615269"> Hypogonadotropic hypogonadism 19 with or without anosmia </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<a href="/entry/619718"> Hypogonadotropic hypogonadism 26 with or without anosmia </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<a href="/entry/614837"> Hypogonadotropic hypogonadism 8 with or without anosmia </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<a href="/entry/228300"> Hypogonadotropic hypogonadism 23 with or without anosmia </a>
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<a href="/entry/152780"> 152780 </a>
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<a href="/entry/244200"> Hypogonadotropic hypogonadism 3 with or without anosmia </a>
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<a href="/entry/615271"> Hypogonadotropic hypogonadism 21 with anosmia </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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<a href="/entry/604808"> FLRT3 </a>
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<span class="mim-font">
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<a href="/entry/308700"> Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) </a>
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<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
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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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<a href="/entry/308700"> 308700 </a>
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<a href="/entry/300836"> ANOS1 </a>
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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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<p>A number sign (#) is used with this entry because hypogonadotropic hypogonadism-2 with or without anosmia (HH2) is caused by heterozygous mutation in the gene encoding fibroblast growth factor receptor-1 (FGFR1; <a href="/entry/136350">136350</a>) on chromosome 8p11, sometimes in association with mutation in other genes, e.g., FGF8 (<a href="/entry/600483">600483</a>) and GNRHR (<a href="/entry/138850">138850</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="#34" 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. <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://doi.org/10.1056/NEJMoa066494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" 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>Although HH was initially considered to be a monogenic disorder, the presence of marked locus heterogeneity, incomplete penetrance within pedigrees, and variable expressivity of pathogenic alleles, together with evidence for mutations in multiple genes in some affected individuals, resulted in a conceptual shift from monogenicity to an oligogenic framework in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for the neuroendocrine control of human reproduction (<a href="#44" class="mim-tip-reference" title="Sykiotis, G. P., Plummer, L., Hughes, V. A., Au, M., Durrani, S., Nayak-Young, S., Dwyer, A. A., Quinton, R., Hall, J. E., Gusella, J. F., Seminara, S. B., Crowley, W. F., Jr., Pitteloud, N. <strong>Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.</strong> Proc. Nat. Acad. Sci. 107: 15140-15144, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20696889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20696889</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20696889[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/10.1073/pnas.1009622107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20696889">Sykiotis et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20696889" 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 Hypogonadotropic Hypogonadism with or without Anosmia</em></strong></p><p>
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Other forms of autosomal hypogonadotropic hypogonadism with or without anosmia include HH3 (<a href="/entry/244200">244200</a>), caused by mutation in the PROKR2 gene (<a href="/entry/607123">607123</a>); HH4 (<a href="/entry/610628">610628</a>), caused by mutation in the PROK2 gene (<a href="/entry/607002">607002</a>); HH5 (<a href="/entry/612370">612370</a>), caused by mutation in the CHD7 gene (<a href="/entry/608892">608892</a>); HH6 (<a href="/entry/612702">612702</a>), caused by mutation in the FGF8 gene (<a href="/entry/600483">600483</a>); HH7 (<a href="/entry/146110">146110</a>), caused by mutation in the GNRHR gene (<a href="/entry/138850">138850</a>); HH8 (<a href="/entry/614837">614837</a>), caused by mutation in the KISS1R gene (<a href="/entry/604161">604161</a>); HH9 (<a href="/entry/614838">614838</a>), caused by mutation in the NELF gene (<a href="/entry/608137">608137</a>); HH10 (<a href="/entry/614839">614839</a>), caused by mutation in the TAC3 gene (<a href="/entry/162330">162330</a>); HH11 (<a href="/entry/614840">614840</a>), caused by mutation in the TACR3 gene (<a href="/entry/162332">162332</a>); HH12 (<a href="/entry/614841">614841</a>), caused by mutation in the GNRH1 gene (<a href="/entry/152760">152760</a>); HH13 (<a href="/entry/614842">614842</a>), caused by mutation in the KISS1 gene (<a href="/entry/603286">603286</a>); HH14 (<a href="/entry/614858">614858</a>), caused by mutation in the WDR11 gene (<a href="/entry/606417">606417</a>); HH15 (<a href="/entry/614880">614880</a>), caused by mutation in the HS6ST1 gene (<a href="/entry/604846">604846</a>); HH16 (<a href="/entry/614897">614897</a>), caused by mutation in the SEMA3A gene (<a href="/entry/603961">603961</a>); HH17 (<a href="/entry/615266">615266</a>), caused by mutation in the SPRY4 gene (<a href="/entry/607984">607984</a>); HH18 (<a href="/entry/615267">615267</a>), caused by mutation in the IL17RD gene (<a href="/entry/606807">606807</a>); HH19 (<a href="/entry/615269">615269</a>), caused by mutation in the DUSP6 gene (<a href="/entry/602748">602748</a>); HH20 (<a href="/entry/615270">615270</a>), caused by mutation in the FGF17 gene (<a href="/entry/603725">603725</a>); HH21 (<a href="/entry/615271">615271</a>), caused by mutation in the FLRT3 gene (<a href="/entry/604808">604808</a>); HH22 (<a href="/entry/616030">616030</a>), caused by mutation in the FEZF1 gene (<a href="/entry/613301">613301</a>); HH23 (<a href="/entry/228300">228300</a>), caused by mutation in the LHB gene (<a href="/entry/152780">152780</a>); HH24 (<a href="/entry/229070">229070</a>), caused by mutation in the FSHB gene (<a href="/entry/136530">136530</a>); HH25 (<a href="/entry/618841">618841</a>), caused by mutation in the NDNF gene (<a href="/entry/616506">616506</a>); and HH26 (<a href="/entry/619718">619718</a>), caused by mutation in the TCF12 gene.</p><p>There is also an X-linked form of the disorder (HH1; <a href="/entry/308700">308700</a>), caused by mutation in the KAL1 gene (<a href="/entry/300836">300836</a>).</p><p>There is evidence that mutation in 2 or more of these genes can work in combination (oligogenicity) to produce GnRH-deficient conditions (summary by <a href="#8" class="mim-tip-reference" title="Chan, Y.-M. <strong>A needle in a haystack: mutations in GNRH1 as a rare cause of isolated GnRH deficiency.</strong> Molec. Cell. Endocr. 346: 51-56, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21722705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21722705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21722705[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.mce.2011.06.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21722705">Chan, 2011</a>). <a href="#44" class="mim-tip-reference" title="Sykiotis, G. P., Plummer, L., Hughes, V. A., Au, M., Durrani, S., Nayak-Young, S., Dwyer, A. A., Quinton, R., Hall, J. E., Gusella, J. F., Seminara, S. B., Crowley, W. F., Jr., Pitteloud, N. <strong>Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.</strong> Proc. Nat. Acad. Sci. 107: 15140-15144, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20696889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20696889</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20696889[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/10.1073/pnas.1009622107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20696889">Sykiotis et al. (2010)</a>, for example, demonstrated that of patients with an identifiable coding sequence mutation in 1 of 8 genes responsible for isolated GnRH deficiency, 11% carried mutations in at least one other of these genes as well. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21722705+20696889" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Reviews</em></strong></p><p>
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<a href="#49" class="mim-tip-reference" title="Valdes-Socin, H., Rubio Almanza, M., Tome Fernandez-Ladreda, M., Debray, F. G., Bours, V., Beckers, A. <strong>Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes.</strong> Front. Endocr. 5: 109, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25071724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25071724</a>] [<a href="https://doi.org/10.3389/fendo.2014.00109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25071724">Valdes-Socin et al. (2014)</a> reviewed the reproductive, neurodevelopmental, and genetic aspects of hypogonadotropic hypogonadism in human pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25071724" 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="#55" class="mim-tip-reference" title="Young, J., Xu, C., Papadkis, G. E., Acierno, J. S., Maione, L., Hietamaki, J., Raivio, T., Pitteloud, N. <strong>Clinical management of congenital hypogonadotropic hypogonadism.</strong> Endocr. Rev. 40: 669-710, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30698671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30698671</a>] [<a href="https://doi.org/10.1210/er.2018-00116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30698671">Young et al. (2019)</a> reviewed the genetics, diagnosis, and clinical management of patients with congenital hypogonadotropic hypogonadism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30698671" 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 some cases of hypogonadotropic hypogonadism and anosmia, midline cranial anomalies (cleft lip, cleft palate and imperfect fusion) are present. In a large kindred with a high rate of consanguinity, <a href="#37" class="mim-tip-reference" title="Rosen, S. W. <strong>The syndrome of hypogonadism, anosmia and midline cranial anomalies. (Abstract)</strong> Proceedings of the 47th Meeting of the Endocrine Society, New York 1965."None>Rosen (1965)</a> found 5 cases of hypogonadism, 3 of anosmia, and 6 of midline cranial anomalies. Both males and females were affected; 2 persons had 2 defects and 2 others showed all 3.</p><p><a href="#45" class="mim-tip-reference" title="Tagatz, G., Fialkow, P. J., Smith, D. W., Spadoni, L. <strong>Hypogonadotropic hypogonadism associated with anosmia in the female.</strong> New Eng. J. Med. 283: 1326-1329, 1970.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5478454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5478454</a>] [<a href="https://doi.org/10.1056/NEJM197012102832407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5478454">Tagatz et al. (1970)</a> described 3 unrelated females with hypogonadotropic hypogonadism and anosmia. No relative was affected and the parents in each case were unrelated. Induction of ovulation with resulting normal term pregnancy was achieved in 2 of the patients with exogenous gonadotropins. <a href="#21" class="mim-tip-reference" title="Hintz, R. L., Menking, M., Sotos, J. F. <strong>Familial holoprosencephaly with endocrine dysgenesis.</strong> J. Pediat. 72: 81-87, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4294576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4294576</a>] [<a href="https://doi.org/10.1016/s0022-3476(68)80403-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4294576">Hintz et al. (1968)</a> may have described the same or a related disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4294576+5478454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Merriam, G. R., Beitins, I. Z., Bode, H. H. <strong>Father-to-son transmission of hypogonadism with anosmia.</strong> Am. J. Dis. Child. 131: 1216-1219, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/335879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">335879</a>] [<a href="https://doi.org/10.1001/archpedi.1977.02120240034007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="335879">Merriam et al. (1977)</a> reported the instructive case of a father with cryptorchidism, hypogonadism, and hyposmia who was rendered fertile by treatment with chorionic gonadotropin and had 3 children. One of the 3, a son, also had the triad mentioned. A brother and sister were apparently normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=335879" 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="#43" class="mim-tip-reference" title="Soules, M. R., Hammond, C. B. <strong>Female Kallmann's syndrome: evidence for a hypothalamic luteinizing hormone-releasing hormone deficiency.</strong> Fertil. Steril. 33: 82-85, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6985875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6985875</a>] [<a href="https://doi.org/10.1016/s0015-0282(16)44484-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6985875">Soules and Hammond (1980)</a> reported the fully studied case of a female. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6985875" 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 study of 23 patients, <a href="#26" class="mim-tip-reference" title="Lieblich, J. M., Rogol, A. D., White, B. J., Rosen, S. W. <strong>Syndrome of anosmia with hypogonadotropic hypogonadism (Kallmann syndrome): clinical and laboratory studies in 23 cases.</strong> Am. J. Med. 73: 506-519, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6812419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6812419</a>] [<a href="https://doi.org/10.1016/0002-9343(82)90329-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6812419">Lieblich et al. (1982)</a> found subtle abnormalities of hypothalamic-pituitary function, although hypogonadism was the only endocrine deficit evident clinically. Some relatives had only anosmia or had hypogonadotropic hypogonadism with normal sense of smell. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6812419" 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>Among 18 probands with anosmia and hypogonadotropic hypogonadism studied at the National Institutes of Health, <a href="#52" class="mim-tip-reference" title="White, B. J., Rogol, A. D., Brown, K. S., Lieblich, J. M., Rosen, S. W. <strong>The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review.</strong> Am. J. Med. Genet. 15: 417-435, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6881209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6881209</a>] [<a href="https://doi.org/10.1002/ajmg.1320150307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6881209">White et al. (1983)</a> found that 7 had affected relatives and 3 had consanguineous parents. Both sexes were equally affected and parents were phenotypically normal. Cleft lip and palate occurred in both eugonadal and hypogonadal persons with anosmia. Segregation analysis was consistent with autosomal recessive inheritance with variable expression. They suggested that association of unilateral renal agenesis, mental retardation, and hypotelorism (e.g., families reported by <a href="#48" class="mim-tip-reference" title="Turner, R. C., Bobrow, M., Bobrow, L. G., MacKinnon, P. C. B., Bonnar, J., Hockaday, T. D. R., Ellis, J. D. <strong>Cryptorchidism in a family with Kallmann's syndrome.</strong> Proc. Roy. Soc. Med. 67: 33-35, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4150739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4150739</a>]" pmid="4150739">Turner et al., 1974</a> and <a href="#51" class="mim-tip-reference" title="Wegenke, J. D., Uehling, D. T., Wear, J. B., Jr., Gordon, E. S., Bargman, J. G., Deacon, J. S. R., Herrmann, J. P. R., Opitz, J. M. <strong>Familial Kallmann syndrome with unilateral renal aplasia.</strong> Clin. Genet. 7: 368-381, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1080088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1080088</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1975.tb00344.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1080088">Wegenke et al., 1975</a>) may indicate a distinct X-linked or male-limited autosomal dominant form (see <a href="/entry/308700">308700</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1080088+4150739+6881209" 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="#15" class="mim-tip-reference" title="Evain-Brion, D., Gendrel, D., Bozzola, M., Chaussain, J. L., Job, J. C. <strong>Diagnosis of Kallmann's syndrome in early infancy.