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<title>
Entry
- #308700 - HYPOGONADOTROPIC HYPOGONADISM 1 WITH OR WITHOUT ANOSMIA; HH1
- OMIM
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<span class="h4">#308700</span>
<br />
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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/308700"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS147950"> <strong>Phenotypic Series</strong> </a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#pathogenesis">Pathogenesis</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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<div><a href="https://hprd.org/summary?hprd_id=02393&isoform_id=02393_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://clinicaltrials.gov/search?cond=HYPOGONADOTROPIC HYPOGONADISM 1 WITH OR WITHOUT ANOSMIA" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=8668&Typ=Pat" title="Normosmic congenital hypogonadotropic hypogonadism" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Normosmic congenital hypog…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3249&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Kallmann syndrome&nbsp;</a></div>
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<div><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>
<div><a href="https://www.diseaseinfosearch.org/x/3949" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=308700[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>
<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;">&#9658;</span>Orphanet</div>
<div id="mimOrphanetFold" class="collapse">
<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>
</div>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/8159fbc4-4e5c-47f5-bb68-03c6e9f35ef2/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
<span class="panel-title">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9658;</span> Variation
</a>
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</span>
</div>
<div id="mimVariationLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="http://www.LOVD.nl/KAL1" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
</div>
</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
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</a>
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</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0090094" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/308700" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:0090094" 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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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:308700" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
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</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 93559003<br />
<strong>ICD10CM:</strong> E23.0<br />
<strong>ORPHA:</strong> 432, 478<br />
<strong>DO:</strong> 0090094<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
308700
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
HYPOGONADOTROPIC HYPOGONADISM 1 WITH OR WITHOUT ANOSMIA; HH1
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
KALLMANN SYNDROME 1; KAL1<br />
KMS<br />
HYPOGONADOTROPIC HYPOGONADISM AND ANOSMIA; HHA<br />
DYSPLASIA OLFACTOGENITALIS OF DE MORSIER<br />
ANOSMIC HYPOGONADISM
</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/X/43?start=-3&limit=10&highlight=43">
Xp22.31
</a>
</span>
</td>
<td>
<span class="mim-font">
Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1)
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/308700"> 308700 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
ANOS1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300836"> 300836 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
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<a href="/clinicalSynopsis/308700" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS147950" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="sr-only">Toggle Dropdown</span>
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&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/308700" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/308700" 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">
- X-linked recessive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845977</a>, <a href="https://bioportal.bioontology.org/search?q=C1279481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279481</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</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> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Facial asymmetry (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13851000119109" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13851000119109</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15253005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15253005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1306710&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1306710</a>, <a href="https://bioportal.bioontology.org/search?q=C0546952&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0546952</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000324</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000324" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000324</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">
- Anosmia or hyposmia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4478399&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4478399</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Genitalia (Male) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Micropenis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/34911001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">34911001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q55.62" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q55.62</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/752.64" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">752.64</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0266435&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0266435</a>, <a href="https://bioportal.bioontology.org/search?q=C4551492&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551492</a>, <a href="https://bioportal.bioontology.org/search?q=C1387005&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1387005</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008736" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008736</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000054" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000054</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000054" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000054</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Internal Genitalia (Male) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cryptorchidism, unilateral or bilateral <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> 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 /> -
Small testes <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/276411001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">276411001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241355&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241355</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008734" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008734</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008734" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008734</a>]</span><br /> -
Azoospermia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/425558002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">425558002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48188009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48188009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N46.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N46.01</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/N46.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N46.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/606.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">606.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0004509&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0004509</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000027</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000027</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">
- Hypothalamic amenorrhea, functional (in some carrier females) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4478396&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4478396</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Unilateral renal aplasia (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675017&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675017</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204942005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204942005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q60.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q60.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q60</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000104" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000104</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Aplasia or hypoplasia of olfactory bulbs <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4478394&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4478394</a>]</span><br /> -
Bimanual synkinesia (mirror movements of the hands, 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 />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ENDOCRINE FEATURES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Hypogonadotropic hypogonadism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22053006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22053006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/33927004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">33927004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405769009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405769009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E23.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E23.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q98.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q98.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q98.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q98.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/758.7" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">758.7</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0271623&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0271623</a>, <a href="https://bioportal.bioontology.org/search?q=C0022735&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0022735</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000044" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000044</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000044" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000044</a>]</span><br /> -
Failure of spontaneous puberty <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4478390&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4478390</a>]</span><br /> -
Low testosterone levels <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 luteinizing hormone (LH) levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4478391&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4478391</a>]</span><br /> -
Apulsatile LH secretion <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4478392&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4478392</a>]</span><br /> -
Low follicular-stimulating hormone (FSH) levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4478393&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4478393</a>]</span><br /> -