</strong> Acta Paediat. Scand. 71: 937-940, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6984277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6984277</a>] [<a href="https://doi.org/10.1111/j.1651-2227.1982.tb09552.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6984277">Evain-Brion et al. (1982)</a> suspected hypogonadotropic hypogonadism in 3 male newborns on the basis of a very small penis, cryptorchidism, and a family history of Kallmann syndrome in 1 and isolated anosmia in the other 2. The diagnosis was confirmed in early infancy by lack of the postnatal rise of LH and testosterone and a blunted response to LHRH and HCG stimulation. In 1 case the mother had anosmia, primary amenorrhea, low gonadotropin and lack of response to LHRH; she had been successfully treated with HMG and HCG to induce ovulation (<a href="#18" class="mim-tip-reference" title="Gorins, A., Elkaim, R., Paniel, B., Cohen, A., Belaisch, J. <strong>Grossesse obtenue par HMG + HCG dans deux cas de dysplasie olfacto-genitale feminine.</strong> Gynecologie 4: 339-342, 1977."None>Gorins et al., 1977</a>). In the second case, 'the father was hyposmic with normal gonadal function, and his grandmother had been anosmic.' In the third case, although the parents were normal, a maternal uncle had cryptorchidism with anosmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6984277" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Klein, V. R., Friedman, J. M., Brookshire, G. S., Brown, O. E., Edman, C. D. <strong>Kallmann syndrome associated with choanal atresia.</strong> Clin. Genet. 31: 224-227, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3594930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3594930</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1987.tb02800.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3594930">Klein et al. (1987)</a> described the association of Kallmann syndrome with choanal atresia. The Kallmann syndrome occurred in an aunt and niece; the niece also had choanal atresia as did her newborn child. The olfactory capacity and gonadal or hormonal status of the infant could not be determined at her age. <a href="#24" class="mim-tip-reference" title="Klein, V. R., Friedman, J. M., Brookshire, G. S., Brown, O. E., Edman, C. D. <strong>Kallmann syndrome associated with choanal atresia.</strong> Clin. Genet. 31: 224-227, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3594930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3594930</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1987.tb02800.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3594930">Klein et al. (1987)</a> suggested that this may be further evidence that Kallmann syndrome represents the least severe form of the holoprosencephaly-hypopituitarism complex, a group of developmental field defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3594930" 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>Kallmann syndrome associated with congenital heart disease may be a distinct entity. <a href="#10" class="mim-tip-reference" title="Cortez, A. B., Galindo, A., Arensman, F. W., Van Dop, C. <strong>Congenital heart disease associated with sporadic Kallmann syndrome.</strong> Am. J. Med. Genet. 46: 551-554, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8322819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8322819</a>] [<a href="https://doi.org/10.1002/ajmg.1320460518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8322819">Cortez et al. (1993)</a> described the case of a 17-year-old boy with Kallmann syndrome and a complex congenital heart malformation. He also had neurosensory hearing loss and mental retardation. They noted that 7 previously reported patients with Kallmann syndrome and cardiac abnormalities were short with heights more than 2 standard deviations below the mean for age, lacked a family history of Kallmann syndrome, and were mentally retarded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8322819" 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="#25" class="mim-tip-reference" title="Levy, C. M., Knudtzon, J. <strong>Kallmann syndrome in two sisters with other developmental anomalies also affecting their father.</strong> Clin. Genet. 43: 51-53, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8462198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8462198</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1993.tb04451.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8462198">Levy and Knudtzon (1993)</a> reported a family in which 2 sisters, aged 13 and 19 years, had hypogonadotropic hypogonadism and anosmia. In addition, they had bilateral vesicoureteral reflux and unilateral hearing loss. One of the girls had unilateral coloboma of the optic nerve. The father had no clinical signs of either hypogonadism or anosmia. However, he had unilateral hearing loss and duplication of the left ureter and died suddenly at the age of 40 from myocardial infarction and undiagnosed coarctation of the aorta. The mother was normal. <a href="#25" class="mim-tip-reference" title="Levy, C. M., Knudtzon, J. <strong>Kallmann syndrome in two sisters with other developmental anomalies also affecting their father.</strong> Clin. Genet. 43: 51-53, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8462198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8462198</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1993.tb04451.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8462198">Levy and Knudtzon (1993)</a> postulated dominant inheritance in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8462198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="The European Recombinant Human LH Study Group. <strong>Recombinant human luteinizing hormone (LH) to support recombinant human follicle-stimulating hormone (FSH)-induced follicular development in LH- and FSH-deficient anovulatory women: a dose-finding study.</strong> J. Clin. Endocr. Metab. 83: 1507-1514, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9589647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9589647</a>] [<a href="https://doi.org/10.1210/jcem.83.5.4770" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9589647">The European Recombinant Human LH Study Group (1998)</a> evaluated the efficacy of recombinant human luteinizing hormone (rhLH; see <a href="/entry/152780">152780</a>) for supporting human recombinant follicle-stimulating hormone (rhFSH)-induced follicular development in hypogonadotropic hypogonadal women (WHO group I anovulation). Thirty-eight patients were randomized to receive rhLH (0, 25, 75, or 225 IU per day) in addition to a fixed dose of rhFSH (150 IU per day). RhLH was found to promote dose-related increases in estradiol (E2) and androstenedione secretion by rhFSH-induced follicles, increase ovarian sensitivity to FSH, and enhance the ability of these follicles to luteinize when exposed to human chorionic gonadotropin (CG; see <a href="/entry/118850">118850</a>). A daily dose of 75 IU rhLH was effective in the majority of women in promoting optimal follicular development and maximal endometrial growth. The authors concluded that a minority of patients may require up to 225 IU per day and that rhLH given subcutaneously at a dose up to 225 IU per day was not immunogenic and was well tolerated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9589647" 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="#54" class="mim-tip-reference" title="Young, J., Rey, R., Couzinet, B., Chanson, P., Josso, N., Schaison, G. <strong>Antimullerian hormone in patients with hypogonadotropic hypogonadism.</strong> J. Clin. Endocr. Metab. 84: 2696-2699, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10443662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10443662</a>] [<a href="https://doi.org/10.1210/jcem.84.8.5972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10443662">Young et al. (1999)</a> measured the serum anti-mullerian hormone (AMH; <a href="/entry/600957">600957</a>) levels in 20 normal men, aged 20 to 60 years, 12 patients with congenital hypogonadotropic hypogonadism (CHH), aged 19 to 30 years, and 18 patients with acquired hypogonadotropic hypogonadism (AHH), aged 19 to 65 years, either untreated or during testosterone (T) or human CG therapy. Mean serum AMH levels in normal adult men were low (20 +/- 4.9 pmol/L). In untreated CHH patients, mean serum AMH levels were significantly higher than in normal men (292 +/- 86 pmol/L; p less than 0.001) and were similar to those previously reported in prepubertal boys. In men with AHH, mean serum AMH levels were also significantly increased (107 +/- 50 pmol/L; p less than 0.01) when compared with healthy men, but were less than in men with CHH. In addition, in 10 patients treated for prostate cancer, a modest but significant increase of serum AMH (from 11.4 +/- 5.7 pmol/L to 49 +/- 9.9 pmol/L; p less than 0.01) was observed 12 months after suppression of the gonadal axis with the GNRH agonist Triptorelin (3.75 mg IM once a month). Plasma T and serum AMH levels were measured at baseline and at 3 and 6 months in 10 HH patients (6 CHH and 4 AHH) treated with human CG (1,500 IU/twice weekly for 6 months) and in 8 HH patients (4 CHH and 4 AHH) treated with T (T enanthate, 250 mg/3 weeks for 6 months). Human CG treatment induced an increase of plasma T (from 1.0 +/- 0.7 to 11 +/- 2.4 and 19 +/- 4.8 nmol/L, at 3 and 6 months, respectively) associated with a dramatic decrease of serum AMH (from 314 +/- 93 to 56 +/- 30 and 17 +/- 4.3 pmol/L). The similar increase in plasma T levels (from 1.4 +/- 1.0 to 15.6 +/- 4.2 and 23 +/- 6.2 ng/ml) obtained with exogenous T induced a lesser decrease of serum AMH (from 221 +/- 107 to 114 +/- 50 and 66 +/- 17 pmol/L). The authors concluded that (1) high plasma AMH levels in CHH patients are related to the absence of pubertal maturation of Sertoli cells; (2) high AMH levels in AHH and its increase after Triptorelin-induced gonadotropin deficiency suggested that the suppression of AMH is a reversible phenomenon; and (3) inhibition of AMH production by Sertoli cells is induced by intratesticular T. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10443662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To test the hypothesis that follicle-stimulating hormone (FSH; see <a href="/entry/136530">136530</a>) might be responsible for AMH upregulation in the absence of androgen inhibition, <a href="#53" class="mim-tip-reference" title="Young, J., Chanson, P., Salenave, S., Noel, M., Brailly, S., O'Flaherty, M., Schaison, G., Rey, R. <strong>Testicular anti-mullerian hormone secretion is stimulated by recombinant human FSH in patients with congenital hypogonadotropic hypogonadism.</strong> J. Clin. Endocr. Metab. 90: 724-728, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15536161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15536161</a>] [<a href="https://doi.org/10.1210/jc.2004-0542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15536161">Young et al. (2005)</a> administered recombinant human FSH to 8 male patients aged 18 to 31 years with untreated congenital hypogonadotropic hypogonadism. Although LH and T did not vary, AMH and inhibin B (see <a href="/entry/147290">147290</a>) levels gradually increased after 20 days of FSH administration. However, in contrast to FSH alone, combined FSH plus CG stimulation of the testis dramatically suppressed the secretion of AMH and induced a modest but significant reduction of circulating inhibin B levels. The authors concluded that FSH stimulates AMH production in the testis when it is at a prepubertal stage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15536161" 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="Gasztonyi, Z., Barsi, P., Czeizel, A. E. <strong>Kallmann syndrome in three unrelated women and an association with femur-fibula-ulna dysostosis in one case.</strong> Am. J. Med. Genet. 93: 176-180, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10925376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10925376</a>] [<a href="https://doi.org/10.1002/1096-8628(20000731)93:3<176::aid-ajmg2>3.0.co;2-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10925376">Gasztonyi et al. (2000)</a> described 3 unrelated women with hypogonadotropic hypogonadism and anosmia. Absence of olfactory bulbs and tracts and different degrees of asymmetric dysplasia of olfactory sulci were demonstrated by MRI. The father of 1 patient and the maternal aunt of another had anosmia, making autosomal dominant inheritance likely. The last patient had Kallmann syndrome and femur-fibula-ulna syndrome (<a href="/entry/228200">228200</a>) as a sporadic occurrence in her family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10925376" 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>Clinical Variability</em></strong></p><p>
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<a href="#11" class="mim-tip-reference" title="Dean, J. C. S., Johnston, A. W., Klopper, A. I. <strong>Isolated hypogonadotrophic hypogonadism: a family with autosomal dominant inheritance.</strong> Clin. Endocr. 32: 341-347, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2111748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2111748</a>] [<a href="https://doi.org/10.1111/j.1365-2265.1990.tb00875.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2111748">Dean et al. (1990)</a> suggested autosomal dominant inheritance with variable expression as the basis for aggregation of isolated hypogonadotropic hypogonadism in the family that they studied. A brother and sister had been most fully studied. Limited examination was performed on 2 aunts and the son of one of the aunts. The sister presented at age 17 with primary amenorrhea. She did not have anosmia. Ovulation was subsequently induced by pulsatile infusion of gonadotropin-releasing hormone (GNRH1; <a href="/entry/152760">152760</a>). The brother presented at age 21 with delayed puberty. He likewise denied anosmia. Both testes were small but were in the scrotum. One paternal aunt had primary amenorrhea and an adopted son, whereas another paternal aunt had menarche at age 23, following which she had 5 or 6 menstrual periods. Six years after her last period, she became pregnant and delivered an apparently normal male infant. In the subsequent 21 years she did not menstruate. The son had immature genitalia and an unbroken voice at age 16 but refused examinations. The father of the brother and sister had died from thromboembolism and was not available for study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2111748" 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="#31" class="mim-tip-reference" title="Pitteloud, N., Hayes, F. J., Boepple, P. A., DeCruz, S., Seminara, S. B., MacLaughlin, D. T., Crowley, W. F., Jr. <strong>The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotype heterogeneity of idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Endocr. Metab. 87: 152-160, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11788640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11788640</a>] [<a href="https://doi.org/10.1210/jcem.87.1.8131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11788640">Pitteloud et al. (2002)</a> examined historical, clinical, biochemical, histologic, and genetic features in 78 men with IHH to gain further insight into the phenotypic heterogeneity of the syndrome. They hypothesized that at least some of the spectrum of phenotypes could be explained by placing the disorder into a developmental and genetic context. Thirty-eight percent of the population had Kallmann syndrome, 54% had normosmic IHH, and 8% had acquired IHH after completion of puberty. Phenotypically, Kallmann syndrome represented the most severe subtype (87% with complete absence of any history or signs of spontaneous pubertal development), normosmic IHH displayed the most heterogeneity (41% with some evidence of spontaneous puberty), and acquired IHH after completion of puberty clustered at the mildest end (all had complete puberty). Classification based on historical or clinical evidence of prior pubertal development, rather than the presence or absence of sense of smell, served to distinguish the population more clearly with respect to other clinical and biochemical features. Mean gonadotropin levels and the finding of apulsatile LH secretion based on frequent sampling (80% vs 55%; p less than 0.05) were statistically different between patients lacking and those exhibiting partial pubertal development, but the overlap was extensive. The authors concluded that use of clinical parameters (presence or absence of some evidence of prior pubertal development, cryptorchidism (<a href="/entry/219050">219050</a>), and microphallus), biochemical markers of testicular growth and differentiation (inhibin B, mullerian inhibitory substance), and genetic evidence provides insight into the time of onset and the severity of GnRH deficiency. The authors further concluded viewing IHH in the full context of its developmental, genetic, and biochemical complexity permits greatest insight into its phenotypic variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11788640" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bhagavath, B., Podolsky, R. H., Ozata, M., Bolu, E., Bick, D. P., Kulharya, A., Sherins, R. J., Layman, L. C. <strong>Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism.</strong> Fertil. Steril. 85: 706-713, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16500342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16500342</a>] [<a href="https://doi.org/10.1016/j.fertnstert.2005.08.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16500342">Bhagavath et al. (2006)</a> studied 315 probands with HH, 185 of whom had previously been studied by <a href="#3" class="mim-tip-reference" title="Bhagavath, B., Ozata, M., Ozdemir, I. C., Bolu, E., Bick, D. P., Sherins, R. J., Layman, L. C. <strong>The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism.</strong> Fertil. Steril. 84: 951-957, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16213849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16213849</a>] [<a href="https://doi.org/10.1016/j.fertnstert.2005.04.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16213849">Bhagavath et al. (2005)</a>; the 315 probands included 258 males and 57 females, and 20 (6.3%) of the probands had 1 or more affected relatives. Of patients in whom information was available, 67 (31.5%) of 213 males and 12 (27.9%) of 43 females were anosmic, and 124 (62%) of 200 males and 16 (45.7%) of 35 females had complete HH. In the 20 HH families, 3 (15%) demonstrated vertical transmission, whereas 2 (5%) had only affected males inherited through presumptive carrier females, suggesting X-linked recessive inheritance. In 10 of the families, including both families that appeared to be X-linked recessive, affected individuals had anosmia (Kallmann syndrome). <a href="#4" class="mim-tip-reference" title="Bhagavath, B., Podolsky, R. H., Ozata, M., Bolu, E., Bick, D. P., Kulharya, A., Sherins, R. J., Layman, L. C. <strong>Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism.</strong> Fertil. Steril. 85: 706-713, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16500342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16500342</a>] [<a href="https://doi.org/10.1016/j.fertnstert.2005.08.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16500342">Bhagavath et al. (2006)</a> noted that in contrast to previous reports of cryptorchidism being more common in Kallmann syndrome than in normosmic HH, cryptorchidism was present in 5 to 6% of both normosmic and hyposmic/anosmic HH patients in their cohort; however, in keeping with previous findings (<a href="#31" class="mim-tip-reference" title="Pitteloud, N., Hayes, F. J., Boepple, P. A., DeCruz, S., Seminara, S. B., MacLaughlin, D. T., Crowley, W. F., Jr. <strong>The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotype heterogeneity of idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Endocr. Metab. 87: 152-160, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11788640/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11788640</a>] [<a href="https://doi.org/10.1210/jcem.87.1.8131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11788640">Pitteloud et al., 2002</a>), cryptorchidism was 4 times more common in cases of complete HH (16%) than in cases of incomplete HH (4%). Additional anomalies included visual abnormalities in 8 (2.5%) of 315 patients, neurologic abnormalities in 7 (2.2%), and renal agenesis in 1 (0.3%). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16213849+11788640+16500342" 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 review, <a href="#55" class="mim-tip-reference" title="Young, J., Xu, C., Papadkis, G. E., Acierno, J. S., Maione, L., Hietamaki, J., Raivio, T., Pitteloud, N. <strong>Clinical management of congenital hypogonadotropic hypogonadism.</strong> Endocr. Rev. 40: 669-710, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30698671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30698671</a>] [<a href="https://doi.org/10.1210/er.2018-00116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30698671">Young et al. (2019)</a> noted that, in many cases, infertility in patients with HH can be successfully treated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30698671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#22" class="mim-tip-reference" title="Hockaday, T. D. R. <strong>Hypogonadism and life-long anosmia.</strong> Postgrad. Med. J. 42: 572-574, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5919183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5919183</a>] [<a href="https://doi.org/10.1136/pgmj.42.491.572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5919183">Hockaday (1966)</a> described 2 cases. In the second case, the father was found to have 'complete anosmia on testing.' Thus, this may have been an autosomal dominant form of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5919183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>On the basis of cases in which the father of affected individuals showed anosmia, <a href="#40" class="mim-tip-reference" title="Santen, R. J., Paulsen, C. A. <strong>Hypogonadotropic eunuchoidism: I. Clinical study of the mode of inheritance.</strong> J. Clin. Endocr. 36: 47-54, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4404632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4404632</a>] [<a href="https://doi.org/10.1210/jcem-36-1-47" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4404632">Santen and Paulsen (1973)</a> concluded that autosomal dominant inheritance is most likely. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4404632" 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>Oligogenic Inheritance</em></strong></p><p>
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<a href="#47" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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/10.1073/pnas.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> studied a large French Canadian pedigree with several consanguineous loops, previously reported by <a href="#52" class="mim-tip-reference" title="White, B. J., Rogol, A. D., Brown, K. S., Lieblich, J. M., Rosen, S. W. <strong>The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review.</strong> Am. J. Med. Genet. 15: 417-435, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6881209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6881209</a>] [<a href="https://doi.org/10.1002/ajmg.1320150307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6881209">White et al. (1983)</a>, in which affected individuals variably presented with hypogonadotropic hypogonadism, anosmia, and cleft palate. In 4 affected family members, <a href="#47" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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/10.1073/pnas.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> identified homozygosity or heterozygosity for a missense mutation in the HS6ST1 gene (<a href="/entry/604846#0002">604846.0002</a>; see HH15, <a href="/entry/614880">614880</a>). Because of the phenotypic variability and reduced penetrance displayed in the family, the authors screened 8 additional known HH-associated genes and detected a missense mutation in FGFR1 that was also present in the 4 affected members as well as 1 unaffected individual (<a href="/entry/136350#0025">136350.0025</a>). In another family in which a man with anosmic HH and his unaffected brother both carried a missense mutation in HS6ST1 (<a href="/entry/604846#0001">604846.0001</a>), screening revealed an additional missense mutation in the NELF gene (<a href="/entry/608137#0001">608137.0001</a>; see HH9, <a href="/entry/614838">614838</a>) in the proband. <a href="#47" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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/10.1073/pnas.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> concluded that HH is an oligogenic disorder in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for neuroendocrine control of human reproduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21700882+6881209" 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 the large consanguineous 10-generation French Canadian family with anosmic HH and cleft palate, previously reported by <a href="#52" class="mim-tip-reference" title="White, B. J., Rogol, A. D., Brown, K. S., Lieblich, J. M., Rosen, S. W. <strong>The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review.</strong> Am. J. Med. Genet. 15: 417-435, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6881209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6881209</a>] [<a href="https://doi.org/10.1002/ajmg.1320150307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6881209">White et al. (1983)</a> and in which <a href="#47" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[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/10.1073/pnas.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> had identified mutations in both the FGFR1 (<a href="/entry/136350#0025">136350.0025</a>) and HS6ST1 (<a href="/entry/604846#0002">604846.0002</a>) genes, <a href="#28" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> identified additional mutations in 2 more genes in the FGF network, FGF17 (<a href="/entry/603725#0001">603725.0001</a>) and FLRT3 (<a href="/entry/604808#0001">604808.0001</a> and <a href="/entry/604808#0002">604808.0002</a>). In 4 more unrelated probands with anosmic HH, <a href="#28" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> identified heterozygosity for missense mutations in FGFR1 (e.g., <a href="/entry/136350#0026">136350.0026</a>) as well as heterozygosity for 4 other genes in the FGF network: IL17RD (<a href="/entry/606807#0002">606807.0002</a>), SPRY4 (<a href="/entry/607984#0002">607984.0002</a>), DUSP6 (<a href="/entry/602748#0002">602748.0002</a>), and FLRT3 (<a href="/entry/604808#0003">604808.0003</a>). <a href="#28" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of congenital hypogonadotropic hypogonadism (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23643382+21700882+6881209" 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 man with Kallmann syndrome, <a href="#1" class="mim-tip-reference" title="Bergstrom, R. W., Hansen, K. L., Clare, C. N., Katz, M. S. <strong>Hypogonadotropic hypogonadism and anosmia (Kallmann's syndrome) associated with a marker chromosome.</strong> J. Androl. 8: 55-60, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3104265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3104265</a>] [<a href="https://doi.org/10.1002/j.1939-4640.1987.tb02421.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3104265">Bergstrom et al. (1987)</a> found a consistent extra small marker chromosome, seemingly derived from chromosome group D or G, with satellites at each end. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3104265" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Best, L. G., Wasdahl, W. A., Larson, L. M., Sturlaugson, J. <strong>Chromosome abnormality in Kallmann syndrome.</strong> Am. J. Med. Genet. 35: 306-309, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2309777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2309777</a>] [<a href="https://doi.org/10.1002/ajmg.1320350303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2309777">Best et al. (1990)</a> described a balanced de novo translocation (7;12)(q22;q24) in an individual with Kallmann syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2309777" 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 male patient with hypogonadotropic hypogonadism and cleft lip and palate, <a href="#23" class="mim-tip-reference" title="Kim, H. G., Herrick, S. R., Lemyre, E., Kishikawa, S., Salisz, J. A., Seminara, S., MacDonald, M. E., Bruns, G. A. P., Morton, C. C., Quade, B. J., Gusella, J. F. <strong>Hypogonadotropic hypogonadism and cleft lip and palate caused by a balanced translocation producing haploinsufficiency for FGFR1. (Letter)</strong> J. Med. Genet. 42: 666-672, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16061567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16061567</a>] [<a href="https://doi.org/10.1136/jmg.2004.026989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16061567">Kim et al. (2005)</a> identified a balanced reciprocal translocation, t(7;8)(p12.3;p11.2). Positional cloning of the breakpoints revealed that the translocation disrupts the FGFR1 gene between exons 2 and 3 and predicts a novel fusion gene product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16061567" 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>Of 59 Kallmann syndrome patients analyzed by <a href="#29" class="mim-tip-reference" title="Oliveira, L. M. B., Seminara, S. B., Beranova, M., Hayes, F. J., Valkenburgh, S. B., Schipani, E., Costa, E. M. F., Latronico, A. C., Crowley, W. F., Jr., Vallejo, M. <strong>The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics.</strong> J. Clin. Endocr. Metab. 86: 1532-1538, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11297579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11297579</a>] [<a href="https://doi.org/10.1210/jcem.86.4.7420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11297579">Oliveira et al. (2001)</a>, 21 were familial and 38 were sporadic cases. Mutations in the coding sequence of KAL1 (<a href="/entry/300836">300836</a>) were identified in only 3 familial cases (14%) and 4 of the sporadic cases (11%). <a href="#29" class="mim-tip-reference" title="Oliveira, L. M. B., Seminara, S. B., Beranova, M., Hayes, F. J., Valkenburgh, S. B., Schipani, E., Costa, E. M. F., Latronico, A. C., Crowley, W. F., Jr., Vallejo, M. <strong>The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics.</strong> J. Clin. Endocr. Metab. 86: 1532-1538, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11297579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11297579</a>] [<a href="https://doi.org/10.1210/jcem.86.4.7420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11297579">Oliveira et al. (2001)</a> concluded that confirmed mutations in the coding sequence of the KAL1 gene occur in the minority of Kallmann syndrome cases, and that the majority of familial (and presumably sporadic) cases of Kallmann syndrome are caused by defects in at least 2 autosomal genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11297579" 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="#12" class="mim-tip-reference" title="Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others. <strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong> Nature Genet. 33: 463-465, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627230</a>] [<a href="https://doi.org/10.1038/ng1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627230">Dode et al. (2003)</a> took advantage of overlapping interstitial deletions at 8p12-p11 in 2 individuals who were affected by different contiguous gene syndromes that both included Kallmann syndrome. The gene encoding fibroblast growth factor receptor-1 (FGFR1; <a href="/entry/136350">136350</a>) was in the critical interval. By determining the nucleotide sequence of the 18 coding exons and splice sites of FGFR1 in 129 unrelated individuals with Kallmann syndrome (91 males and 38 females), they detected heterozygous mutations in 4 familial cases and 8 sporadic cases (see, e.g., <a href="/entry/136350#0002">136350.0002</a>-<a href="/entry/136350#0006">136350.0006</a>). In addition, they found that 1 individual, who was born to consanguineous parents and was affected by Kallmann syndrome with cleft palate, agenesis of the corpus callosum, unilateral hearing loss, and fusion of the fourth and fifth metacarpal bones, was homozygous with respect to a deleterious missense mutation (<a href="/entry/136350#0007">136350.0007</a>). Moreover, cleft palate or lip and selective tooth agenesis, 2 anomalies that are occasionally associated with Kallmann syndrome (<a href="#52" class="mim-tip-reference" title="White, B. J., Rogol, A. D., Brown, K. S., Lieblich, J. M., Rosen, S. W. <strong>The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review.</strong> Am. J. Med. Genet. 15: 417-435, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6881209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6881209</a>] [<a href="https://doi.org/10.1002/ajmg.1320150307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6881209">White et al., 1983</a>; <a href="#20" class="mim-tip-reference" title="Hardelin, J.-P. <strong>Kallmann syndrome: towards molecular pathogenesis.</strong> Molec. Cell. Endocr. 179: 75-81, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11420131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11420131</a>] [<a href="https://doi.org/10.1016/s0303-7207(01)00462-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11420131">Hardelin, 2001</a>) and were present in 5 individuals with mutations in FGFR1, can now be ascribed to this disease. In 1 family with an FGFR1 mutation, bimanual synkinesia was identified, indicating that it can occur in autosomal Kallmann syndrome, although it had previously been considered to be specific to the X-linked form of the disorder. The results of these studies suggested that olfactory bulb development in humans is crucially sensitive to reduced dosage of FGFR1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11420131+12627230+6881209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Sato, N., Katsumata, N., Kagami, M., Hasegawa, T., Hori, N., Kawakita, S., Minowada, S., Shimotsuka, A., Shishiba, Y., Yokozawa, M., Yasuda, T., Nagasaki, K., Hasegawa, D., Hasegawa, Y., Tachibana, K., Naiki, Y., Horikawa, R., Tanaka, T., Ogata, T. <strong>Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients.</strong> J. Clin. Endocr. Metab. 89: 1079-1088, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15001591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15001591</a>] [<a href="https://doi.org/10.1210/jc.2003-030476" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15001591">Sato et al. (2004)</a> studied 25 male and 3 female Japanese individuals, aged 10 to 53 years, with Kallmann syndrome. Ten males were from 5 families, and the remaining 15 males and 3 females were apparently sporadic cases. The authors found 2 novel intragenic FGFR1 mutations in 2 sporadic male cases. The 2 males with FGFR1 mutations had hypogonadotropic hypogonadism and anosmia and lacked other features. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in 1 female and cleft palate, cleft palate with perceptive deafness, and selective tooth agenesis with perceptive deafness in 1 male each, in addition to a variable extent of hypogonadotropic hypogonadism and olfactory dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15001591" 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="#30" class="mim-tip-reference" title="Pitteloud, N., Acierno, J. S., Jr., Meysing, A., Eliseenkova, A. V., Ma, J., Ibrahimi, O. A., Metzger, D. L., Hayes, F. J., Dwyer, A. A., Hughes, V. A., Yialamas, M., Hall, J. E., Grant, E., Mohammadi, M., Crowley, W. F., Jr. <strong>Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 103: 6281-6286, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16606836[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/10.1073/pnas.0600962103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606836">Pitteloud et al. (2006)</a> examined the FGFR1 gene in 7 unrelated patients with normosmic IHH and identified heterozygous mutations in 3 individuals. An 18-year-old female diagnosed with partial IHH and her brother, who had Kallmann syndrome, were found to have a heterozygous missense mutation in the FGFR1 gene (<a href="/entry/136350#0013">136350.0013</a>); their father, who was also heterozygous for the mutation, had congenital anosmia. In a 25-year-old Hispanic male with normosmic IHH and unilateral cryptorchidism who also had 2 congenitally missing teeth, <a href="#30" class="mim-tip-reference" title="Pitteloud, N., Acierno, J. S., Jr., Meysing, A., Eliseenkova, A. V., Ma, J., Ibrahimi, O. A., Metzger, D. L., Hayes, F. J., Dwyer, A. A., Hughes, V. A., Yialamas, M., Hall, J. E., Grant, E., Mohammadi, M., Crowley, W. F., Jr. <strong>Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 103: 6281-6286, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16606836[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/10.1073/pnas.0600962103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606836">Pitteloud et al. (2006)</a> identified complex heterozygosity for 2 mutations of the FGFR1 gene on the same allele (<a href="/entry/136350#0014">136350.0014</a>). The patient's mother, who was also heterozygous for the mutations, had congenital anosmia and normal puberty. In 2 brothers with normosmic IHH, 1 of whom also had cleft lip and palate and 3 missing teeth, <a href="#30" class="mim-tip-reference" title="Pitteloud, N., Acierno, J. S., Jr., Meysing, A., Eliseenkova, A. V., Ma, J., Ibrahimi, O. A., Metzger, D. L., Hayes, F. J., Dwyer, A. A., Hughes, V. A., Yialamas, M., Hall, J. E., Grant, E., Mohammadi, M., Crowley, W. F., Jr. <strong>Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 103: 6281-6286, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16606836[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/10.1073/pnas.0600962103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606836">Pitteloud et al. (2006)</a> identified heterozygosity for a nonsense mutation in the FGFR1 gene (<a href="/entry/136350#0015">136350.0015</a>). The sibs' father, who was also heterozygous for the mutation, reported having delayed puberty. Structural and biochemical analysis of the mutations revealed that all resulted in receptor loss of function. Noting the mixed pedigrees caused by mutation in FGFR1, <a href="#30" class="mim-tip-reference" title="Pitteloud, N., Acierno, J. S., Jr., Meysing, A., Eliseenkova, A. V., Ma, J., Ibrahimi, O. A., Metzger, D. L., Hayes, F. J., Dwyer, A. A., Hughes, V. A., Yialamas, M., Hall, J. E., Grant, E., Mohammadi, M., Crowley, W. F., Jr. <strong>Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 103: 6281-6286, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16606836[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/10.1073/pnas.0600962103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606836">Pitteloud et al. (2006)</a> suggested that Kallmann syndrome and normosmic IHH are part of the same spectrum of disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606836" 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 16-year-old female with cleft lip and palate who presented with anosmia, irregular menstrual periods, and agenesis of 2 teeth, <a href="#36" class="mim-tip-reference" title="Riley, B. M., Mansilla, M. A., Ma, J., Daack-Hirsch, S., Maher, B. S., Raffensperger, L. M., Russo, E. T., Vieira, A. R., Dode, C., Mohammadi, M., Marazita, M. L., Murray, J. C. <strong>Impaired FGF signaling contributes to cleft lip and palate.</strong> Proc. Nat. Acad. Sci. 104: 4512-4517, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360555</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360555[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/10.1073/pnas.0607956104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360555">Riley et al. (2007)</a> identified a nonsense mutation in the FGFR1 gene (<a href="/entry/136350#0018">136350.0018</a>). Her father, who also carried the mutation, had isolated cleft lip and palate and a normal sense of smell and was fertile. The mutation was not found in the unaffected mother or brother; a deceased paternal great aunt was also reported to have cleft lip. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17360555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Raivio, T., Sidis, Y., Plummer, L., Chen, H., Ma, J., Mukherjee, A., Jacobson-Dickman, E., Quinton, R., Van Vliet, G., Lavoie, H., Hughes, V. A., Dwyer, A., Hayes, F. J., Xu, S., Sparks, S., Kaiser, U. B., Mohammadi, M., Pitteloud, N. <strong>Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Endocr. Metab. 94: 4380-4390, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19820032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19820032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19820032[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/10.1210/jc.2009-0179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19820032">Raivio et al. (2009)</a> sequenced the FGFR1 gene in 134 patients with normosmic IHH and identified heterozygous loss-of-function mutations in 9 (7%). Screening of 5 more HH-associated genes in the 9 mutation-positive patients revealed additional mutations in 5 patients, including mutations in the GNRHR (<a href="/entry/138850">138850</a>), PROKR2 (<a href="/entry/607123">607123</a>), and FGF8 (<a href="/entry/600483">600483</a>) genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19820032" 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="#50" class="mim-tip-reference" title="Villanueva, C., Jacobson-Dickman, E., Xu, C., Manouvrier, S., Dwyer, A. A., Sykiotis, G. P., Beenken, A., Liu, Y., Tommiska, J., Hu, Y., Tiosano, D., Gerard, M., and 15 others. <strong>Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.</strong> Genet. Med. 17: 651-659, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394172[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/10.1038/gim.2014.166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394172">Villanueva et al. (2015)</a> studied 7 probands with mutations in the FGFR1 gene (see, e.g., <a href="/entry/136350#0026">136350.0026</a>) who exhibited HH as well as split hand/foot malformations (SHFM). In 6 families that were screened for mutation in 4 to 6 known HH-associated genes, the probands were heterozygous for FGFR1 mutations and exhibited SHFM limited to one or both feet. Other features exhibited by affected individuals included dental anomalies and cleft lip and/or palate. In 2 of these families, Incomplete penetrance was demonstrated by unaffected female carriers, and in 3 of the families, parental mutation status was not reported. In a consanguineous Turkish family, screened for mutation in 13 known HH-associated genes, the proband was homozygous for an FGFR1 missense mutation and had SHFM involving both hands and both feet as well as absent septum pellucidum and hypoplastic anterior corpus callosum on MRI. His unaffected parents and an anosmic sister were heterozygous for the mutation; in addition, 3 sibs with reportedly severe skeletal anomalies had died as neonates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25394172" 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>
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<a href="#6" 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. <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://doi.org/10.1056/NEJMoa0911064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21247312">Caronia et al. (2011)</a> studied 55 women with functional hypothalamic amenorrhea, all of whom 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="#6" 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. <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://doi.org/10.1056/NEJMoa0911064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" 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><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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From a cohort of 104 probands with KS or HH, <a href="#39" class="mim-tip-reference" title="Salian-Mehta, S., Xu, M., Knox, A. J., Plummer, L., Slavov, D., Taylor, M., Bevers, S., Hodges, R. S., Crowley, W. F., Jr., Wierman, M. E. <strong>Functional consequences of AXL sequence variants in hypogonadotropic hypogonadism.</strong> J. Clin. Endocr. Metab. 99: 1452-1460, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24476074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24476074</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24476074[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/10.1210/jc.2013-3426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24476074">Salian-Mehta et al. (2014)</a> identified 4 patients, 2 with KS and 2 with HH, who were negative for mutation in 14 known KS- or HH-associated genes but who had heterozygous mutations in the AXL gene (<a href="/entry/109135">109135</a>), including 3 missense mutations and 1 splice site mutation. Segregation was not reported in 3 of the families; in case 1, the mutation was also present in the proband's unaffected father. The 3 missense variants were found in public variant databases. In vitro functional analysis showed no abnormally spliced products or difference in splicing efficiency with the splicing mutation compared to wildtype AXL, and the missense mutations did not alter Gas6 (<a href="/entry/600441">600441</a>) ligand binding. However, in GT1-7 and GnRH neuronal cells expressing 2 of the missense mutations (S202C or Q361P), defective ligand-dependent receptor processing and aberrant neuronal migration were observed, and the Q361P mutant also showed defective ligand-independent chemotaxis. The authors suggested that the probands' phenotypes might result from concomitant mutations in other genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24476074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By whole-exome sequencing of 133 patients with hypogonadotropic hypogonadism with or without anosmia, <a href="#5" class="mim-tip-reference" title="Bouilly, J., Messina, A., Papadakis, G., Cassatella, D., Xu, C., Acierno, J. S., Tata, B., Sykiotis, G., Santini, S., Sidis, Y., Elowe-Gruau, E., Phan-Hug, F., and 10 others. <strong>DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development.</strong> Hum. Molec. Genet. 27: 359-372, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29202173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29202173</a>] [<a href="https://doi.org/10.1093/hmg/ddx408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29202173">Bouilly et al. (2018)</a> identified 7 patients from 6 families with heterozygous variants in the DCC gene (<a href="/entry/601614">601614</a>), occurring alone in 3 families, and in combination with heterozygous or homozygous variants in 1 or more HH-associated genes in 3 families. The designations for 2 of the families, as well as for 2 of the probands, were discrepant between Figure 4 and the case summaries. Familial segregation was not reported for 2 of the families. Unaffected carriers were present in 3 families, and in 1 family, the proband's mother, who did not carry a DCC mutation, had delayed puberty, whereas mutation status was unknown for the proband's unaffected father. Immunofluorescence analysis of immortalized GnRH neurons demonstrated that the identified DCC variants significantly impaired cytoskeletal and membrane rearrangement involved in cell protrusion formation, consistent with impairment of GnRH neuron migration. The authors suggested that the incomplete penetrance and variable expressivity observed both within and across families with HH might be explained by oligogenic inheritance or by the presence of mutations in unknown HH loci. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29202173" 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 discussion of a possible association between HH and mutation in the SEMA3G gene, see <a href="/entry/620997">620997</a>.</p>
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<p>In 2 sisters with primary amenorrhea and no breast development at 25 and 18 years of age, respectively, <a href="#42" class="mim-tip-reference" title="Seminara, S. B., Beranova, M., Oliveira, L. M. B., Martin, K. A., Crowley, W. F., Jr., Hall, J. E. <strong>Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations.</strong> J. Clin. Endocr. Metab. 85: 556-562, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10690855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10690855</a>] [<a href="https://doi.org/10.1210/jcem.85.2.6357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10690855">Seminara et al. (2000)</a> identified compound heterozygosity for mutations in the GNRHR gene: Q106R (<a href="/entry/138850#0001">138850.0001</a>) on one allele and R262Q (<a href="/entry/138850#0002">138850.0002</a>) on the other. The apparently unaffected parents were heterozygous for the mutations. The older sister conceived 3 times on pulsatile GnRH and twice on exogenous gonadotropin therapy, but suffered recurrent pregnancy loss; an embryo/trophoblast toxic factor was identified. The younger sister was treated with exogenous gonadotropins and gave birth to 3 children, with 1 singleton and 1 twin pregnancy. <a href="#32" class="mim-tip-reference" title="Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. <strong>Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Invest. 117: 457-463, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17235395[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/10.1172/JCI29884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235395">Pitteloud et al. (2007)</a> reexamined the family studied by <a href="#42" class="mim-tip-reference" title="Seminara, S. B., Beranova, M., Oliveira, L. M. B., Martin, K. A., Crowley, W. F., Jr., Hall, J. E. <strong>Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations.</strong> J. Clin. Endocr. Metab. 85: 556-562, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10690855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10690855</a>] [<a href="https://doi.org/10.1210/jcem.85.2.6357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10690855">Seminara et al. (2000)</a> and identified heterozygosity for an additional missense mutation in the FGFR1 gene (<a href="/entry/136350#0016">136350.0016</a>) in the 2 sisters and in their father, who had a history of delayed puberty. Mutation analysis of the children of the younger sister revealed that her unaffected daughter who had undergone normal puberty was heterozygous for the mutation in FGFR1 but had no mutations in the GNRHR gene; and her prepubertal 10-year-old twin sons, born without cryptorchidism or microphallus, were each heterozygous for 1 of the mutations in GNRHR but did not have any mutations in the FGFR1 gene. In another family in which the proband had severe Kallmann syndrome, his father had a history of delayed puberty and congenital anosmia, his mother had clinodactyly and Duane ocular retraction syndrome, his sister had midline defects with a bifid nose and high-arched palate, and his brother had clinodactyly alone, <a href="#32" class="mim-tip-reference" title="Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. <strong>Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Invest. 117: 457-463, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17235395[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/10.1172/JCI29884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235395">Pitteloud et al. (2007)</a> identified heterozygosity for a missense mutation in the FGFR1 gene (L342S; <a href="/entry/136350#0017">136350.0017</a>) in the proband, his father, and his sister. Heterozygosity for an additional mutation, an 8-bp deletion in the NELF gene (<a href="/entry/608137#0002">608137.0002</a>), was identified in the proband, his mother, and his brother. The mother and both sibs of the proband had normal puberty and a normal sense of smell by formal testing. <a href="#32" class="mim-tip-reference" title="Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. <strong>Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Invest. 117: 457-463, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17235395[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/10.1172/JCI29884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235395">Pitteloud et al. (2007)</a> concluded that mutations in 2 different genes can synergize to produce a more severe phenotype in families with hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10690855+17235395" 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="#38" class="mim-tip-reference" title="Salenave, S., Chanson, P., Bry, H., Pugeat, M., Cabrol, S., Carel, J. C., Murat, A., Lecomte, P., Brailly, S., Hardelin, J.-P., Dode, C., Young, J. <strong>Kallmann's syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations.</strong> J. Clin. Endocr. Metab. 93: 758-763, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18160472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18160472</a>] [<a href="https://doi.org/10.1210/jc.2007-1168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18160472">Salenave et al. (2008)</a> studied the endocrine features reflecting gonadotropic-testicular axis function in 39 men; 21 had mutations in KAL1 (<a href="/entry/300836">300836</a>) and 18 in FGFR1, but none had additional mutations in PROK2 (<a href="/entry/607002">607002</a>) or PROKR2 (<a href="/entry/607123">607123</a>) genes. Puberty failed to occur in the patients with KAL1 mutations, all of whom had complete congenital hypogonadotropic hypogonadism. The fathers of 3 unrelated men with KS, who also carried the respective FGFR1 mutations, had normal puberty, were eugonadal, and had normal testosterone and gonadotropin levels. Cryptorchidism was more frequent and testicular volume was smaller in HH subjects with KAL1 mutations than in subjects with FGFR1 mutations. The mean basal plasma FSH (see <a href="/entry/136530">136530</a>) level, serum inhibin B (see <a href="/entry/147290">147290</a>) level, basal LH (see <a href="/entry/152780">152780</a>) plasma level, and GnRH-stimulated LH plasma level were significantly lower in the subjects with KAL1 mutations. LH pulsatility was studied in 13 complete HH subjects with KAL1 mutations and 7 subjects with FGFR1 mutations; LH secretion was nonpulsatile in all the subjects, but mean LH levels were lower in those with KAL1 mutations. <a href="#38" class="mim-tip-reference" title="Salenave, S., Chanson, P., Bry, H., Pugeat, M., Cabrol, S., Carel, J. C., Murat, A., Lecomte, P., Brailly, S., Hardelin, J.-P., Dode, C., Young, J. <strong>Kallmann's syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations.</strong> J. Clin. Endocr. Metab. 93: 758-763, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18160472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18160472</a>] [<a href="https://doi.org/10.1210/jc.2007-1168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18160472">Salenave et al. (2008)</a> concluded that men with KS and documented KAL1 mutations have a more severe reproductive phenotype than men with FGFR1 mutations, which are associated with a broad spectrum of phenotypes, ranging from complete HH to normality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18160472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Sykiotis, G. P., Plummer, L., Hughes, V. A., Au, M., Durrani, S., Nayak-Young, S., Dwyer, A. A., Quinton, R., Hall, J. E., Gusella, J. F., Seminara, S. B., Crowley, W. F., Jr., Pitteloud, N. <strong>Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.</strong> Proc. Nat. Acad. Sci. 107: 15140-15144, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20696889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20696889</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20696889[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/10.1073/pnas.1009622107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20696889">Sykiotis et al. (2010)</a> analyzed 8 known HH-associated genes, including KAL1, FGFR1, PROKR2, PROK2, FGF8, GNRHR, KISS1R, and NELF, in 397 well-phenotyped HH patients, of whom 44 women and 155 men had anosmia/hyposmia, and 52 women and 146 men were normosmic. Compared to 179 controls tested, HH patients were significantly more likely to harbor rare protein-altering variants (22% vs 10%; p = 0.001). A single variant allele was identified in 68 (17%) of the patients, and oligogenicity was found as frequently as homozygosity or compound heterozygosity in this cohort: 10 (2.5%) of the patients had rare variants in both alleles of a single gene, and 10 (2.5%) had variants in 2 or more alleles of different genes. Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%; no oligogenicity was detected among the controls (p less than 0.05), even though deleterious alleles were present. In the 10 oligogenic pedigrees, 3 of which were new and 7 of which had previously been reported (<a href="#33" class="mim-tip-reference" title="Pitteloud, N., Zhang, C., Pignatelli, D., Li, J.-D., Raivio, T., Cole, L. W., Plummer, L., Jacobson-Dickman, E. E., Mellon, P. L., Zhou, Q.-Y., Crowley, W. F., Jr. <strong>Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 104: 17447-17452, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17959774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17959774</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17959774[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/10.1073/pnas.0707173104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17959774">Pitteloud et al., 2007</a>; <a href="#16" class="mim-tip-reference" title="Falardeau, J., Chung, W. C. J., Beenken, A., Raivio, T., Plummer, L., Sidis, Y., Jacobson-Dickman, E. E., Eliseenkova, A. V., Ma, J., Dwyer, A., Quinton, R., Na, S., and 9 others. <strong>Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice.</strong> J. Clin. Invest. 118: 2822-2831, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596921</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18596921[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/10.1172/JCI34538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596921">Falardeau et al., 2008</a>; <a href="#9" 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. <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://doi.org/10.1210/jc.2007-2654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18559922">Cole et al., 2008</a>; <a href="#35" class="mim-tip-reference" title="Raivio, T., Sidis, Y., Plummer, L., Chen, H., Ma, J., Mukherjee, A., Jacobson-Dickman, E., Quinton, R., Van Vliet, G., Lavoie, H., Hughes, V. A., Dwyer, A., Hayes, F. J., Xu, S., Sparks, S., Kaiser, U. B., Mohammadi, M., Pitteloud, N. <strong>Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Endocr. Metab. 94: 4380-4390, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19820032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19820032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19820032[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/10.1210/jc.2009-0179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19820032">Raivio et al., 2009</a>; <a href="#7" class="mim-tip-reference" title="Chan, Y.-M., de Guillebon, A., Lang-Muritano, M., Plummer, L., Cerrato, F., Tsiaras, S., Gaspert, A., Lavoie, H. B., Wu, C.-H., Crowley, W. F., Jr., Amory, J. K., Pitteloud, N., Seminara, S. B. <strong>GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 106: 11703-11708, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19567835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19567835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19567835[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/10.1073/pnas.0903449106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19567835">Chan et al., 2009</a>), the higher the number of affected genes and alleles that an individual harbored, the more likely he or she was to have HH as opposed to a milder or partial phenotype, such as delayed puberty, isolated anosmia, or isolated cleft lip/palate. <a href="#44" class="mim-tip-reference" title="Sykiotis, G. P., Plummer, L., Hughes, V. A., Au, M., Durrani, S., Nayak-Young, S., Dwyer, A. A., Quinton, R., Hall, J. E., Gusella, J. F., Seminara, S. B., Crowley, W. F., Jr., Pitteloud, N. <strong>Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.</strong> Proc. Nat. Acad. Sci. 107: 15140-15144, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20696889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20696889</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20696889[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/10.1073/pnas.1009622107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20696889">Sykiotis et al. (2010)</a> concluded that GnRH deficiency should be considered to be an oligogenic disorder, and noted that the fact that no rare protein-altering variants were found in the majority (78%) of patients indicated that the 8 genes sequenced accounted for only a fraction of the genetic etiology of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17959774+18596921+18559922+20696889+19567835+19820032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To assess oligogenicity in hypogonadotropic hypogonadism, <a href="#28" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> analyzed 350 HH probands of European descent for mutation in 17 HH-associated genes. Mutations were identified in 124 (35%) of the probands, and 24 (19%) of the mutation-positive probands carried at least 2 mutant alleles from different genes. <a href="#28" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> noted that 23 of the 24 oligogenic cases involved at least 1 gene associated with the fibroblast growth factor (FGF) network (see <a href="/entry/601513">601513</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23643382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="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://doi.org/10.1371/journal.pgen.0020175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17054399">Dode et al. (2006)</a> stated that loss-of-function mutations in the KAL1 (<a href="/entry/300836">300836</a>) and FGFR1 genes account for approximately 20% of all cases of Kallmann syndrome and that mutations in the PROKR2 and PROK2 genes account for an additional 10%. <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><a href="#19" class="mim-tip-reference" title="Gurbuz, F., Kotan, L. D., Mengen, E., Siklar, Z., Berberoglu, M., Dokmetas, S., Kilicli, M. F., Guven, A., Kirel, B., Saka, N., Poyrazoglu, S., Cesur, Y., and 9 others. <strong>Distribution of gene mutations associated with familial normosmic idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Res. Pediat. Endocr. 4: 121-126, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22766261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22766261</a>] [<a href="https://doi.org/10.4274/jcrpe.725" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22766261">Gurbuz et al. (2012)</a> reviewed all causative mutations detected in multiplex families with normosmic hypogonadotropic hypogonadism over a 7-year period in Turkey. Mutations that segregated with disease were identified in 17 (77.2%) of 22 families studied, including mutations of the GNRHR gene in 7 (31.8%) of the families, TACR3 in 6 (27.2%), KISSR in 2 (9%), TAC3 in 1 (4.5%), and KISS1 in 1 (4.5%). Inheritance was autosomal recessive in all 17 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22766261" 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 family with Kallmann syndrome inherited presumably as an autosomal recessive, <a href="#14" class="mim-tip-reference" title="Dornan, J., Barnard, J. M., Farid, N. R. <strong>Lack of close linkage of hypogonadotropic hypogonadism with HLA.</strong> Tissue Antigens 15: 510-511, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7444936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7444936</a>] [<a href="https://doi.org/10.1111/j.1399-0039.1980.tb00217.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7444936">Dornan et al. (1980)</a> excluded close linkage with HLA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7444936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1002/j.1939-4640.1987.tb02421.x" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2309777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2309777</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2309777" 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/10.1002/ajmg.1320350303" target="_blank">Full Text</a>]
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Bhagavath, B., Ozata, M., Ozdemir, I. C., Bolu, E., Bick, D. P., Sherins, R. J., Layman, L. C.
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<strong>The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism.</strong>
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Fertil. Steril. 84: 951-957, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16213849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16213849</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16213849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.fertnstert.2005.04.029" target="_blank">Full Text</a>]
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Bhagavath, B., Podolsky, R. H., Ozata, M., Bolu, E., Bick, D. P., Kulharya, A., Sherins, R. J., Layman, L. C.
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<strong>Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism.</strong>
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Fertil. Steril. 85: 706-713, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16500342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16500342</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16500342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bouilly, J., Messina, A., Papadakis, G., Cassatella, D., Xu, C., Acierno, J. S., Tata, B., Sykiotis, G., Santini, S., Sidis, Y., Elowe-Gruau, E., Phan-Hug, F., and 10 others.
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<strong>DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development.</strong>
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Hum. Molec. Genet. 27: 359-372, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29202173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29202173</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29202173" 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/10.1093/hmg/ddx408" target="_blank">Full Text</a>]
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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.
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<strong>A genetic basis for functional hypothalamic amenorrhea.</strong>
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[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>]
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[<a href="https://doi.org/10.1056/NEJMoa0911064" target="_blank">Full Text</a>]
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Chan, Y.-M., de Guillebon, A., Lang-Muritano, M., Plummer, L., Cerrato, F., Tsiaras, S., Gaspert, A., Lavoie, H. B., Wu, C.-H., Crowley, W. F., Jr., Amory, J. K., Pitteloud, N., Seminara, S. B.
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<strong>GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism.</strong>
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Proc. Nat. Acad. Sci. 106: 11703-11708, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19567835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19567835</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19567835[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=19567835" 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/10.1073/pnas.0903449106" target="_blank">Full Text</a>]
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Chan, Y.-M.
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<strong>A needle in a haystack: mutations in GNRH1 as a rare cause of isolated GnRH deficiency.</strong>
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Molec. Cell. Endocr. 346: 51-56, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21722705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21722705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21722705[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=21722705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1993.tb04451.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9343(82)90329-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archpedi.1977.02120240034007" target="_blank">Full Text</a>]
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<strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong>
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[<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.86.4.7420" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0600962103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.87.1.8131" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI29884" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2009-0179" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2007-1168" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320150307" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2004-0542" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/er.2018-00116" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 01/25/2022
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Marla J. F. O'Neill - updated : 01/27/2021<br>Marla J. F. O'Neill - updated : 04/07/2020<br>Marla J. F. O'Neill - updated : 04/01/2020<br>Marla J. F. O'Neill - updated : 04/06/2017<br>Marla J. F. O'Neill - updated : 09/10/2015<br>Marla J. F. O'Neill - updated : 3/31/2015<br>Marla J. F. O'Neill - updated : 3/26/2015<br>Marla J. F. O'Neill - updated : 10/23/2014<br>Marla J. F. O'Neill - updated : 10/15/2014<br>Marla J. F. O'Neill - updated : 6/5/2013<br>Marla J. F. O'Neill - updated : 10/23/2012<br>Marla J. F. O'Neill - updated : 10/17/2012<br>Marla J. F. O'Neill - updated : 10/11/2012<br>Marla J. F. O'Neill - updated : 9/25/2012<br>Marla J. F. O'Neill - updated : 3/23/2009<br>Marla J. F. O'Neill - updated : 10/31/2008<br>Marla J. F. O'Neill - updated : 4/30/2007<br>Marla J. F. O'Neill - updated : 3/13/2007<br>Marla J. F. O'Neill - updated : 6/2/2006<br>Marla J. F. O'Neill - updated : 9/13/2005<br>John A. Phillips, III - updated : 3/31/2005<br>Victor A. McKusick - updated : 3/19/2003<br>John A. Phillips, III - updated : 11/8/2001<br>Victor A. McKusick - updated : 8/7/2000
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Victor A. McKusick : 6/2/1986
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carol : 12/05/2024
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alopez : 12/04/2024<br>carol : 01/25/2022<br>alopez : 01/27/2021<br>carol : 04/07/2020<br>carol : 04/01/2020<br>carol : 04/06/2017<br>carol : 04/06/2017<br>carol : 02/28/2017<br>carol : 08/04/2016<br>alopez : 08/04/2016<br>carol : 09/10/2015<br>alopez : 4/1/2015<br>mcolton : 3/31/2015<br>carol : 3/27/2015<br>mcolton : 3/26/2015<br>carol : 10/24/2014<br>mcolton : 10/23/2014<br>carol : 10/15/2014<br>carol : 9/25/2014<br>mcolton : 9/24/2014<br>alopez : 6/5/2013<br>carol : 10/23/2012<br>terry : 10/22/2012<br>carol : 10/19/2012<br>carol : 10/17/2012<br>carol : 10/11/2012<br>carol : 10/11/2012<br>terry : 10/3/2012<br>carol : 9/27/2012<br>carol : 9/27/2012<br>carol : 9/25/2012<br>carol : 9/14/2012<br>carol : 8/1/2012<br>alopez : 3/10/2011<br>wwang : 3/30/2009<br>terry : 3/23/2009<br>wwang : 11/6/2008<br>terry : 10/31/2008<br>wwang : 4/30/2007<br>carol : 4/3/2007<br>carol : 3/13/2007<br>carol : 3/13/2007<br>carol : 12/6/2006<br>carol : 12/6/2006<br>carol : 12/5/2006<br>carol : 6/2/2006<br>terry : 6/2/2006<br>carol : 9/13/2005<br>terry : 9/13/2005<br>alopez : 3/31/2005<br>tkritzer : 5/7/2003<br>alopez : 4/1/2003<br>alopez : 3/20/2003<br>alopez : 3/20/2003<br>terry : 3/19/2003<br>alopez : 11/8/2001<br>carol : 8/7/2000<br>mark : 1/20/1996<br>mark : 1/19/1996<br>terry : 10/27/1995<br>mimadm : 11/5/1994<br>carol : 1/26/1994<br>carol : 10/20/1993<br>carol : 7/7/1993<br>supermim : 3/16/1992
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HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA; HH2
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KALLMANN SYNDROME 2; KAL2
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<strong>ORPHA:</strong> 432, 478;
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<strong>DO:</strong> 0090083;
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<strong>Phenotype-Gene Relationships</strong>
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8p11.23
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Hypogonadotropic hypogonadism 2 with or without anosmia
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147950
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Autosomal dominant
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136350
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<p>A number sign (#) is used with this entry because hypogonadotropic hypogonadism-2 with or without anosmia (HH2) is caused by heterozygous mutation in the gene encoding fibroblast growth factor receptor-1 (FGFR1; 136350) on chromosome 8p11, sometimes in association with mutation in other genes, e.g., FGF8 (600483) and GNRHR (138850).</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>Although HH was initially considered to be a monogenic disorder, the presence of marked locus heterogeneity, incomplete penetrance within pedigrees, and variable expressivity of pathogenic alleles, together with evidence for mutations in multiple genes in some affected individuals, resulted in a conceptual shift from monogenicity to an oligogenic framework in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for the neuroendocrine control of human reproduction (Sykiotis et al., 2010). </p><p><strong><em>Genetic Heterogeneity of Hypogonadotropic Hypogonadism with or without Anosmia</em></strong></p><p>
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Other forms of autosomal hypogonadotropic hypogonadism with or without anosmia include HH3 (244200), caused by mutation in the PROKR2 gene (607123); HH4 (610628), caused by mutation in the PROK2 gene (607002); HH5 (612370), caused by mutation in the CHD7 gene (608892); HH6 (612702), caused by mutation in the FGF8 gene (600483); HH7 (146110), caused by mutation in the GNRHR gene (138850); HH8 (614837), caused by mutation in the KISS1R gene (604161); HH9 (614838), caused by mutation in the NELF gene (608137); HH10 (614839), caused by mutation in the TAC3 gene (162330); HH11 (614840), caused by mutation in the TACR3 gene (162332); HH12 (614841), caused by mutation in the GNRH1 gene (152760); HH13 (614842), caused by mutation in the KISS1 gene (603286); HH14 (614858), caused by mutation in the WDR11 gene (606417); HH15 (614880), caused by mutation in the HS6ST1 gene (604846); HH16 (614897), caused by mutation in the SEMA3A gene (603961); HH17 (615266), caused by mutation in the SPRY4 gene (607984); HH18 (615267), caused by mutation in the IL17RD gene (606807); HH19 (615269), caused by mutation in the DUSP6 gene (602748); HH20 (615270), caused by mutation in the FGF17 gene (603725); HH21 (615271), caused by mutation in the FLRT3 gene (604808); HH22 (616030), caused by mutation in the FEZF1 gene (613301); HH23 (228300), caused by mutation in the LHB gene (152780); HH24 (229070), caused by mutation in the FSHB gene (136530); HH25 (618841), caused by mutation in the NDNF gene (616506); and HH26 (619718), caused by mutation in the TCF12 gene.</p><p>There is also an X-linked form of the disorder (HH1; 308700), caused by mutation in the KAL1 gene (300836).</p><p>There is evidence that mutation in 2 or more of these genes can work in combination (oligogenicity) to produce GnRH-deficient conditions (summary by Chan, 2011). Sykiotis et al. (2010), for example, demonstrated that of patients with an identifiable coding sequence mutation in 1 of 8 genes responsible for isolated GnRH deficiency, 11% carried mutations in at least one other of these genes as well. </p><p><strong><em>Reviews</em></strong></p><p>
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Valdes-Socin et al. (2014) reviewed the reproductive, neurodevelopmental, and genetic aspects of hypogonadotropic hypogonadism in human pathology. </p><p>Young et al. (2019) reviewed the genetics, diagnosis, and clinical management of patients with congenital hypogonadotropic hypogonadism. </p>
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<strong>Clinical Features</strong>
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<p>In some cases of hypogonadotropic hypogonadism and anosmia, midline cranial anomalies (cleft lip, cleft palate and imperfect fusion) are present. In a large kindred with a high rate of consanguinity, Rosen (1965) found 5 cases of hypogonadism, 3 of anosmia, and 6 of midline cranial anomalies. Both males and females were affected; 2 persons had 2 defects and 2 others showed all 3.</p><p>Tagatz et al. (1970) described 3 unrelated females with hypogonadotropic hypogonadism and anosmia. No relative was affected and the parents in each case were unrelated. Induction of ovulation with resulting normal term pregnancy was achieved in 2 of the patients with exogenous gonadotropins. Hintz et al. (1968) may have described the same or a related disorder. </p><p>Merriam et al. (1977) reported the instructive case of a father with cryptorchidism, hypogonadism, and hyposmia who was rendered fertile by treatment with chorionic gonadotropin and had 3 children. One of the 3, a son, also had the triad mentioned. A brother and sister were apparently normal. </p><p>Soules and Hammond (1980) reported the fully studied case of a female. </p><p>In a study of 23 patients, Lieblich et al. (1982) found subtle abnormalities of hypothalamic-pituitary function, although hypogonadism was the only endocrine deficit evident clinically. Some relatives had only anosmia or had hypogonadotropic hypogonadism with normal sense of smell. </p><p>Among 18 probands with anosmia and hypogonadotropic hypogonadism studied at the National Institutes of Health, White et al. (1983) found that 7 had affected relatives and 3 had consanguineous parents. Both sexes were equally affected and parents were phenotypically normal. Cleft lip and palate occurred in both eugonadal and hypogonadal persons with anosmia. Segregation analysis was consistent with autosomal recessive inheritance with variable expression. They suggested that association of unilateral renal agenesis, mental retardation, and hypotelorism (e.g., families reported by Turner et al., 1974 and Wegenke et al., 1975) may indicate a distinct X-linked or male-limited autosomal dominant form (see 308700). </p><p>Evain-Brion et al. (1982) suspected hypogonadotropic hypogonadism in 3 male newborns on the basis of a very small penis, cryptorchidism, and a family history of Kallmann syndrome in 1 and isolated anosmia in the other 2. The diagnosis was confirmed in early infancy by lack of the postnatal rise of LH and testosterone and a blunted response to LHRH and HCG stimulation. In 1 case the mother had anosmia, primary amenorrhea, low gonadotropin and lack of response to LHRH; she had been successfully treated with HMG and HCG to induce ovulation (Gorins et al., 1977). In the second case, 'the father was hyposmic with normal gonadal function, and his grandmother had been anosmic.' In the third case, although the parents were normal, a maternal uncle had cryptorchidism with anosmia. </p><p>Klein et al. (1987) described the association of Kallmann syndrome with choanal atresia. The Kallmann syndrome occurred in an aunt and niece; the niece also had choanal atresia as did her newborn child. The olfactory capacity and gonadal or hormonal status of the infant could not be determined at her age. Klein et al. (1987) suggested that this may be further evidence that Kallmann syndrome represents the least severe form of the holoprosencephaly-hypopituitarism complex, a group of developmental field defects. </p><p>Kallmann syndrome associated with congenital heart disease may be a distinct entity. Cortez et al. (1993) described the case of a 17-year-old boy with Kallmann syndrome and a complex congenital heart malformation. He also had neurosensory hearing loss and mental retardation. They noted that 7 previously reported patients with Kallmann syndrome and cardiac abnormalities were short with heights more than 2 standard deviations below the mean for age, lacked a family history of Kallmann syndrome, and were mentally retarded. </p><p>Levy and Knudtzon (1993) reported a family in which 2 sisters, aged 13 and 19 years, had hypogonadotropic hypogonadism and anosmia. In addition, they had bilateral vesicoureteral reflux and unilateral hearing loss. One of the girls had unilateral coloboma of the optic nerve. The father had no clinical signs of either hypogonadism or anosmia. However, he had unilateral hearing loss and duplication of the left ureter and died suddenly at the age of 40 from myocardial infarction and undiagnosed coarctation of the aorta. The mother was normal. Levy and Knudtzon (1993) postulated dominant inheritance in this family. </p><p>The European Recombinant Human LH Study Group (1998) evaluated the efficacy of recombinant human luteinizing hormone (rhLH; see 152780) for supporting human recombinant follicle-stimulating hormone (rhFSH)-induced follicular development in hypogonadotropic hypogonadal women (WHO group I anovulation). Thirty-eight patients were randomized to receive rhLH (0, 25, 75, or 225 IU per day) in addition to a fixed dose of rhFSH (150 IU per day). RhLH was found to promote dose-related increases in estradiol (E2) and androstenedione secretion by rhFSH-induced follicles, increase ovarian sensitivity to FSH, and enhance the ability of these follicles to luteinize when exposed to human chorionic gonadotropin (CG; see 118850). A daily dose of 75 IU rhLH was effective in the majority of women in promoting optimal follicular development and maximal endometrial growth. The authors concluded that a minority of patients may require up to 225 IU per day and that rhLH given subcutaneously at a dose up to 225 IU per day was not immunogenic and was well tolerated. </p><p>Young et al. (1999) measured the serum anti-mullerian hormone (AMH; 600957) levels in 20 normal men, aged 20 to 60 years, 12 patients with congenital hypogonadotropic hypogonadism (CHH), aged 19 to 30 years, and 18 patients with acquired hypogonadotropic hypogonadism (AHH), aged 19 to 65 years, either untreated or during testosterone (T) or human CG therapy. Mean serum AMH levels in normal adult men were low (20 +/- 4.9 pmol/L). In untreated CHH patients, mean serum AMH levels were significantly higher than in normal men (292 +/- 86 pmol/L; p less than 0.001) and were similar to those previously reported in prepubertal boys. In men with AHH, mean serum AMH levels were also significantly increased (107 +/- 50 pmol/L; p less than 0.01) when compared with healthy men, but were less than in men with CHH. In addition, in 10 patients treated for prostate cancer, a modest but significant increase of serum AMH (from 11.4 +/- 5.7 pmol/L to 49 +/- 9.9 pmol/L; p less than 0.01) was observed 12 months after suppression of the gonadal axis with the GNRH agonist Triptorelin (3.75 mg IM once a month). Plasma T and serum AMH levels were measured at baseline and at 3 and 6 months in 10 HH patients (6 CHH and 4 AHH) treated with human CG (1,500 IU/twice weekly for 6 months) and in 8 HH patients (4 CHH and 4 AHH) treated with T (T enanthate, 250 mg/3 weeks for 6 months). Human CG treatment induced an increase of plasma T (from 1.0 +/- 0.7 to 11 +/- 2.4 and 19 +/- 4.8 nmol/L, at 3 and 6 months, respectively) associated with a dramatic decrease of serum AMH (from 314 +/- 93 to 56 +/- 30 and 17 +/- 4.3 pmol/L). The similar increase in plasma T levels (from 1.4 +/- 1.0 to 15.6 +/- 4.2 and 23 +/- 6.2 ng/ml) obtained with exogenous T induced a lesser decrease of serum AMH (from 221 +/- 107 to 114 +/- 50 and 66 +/- 17 pmol/L). The authors concluded that (1) high plasma AMH levels in CHH patients are related to the absence of pubertal maturation of Sertoli cells; (2) high AMH levels in AHH and its increase after Triptorelin-induced gonadotropin deficiency suggested that the suppression of AMH is a reversible phenomenon; and (3) inhibition of AMH production by Sertoli cells is induced by intratesticular T. </p><p>To test the hypothesis that follicle-stimulating hormone (FSH; see 136530) might be responsible for AMH upregulation in the absence of androgen inhibition, Young et al. (2005) administered recombinant human FSH to 8 male patients aged 18 to 31 years with untreated congenital hypogonadotropic hypogonadism. Although LH and T did not vary, AMH and inhibin B (see 147290) levels gradually increased after 20 days of FSH administration. However, in contrast to FSH alone, combined FSH plus CG stimulation of the testis dramatically suppressed the secretion of AMH and induced a modest but significant reduction of circulating inhibin B levels. The authors concluded that FSH stimulates AMH production in the testis when it is at a prepubertal stage. </p><p>Gasztonyi et al. (2000) described 3 unrelated women with hypogonadotropic hypogonadism and anosmia. Absence of olfactory bulbs and tracts and different degrees of asymmetric dysplasia of olfactory sulci were demonstrated by MRI. The father of 1 patient and the maternal aunt of another had anosmia, making autosomal dominant inheritance likely. The last patient had Kallmann syndrome and femur-fibula-ulna syndrome (228200) as a sporadic occurrence in her family. </p><p><strong><em>Clinical Variability</em></strong></p><p>
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Dean et al. (1990) suggested autosomal dominant inheritance with variable expression as the basis for aggregation of isolated hypogonadotropic hypogonadism in the family that they studied. A brother and sister had been most fully studied. Limited examination was performed on 2 aunts and the son of one of the aunts. The sister presented at age 17 with primary amenorrhea. She did not have anosmia. Ovulation was subsequently induced by pulsatile infusion of gonadotropin-releasing hormone (GNRH1; 152760). The brother presented at age 21 with delayed puberty. He likewise denied anosmia. Both testes were small but were in the scrotum. One paternal aunt had primary amenorrhea and an adopted son, whereas another paternal aunt had menarche at age 23, following which she had 5 or 6 menstrual periods. Six years after her last period, she became pregnant and delivered an apparently normal male infant. In the subsequent 21 years she did not menstruate. The son had immature genitalia and an unbroken voice at age 16 but refused examinations. The father of the brother and sister had died from thromboembolism and was not available for study. </p><p>Pitteloud et al. (2002) examined historical, clinical, biochemical, histologic, and genetic features in 78 men with IHH to gain further insight into the phenotypic heterogeneity of the syndrome. They hypothesized that at least some of the spectrum of phenotypes could be explained by placing the disorder into a developmental and genetic context. Thirty-eight percent of the population had Kallmann syndrome, 54% had normosmic IHH, and 8% had acquired IHH after completion of puberty. Phenotypically, Kallmann syndrome represented the most severe subtype (87% with complete absence of any history or signs of spontaneous pubertal development), normosmic IHH displayed the most heterogeneity (41% with some evidence of spontaneous puberty), and acquired IHH after completion of puberty clustered at the mildest end (all had complete puberty). Classification based on historical or clinical evidence of prior pubertal development, rather than the presence or absence of sense of smell, served to distinguish the population more clearly with respect to other clinical and biochemical features. Mean gonadotropin levels and the finding of apulsatile LH secretion based on frequent sampling (80% vs 55%; p less than 0.05) were statistically different between patients lacking and those exhibiting partial pubertal development, but the overlap was extensive. The authors concluded that use of clinical parameters (presence or absence of some evidence of prior pubertal development, cryptorchidism (219050), and microphallus), biochemical markers of testicular growth and differentiation (inhibin B, mullerian inhibitory substance), and genetic evidence provides insight into the time of onset and the severity of GnRH deficiency. The authors further concluded viewing IHH in the full context of its developmental, genetic, and biochemical complexity permits greatest insight into its phenotypic variability. </p><p>Bhagavath et al. (2006) studied 315 probands with HH, 185 of whom had previously been studied by Bhagavath et al. (2005); the 315 probands included 258 males and 57 females, and 20 (6.3%) of the probands had 1 or more affected relatives. Of patients in whom information was available, 67 (31.5%) of 213 males and 12 (27.9%) of 43 females were anosmic, and 124 (62%) of 200 males and 16 (45.7%) of 35 females had complete HH. In the 20 HH families, 3 (15%) demonstrated vertical transmission, whereas 2 (5%) had only affected males inherited through presumptive carrier females, suggesting X-linked recessive inheritance. In 10 of the families, including both families that appeared to be X-linked recessive, affected individuals had anosmia (Kallmann syndrome). Bhagavath et al. (2006) noted that in contrast to previous reports of cryptorchidism being more common in Kallmann syndrome than in normosmic HH, cryptorchidism was present in 5 to 6% of both normosmic and hyposmic/anosmic HH patients in their cohort; however, in keeping with previous findings (Pitteloud et al., 2002), cryptorchidism was 4 times more common in cases of complete HH (16%) than in cases of incomplete HH (4%). Additional anomalies included visual abnormalities in 8 (2.5%) of 315 patients, neurologic abnormalities in 7 (2.2%), and renal agenesis in 1 (0.3%). </p>
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<h4>
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<strong>Clinical Management</strong>
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</h4>
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<p>In a review, Young et al. (2019) noted that, in many cases, infertility in patients with HH can be successfully treated. </p>
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<h4>
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<span class="mim-font">
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<strong>Inheritance</strong>
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</span>
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</h4>
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<p>Hockaday (1966) described 2 cases. In the second case, the father was found to have 'complete anosmia on testing.' Thus, this may have been an autosomal dominant form of the disorder. </p><p>On the basis of cases in which the father of affected individuals showed anosmia, Santen and Paulsen (1973) concluded that autosomal dominant inheritance is most likely. </p><p><strong><em>Oligogenic Inheritance</em></strong></p><p>
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Tornberg et al. (2011) studied a large French Canadian pedigree with several consanguineous loops, previously reported by White et al. (1983), in which affected individuals variably presented with hypogonadotropic hypogonadism, anosmia, and cleft palate. In 4 affected family members, Tornberg et al. (2011) identified homozygosity or heterozygosity for a missense mutation in the HS6ST1 gene (604846.0002; see HH15, 614880). Because of the phenotypic variability and reduced penetrance displayed in the family, the authors screened 8 additional known HH-associated genes and detected a missense mutation in FGFR1 that was also present in the 4 affected members as well as 1 unaffected individual (136350.0025). In another family in which a man with anosmic HH and his unaffected brother both carried a missense mutation in HS6ST1 (604846.0001), screening revealed an additional missense mutation in the NELF gene (608137.0001; see HH9, 614838) in the proband. Tornberg et al. (2011) concluded that HH is an oligogenic disorder in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for neuroendocrine control of human reproduction. </p><p>In the large consanguineous 10-generation French Canadian family with anosmic HH and cleft palate, previously reported by White et al. (1983) and in which Tornberg et al. (2011) had identified mutations in both the FGFR1 (136350.0025) and HS6ST1 (604846.0002) genes, Miraoui et al. (2013) identified additional mutations in 2 more genes in the FGF network, FGF17 (603725.0001) and FLRT3 (604808.0001 and 604808.0002). In 4 more unrelated probands with anosmic HH, Miraoui et al. (2013) identified heterozygosity for missense mutations in FGFR1 (e.g., 136350.0026) as well as heterozygosity for 4 other genes in the FGF network: IL17RD (606807.0002), SPRY4 (607984.0002), DUSP6 (602748.0002), and FLRT3 (604808.0003). Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of congenital hypogonadotropic hypogonadism (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH. </p>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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<p>In a man with Kallmann syndrome, Bergstrom et al. (1987) found a consistent extra small marker chromosome, seemingly derived from chromosome group D or G, with satellites at each end. </p><p>Best et al. (1990) described a balanced de novo translocation (7;12)(q22;q24) in an individual with Kallmann syndrome. </p><p>In a male patient with hypogonadotropic hypogonadism and cleft lip and palate, Kim et al. (2005) identified a balanced reciprocal translocation, t(7;8)(p12.3;p11.2). Positional cloning of the breakpoints revealed that the translocation disrupts the FGFR1 gene between exons 2 and 3 and predicts a novel fusion gene product. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>Of 59 Kallmann syndrome patients analyzed by Oliveira et al. (2001), 21 were familial and 38 were sporadic cases. Mutations in the coding sequence of KAL1 (300836) were identified in only 3 familial cases (14%) and 4 of the sporadic cases (11%). Oliveira et al. (2001) concluded that confirmed mutations in the coding sequence of the KAL1 gene occur in the minority of Kallmann syndrome cases, and that the majority of familial (and presumably sporadic) cases of Kallmann syndrome are caused by defects in at least 2 autosomal genes. </p><p>Dode et al. (2003) took advantage of overlapping interstitial deletions at 8p12-p11 in 2 individuals who were affected by different contiguous gene syndromes that both included Kallmann syndrome. The gene encoding fibroblast growth factor receptor-1 (FGFR1; 136350) was in the critical interval. By determining the nucleotide sequence of the 18 coding exons and splice sites of FGFR1 in 129 unrelated individuals with Kallmann syndrome (91 males and 38 females), they detected heterozygous mutations in 4 familial cases and 8 sporadic cases (see, e.g., 136350.0002-136350.0006). In addition, they found that 1 individual, who was born to consanguineous parents and was affected by Kallmann syndrome with cleft palate, agenesis of the corpus callosum, unilateral hearing loss, and fusion of the fourth and fifth metacarpal bones, was homozygous with respect to a deleterious missense mutation (136350.0007). Moreover, cleft palate or lip and selective tooth agenesis, 2 anomalies that are occasionally associated with Kallmann syndrome (White et al., 1983; Hardelin, 2001) and were present in 5 individuals with mutations in FGFR1, can now be ascribed to this disease. In 1 family with an FGFR1 mutation, bimanual synkinesia was identified, indicating that it can occur in autosomal Kallmann syndrome, although it had previously been considered to be specific to the X-linked form of the disorder. The results of these studies suggested that olfactory bulb development in humans is crucially sensitive to reduced dosage of FGFR1. </p><p>Sato et al. (2004) studied 25 male and 3 female Japanese individuals, aged 10 to 53 years, with Kallmann syndrome. Ten males were from 5 families, and the remaining 15 males and 3 females were apparently sporadic cases. The authors found 2 novel intragenic FGFR1 mutations in 2 sporadic male cases. The 2 males with FGFR1 mutations had hypogonadotropic hypogonadism and anosmia and lacked other features. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in 1 female and cleft palate, cleft palate with perceptive deafness, and selective tooth agenesis with perceptive deafness in 1 male each, in addition to a variable extent of hypogonadotropic hypogonadism and olfactory dysfunction. </p><p>Pitteloud et al. (2006) examined the FGFR1 gene in 7 unrelated patients with normosmic IHH and identified heterozygous mutations in 3 individuals. An 18-year-old female diagnosed with partial IHH and her brother, who had Kallmann syndrome, were found to have a heterozygous missense mutation in the FGFR1 gene (136350.0013); their father, who was also heterozygous for the mutation, had congenital anosmia. In a 25-year-old Hispanic male with normosmic IHH and unilateral cryptorchidism who also had 2 congenitally missing teeth, Pitteloud et al. (2006) identified complex heterozygosity for 2 mutations of the FGFR1 gene on the same allele (136350.0014). The patient's mother, who was also heterozygous for the mutations, had congenital anosmia and normal puberty. In 2 brothers with normosmic IHH, 1 of whom also had cleft lip and palate and 3 missing teeth, Pitteloud et al. (2006) identified heterozygosity for a nonsense mutation in the FGFR1 gene (136350.0015). The sibs' father, who was also heterozygous for the mutation, reported having delayed puberty. Structural and biochemical analysis of the mutations revealed that all resulted in receptor loss of function. Noting the mixed pedigrees caused by mutation in FGFR1, Pitteloud et al. (2006) suggested that Kallmann syndrome and normosmic IHH are part of the same spectrum of disease. </p><p>In a 16-year-old female with cleft lip and palate who presented with anosmia, irregular menstrual periods, and agenesis of 2 teeth, Riley et al. (2007) identified a nonsense mutation in the FGFR1 gene (136350.0018). Her father, who also carried the mutation, had isolated cleft lip and palate and a normal sense of smell and was fertile. The mutation was not found in the unaffected mother or brother; a deceased paternal great aunt was also reported to have cleft lip. </p><p>Raivio et al. (2009) sequenced the FGFR1 gene in 134 patients with normosmic IHH and identified heterozygous loss-of-function mutations in 9 (7%). Screening of 5 more HH-associated genes in the 9 mutation-positive patients revealed additional mutations in 5 patients, including mutations in the GNRHR (138850), PROKR2 (607123), and FGF8 (600483) genes. </p><p>Villanueva et al. (2015) studied 7 probands with mutations in the FGFR1 gene (see, e.g., 136350.0026) who exhibited HH as well as split hand/foot malformations (SHFM). In 6 families that were screened for mutation in 4 to 6 known HH-associated genes, the probands were heterozygous for FGFR1 mutations and exhibited SHFM limited to one or both feet. Other features exhibited by affected individuals included dental anomalies and cleft lip and/or palate. In 2 of these families, Incomplete penetrance was demonstrated by unaffected female carriers, and in 3 of the families, parental mutation status was not reported. In a consanguineous Turkish family, screened for mutation in 13 known HH-associated genes, the proband was homozygous for an FGFR1 missense mutation and had SHFM involving both hands and both feet as well as absent septum pellucidum and hypoplastic anterior corpus callosum on MRI. His unaffected parents and an anosmic sister were heterozygous for the mutation; in addition, 3 sibs with reportedly severe skeletal anomalies had died as neonates. </p><p><strong><em>Possible Association with Functional Hypothalamic Amenorrhea in Carrier Females</em></strong></p><p>
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Caronia et al. (2011) studied 55 women with functional hypothalamic amenorrhea, all of whom 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><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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From a cohort of 104 probands with KS or HH, Salian-Mehta et al. (2014) identified 4 patients, 2 with KS and 2 with HH, who were negative for mutation in 14 known KS- or HH-associated genes but who had heterozygous mutations in the AXL gene (109135), including 3 missense mutations and 1 splice site mutation. Segregation was not reported in 3 of the families; in case 1, the mutation was also present in the proband's unaffected father. The 3 missense variants were found in public variant databases. In vitro functional analysis showed no abnormally spliced products or difference in splicing efficiency with the splicing mutation compared to wildtype AXL, and the missense mutations did not alter Gas6 (600441) ligand binding. However, in GT1-7 and GnRH neuronal cells expressing 2 of the missense mutations (S202C or Q361P), defective ligand-dependent receptor processing and aberrant neuronal migration were observed, and the Q361P mutant also showed defective ligand-independent chemotaxis. The authors suggested that the probands' phenotypes might result from concomitant mutations in other genes. </p><p>By whole-exome sequencing of 133 patients with hypogonadotropic hypogonadism with or without anosmia, Bouilly et al. (2018) identified 7 patients from 6 families with heterozygous variants in the DCC gene (601614), occurring alone in 3 families, and in combination with heterozygous or homozygous variants in 1 or more HH-associated genes in 3 families. The designations for 2 of the families, as well as for 2 of the probands, were discrepant between Figure 4 and the case summaries. Familial segregation was not reported for 2 of the families. Unaffected carriers were present in 3 families, and in 1 family, the proband's mother, who did not carry a DCC mutation, had delayed puberty, whereas mutation status was unknown for the proband's unaffected father. Immunofluorescence analysis of immortalized GnRH neurons demonstrated that the identified DCC variants significantly impaired cytoskeletal and membrane rearrangement involved in cell protrusion formation, consistent with impairment of GnRH neuron migration. The authors suggested that the incomplete penetrance and variable expressivity observed both within and across families with HH might be explained by oligogenic inheritance or by the presence of mutations in unknown HH loci. </p><p>For discussion of a possible association between HH and mutation in the SEMA3G gene, see 620997.</p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 2 sisters with primary amenorrhea and no breast development at 25 and 18 years of age, respectively, Seminara et al. (2000) identified compound heterozygosity for mutations in the GNRHR gene: Q106R (138850.0001) on one allele and R262Q (138850.0002) on the other. The apparently unaffected parents were heterozygous for the mutations. The older sister conceived 3 times on pulsatile GnRH and twice on exogenous gonadotropin therapy, but suffered recurrent pregnancy loss; an embryo/trophoblast toxic factor was identified. The younger sister was treated with exogenous gonadotropins and gave birth to 3 children, with 1 singleton and 1 twin pregnancy. Pitteloud et al. (2007) reexamined the family studied by Seminara et al. (2000) and identified heterozygosity for an additional missense mutation in the FGFR1 gene (136350.0016) in the 2 sisters and in their father, who had a history of delayed puberty. Mutation analysis of the children of the younger sister revealed that her unaffected daughter who had undergone normal puberty was heterozygous for the mutation in FGFR1 but had no mutations in the GNRHR gene; and her prepubertal 10-year-old twin sons, born without cryptorchidism or microphallus, were each heterozygous for 1 of the mutations in GNRHR but did not have any mutations in the FGFR1 gene. In another family in which the proband had severe Kallmann syndrome, his father had a history of delayed puberty and congenital anosmia, his mother had clinodactyly and Duane ocular retraction syndrome, his sister had midline defects with a bifid nose and high-arched palate, and his brother had clinodactyly alone, Pitteloud et al. (2007) identified heterozygosity for a missense mutation in the FGFR1 gene (L342S; 136350.0017) in the proband, his father, and his sister. Heterozygosity for an additional mutation, an 8-bp deletion in the NELF gene (608137.0002), was identified in the proband, his mother, and his brother. The mother and both sibs of the proband had normal puberty and a normal sense of smell by formal testing. Pitteloud et al. (2007) concluded that mutations in 2 different genes can synergize to produce a more severe phenotype in families with hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency. </p><p>Salenave et al. (2008) studied the endocrine features reflecting gonadotropic-testicular axis function in 39 men; 21 had mutations in KAL1 (300836) and 18 in FGFR1, but none had additional mutations in PROK2 (607002) or PROKR2 (607123) genes. Puberty failed to occur in the patients with KAL1 mutations, all of whom had complete congenital hypogonadotropic hypogonadism. The fathers of 3 unrelated men with KS, who also carried the respective FGFR1 mutations, had normal puberty, were eugonadal, and had normal testosterone and gonadotropin levels. Cryptorchidism was more frequent and testicular volume was smaller in HH subjects with KAL1 mutations than in subjects with FGFR1 mutations. The mean basal plasma FSH (see 136530) level, serum inhibin B (see 147290) level, basal LH (see 152780) plasma level, and GnRH-stimulated LH plasma level were significantly lower in the subjects with KAL1 mutations. LH pulsatility was studied in 13 complete HH subjects with KAL1 mutations and 7 subjects with FGFR1 mutations; LH secretion was nonpulsatile in all the subjects, but mean LH levels were lower in those with KAL1 mutations. Salenave et al. (2008) concluded that men with KS and documented KAL1 mutations have a more severe reproductive phenotype than men with FGFR1 mutations, which are associated with a broad spectrum of phenotypes, ranging from complete HH to normality. </p><p>Sykiotis et al. (2010) analyzed 8 known HH-associated genes, including KAL1, FGFR1, PROKR2, PROK2, FGF8, GNRHR, KISS1R, and NELF, in 397 well-phenotyped HH patients, of whom 44 women and 155 men had anosmia/hyposmia, and 52 women and 146 men were normosmic. Compared to 179 controls tested, HH patients were significantly more likely to harbor rare protein-altering variants (22% vs 10%; p = 0.001). A single variant allele was identified in 68 (17%) of the patients, and oligogenicity was found as frequently as homozygosity or compound heterozygosity in this cohort: 10 (2.5%) of the patients had rare variants in both alleles of a single gene, and 10 (2.5%) had variants in 2 or more alleles of different genes. Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%; no oligogenicity was detected among the controls (p less than 0.05), even though deleterious alleles were present. In the 10 oligogenic pedigrees, 3 of which were new and 7 of which had previously been reported (Pitteloud et al., 2007; Falardeau et al., 2008; Cole et al., 2008; Raivio et al., 2009; Chan et al., 2009), the higher the number of affected genes and alleles that an individual harbored, the more likely he or she was to have HH as opposed to a milder or partial phenotype, such as delayed puberty, isolated anosmia, or isolated cleft lip/palate. Sykiotis et al. (2010) concluded that GnRH deficiency should be considered to be an oligogenic disorder, and noted that the fact that no rare protein-altering variants were found in the majority (78%) of patients indicated that the 8 genes sequenced accounted for only a fraction of the genetic etiology of the disease. </p><p>To assess oligogenicity in hypogonadotropic hypogonadism, Miraoui et al. (2013) analyzed 350 HH probands of European descent for mutation in 17 HH-associated genes. Mutations were identified in 124 (35%) of the probands, and 24 (19%) of the mutation-positive probands carried at least 2 mutant alleles from different genes. Miraoui et al. (2013) noted that 23 of the 24 oligogenic cases involved at least 1 gene associated with the fibroblast growth factor (FGF) network (see 601513). </p><p>Dode et al. (2006) stated that loss-of-function mutations in the KAL1 (300836) and FGFR1 genes account for approximately 20% of all cases of Kallmann syndrome and that mutations in the PROKR2 and PROK2 genes account for an additional 10%. </p><p>Gurbuz et al. (2012) reviewed all causative mutations detected in multiplex families with normosmic hypogonadotropic hypogonadism over a 7-year period in Turkey. Mutations that segregated with disease were identified in 17 (77.2%) of 22 families studied, including mutations of the GNRHR gene in 7 (31.8%) of the families, TACR3 in 6 (27.2%), KISSR in 2 (9%), TAC3 in 1 (4.5%), and KISS1 in 1 (4.5%). Inheritance was autosomal recessive in all 17 families. </p>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a family with Kallmann syndrome inherited presumably as an autosomal recessive, Dornan et al. (1980) excluded close linkage with HLA. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bergstrom, R. W., Hansen, K. L., Clare, C. N., Katz, M. S.
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<strong>Hypogonadotropic hypogonadism and anosmia (Kallmann's syndrome) associated with a marker chromosome.</strong>
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J. Androl. 8: 55-60, 1987.
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[PubMed: 3104265]
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[Full Text: https://doi.org/10.1002/j.1939-4640.1987.tb02421.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Best, L. G., Wasdahl, W. A., Larson, L. M., Sturlaugson, J.
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<strong>Chromosome abnormality in Kallmann syndrome.</strong>
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Am. J. Med. Genet. 35: 306-309, 1990.
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[PubMed: 2309777]
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[Full Text: https://doi.org/10.1002/ajmg.1320350303]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bhagavath, B., Ozata, M., Ozdemir, I. C., Bolu, E., Bick, D. P., Sherins, R. J., Layman, L. C.
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<strong>The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism.</strong>
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Fertil. Steril. 84: 951-957, 2005.
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[PubMed: 16213849]
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[Full Text: https://doi.org/10.1016/j.fertnstert.2005.04.029]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bhagavath, B., Podolsky, R. H., Ozata, M., Bolu, E., Bick, D. P., Kulharya, A., Sherins, R. J., Layman, L. C.
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<strong>Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism.</strong>
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Fertil. Steril. 85: 706-713, 2006.
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[PubMed: 16500342]
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[Full Text: https://doi.org/10.1016/j.fertnstert.2005.08.044]
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</p>
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</li>
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