Low inhibin B levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4013509&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4013509</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Heterozygous females may be susceptible to functional hypothalamic amenorrhea<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the KAL1 gene gene (KAL1, <a href="/entry/300836#0001">300836.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Hypogonadotropic hypogonadism with or without anosmia
- <a href="/phenotypicSeries/PS147950">PS147950</a>
- 27 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/952?start=-3&limit=10&highlight=952"> 1p13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619755"> ?Hypogonadotropic hypogonadism 27 without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619755"> 619755 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162361"> NHLH2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162361"> 162361 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/1607?start=-3&limit=10&highlight=1607"> 1q32.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614842"> ?Hypogonadotropic hypogonadism 13 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614842"> 614842 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603286"> KISS1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603286"> 603286 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/631?start=-3&limit=10&highlight=631"> 2q14.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614880"> {Hypogonadotropic hypogonadism 15 with or without anosmia} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614880"> 614880 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604846"> HS6ST1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604846"> 604846 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/410?start=-3&limit=10&highlight=410"> 3p14.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615267"> Hypogonadotropic hypogonadism 18 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>, <abbr class="mim-tip-hint" title="Digenic dominant">DD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615267"> 615267 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606807"> IL17RD </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606807"> 606807 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/459?start=-3&limit=10&highlight=459"> 3p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610628"> Hypogonadotropic hypogonadism 4 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/610628"> 610628 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607002"> PROK2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607002"> 607002 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/255?start=-3&limit=10&highlight=255"> 4q13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/146110"> Hypogonadotropic hypogonadism 7 without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/146110"> 146110 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/138850"> GNRHR </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/138850"> 138850 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/456?start=-3&limit=10&highlight=456"> 4q24 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614840"> Hypogonadotropic hypogonadism 11 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614840"> 614840 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162332"> TACR3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162332"> 162332 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/524?start=-3&limit=10&highlight=524"> 4q27 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618841"> Hypogonadotropic hypogonadism 25 with anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/618841"> 618841 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616506"> NDNF </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616506"> 616506 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/5/616?start=-3&limit=10&highlight=616"> 5q31.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615266"> Hypogonadotropic hypogonadism 17 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615266"> 615266 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607984"> SPRY4 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607984"> 607984 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/380?start=-3&limit=10&highlight=380"> 7q21.11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614897"> {Hypogonadotropic hypogonadism 16 with or without anosmia} </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614897"> 614897 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603961"> SEMA3A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603961"> 603961 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/7/622?start=-3&limit=10&highlight=622"> 7q31.32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616030"> Hypogonadotropic hypogonadism 22, with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616030"> 616030 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613301"> FEZF1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613301"> 613301 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/99?start=-3&limit=10&highlight=99"> 8p21.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615270"> Hypogonadotropic hypogonadism 20 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615270"> 615270 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603725"> FGF17 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603725"> 603725 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/139?start=-3&limit=10&highlight=139"> 8p21.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614841"> ?Hypogonadotropic hypogonadism 12 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614841"> 614841 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/152760"> GNRH1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/152760"> 152760 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/211?start=-3&limit=10&highlight=211"> 8p11.23 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147950"> Hypogonadotropic hypogonadism 2 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147950"> 147950 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/136350"> FGFR1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/136350"> 136350 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/295?start=-3&limit=10&highlight=295"> 8q12.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612370"> Hypogonadotropic hypogonadism 5 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612370"> 612370 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608892"> CHD7 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608892"> 608892 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/698?start=-3&limit=10&highlight=698"> 9q34.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614838"> Hypogonadotropic hypogonadism 9 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614838"> 614838 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608137"> NSMF </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608137"> 608137 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/502?start=-3&limit=10&highlight=502"> 10q24.32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612702"> Hypogonadotropic hypogonadism 6 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612702"> 612702 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600483"> FGF8 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600483"> 600483 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/10/617?start=-3&limit=10&highlight=617"> 10q26.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614858"> Hypogonadotropic hypogonadism 14 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614858"> 614858 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606417"> WDR11 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606417"> 606417 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/266?start=-3&limit=10&highlight=266"> 11p14.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/229070"> Hypogonadotropic hypogonadism 24 without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/229070"> 229070 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/136530"> FSHB </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/136530"> 136530 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/528?start=-3&limit=10&highlight=528"> 12q13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614839"> Hypogonadotropic hypogonadism 10 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614839"> 614839 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162330"> TAC3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162330"> 162330 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/669?start=-3&limit=10&highlight=669"> 12q21.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615269"> Hypogonadotropic hypogonadism 19 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615269"> 615269 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602748"> DUSP6 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602748"> 602748 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/15/242?start=-3&limit=10&highlight=242"> 15q21.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619718"> Hypogonadotropic hypogonadism 26 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619718"> 619718 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600480"> TCF12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600480"> 600480 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/35?start=-3&limit=10&highlight=35"> 19p13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614837"> Hypogonadotropic hypogonadism 8 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614837"> 614837 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604161"> KISS1R </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604161"> 604161 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/923?start=-3&limit=10&highlight=923"> 19q13.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/228300"> Hypogonadotropic hypogonadism 23 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/228300"> 228300 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/152780"> LHB </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/152780"> 152780 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/80?start=-3&limit=10&highlight=80"> 20p12.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/244200"> Hypogonadotropic hypogonadism 3 with or without anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/244200"> 244200 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607123"> PROKR2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607123"> 607123 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/108?start=-3&limit=10&highlight=108"> 20p12.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615271"> Hypogonadotropic hypogonadism 21 with anosmia </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615271"> 615271 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604808"> FLRT3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604808"> 604808 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/X/43?start=-3&limit=10&highlight=43"> Xp22.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/308700"> Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/308700"> 308700 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300836"> ANOS1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/300836"> 300836 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
<div class="text-right small">
<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="text" class="mim-anchor"></a>
<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon &lt;span class='glyphicon glyphicon-plus-sign'&gt;&lt;/span&gt at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
<strong>TEXT</strong>
</span>
</span>
</h4>
<div id="mimTextFold" class="collapse in ">
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because hypogonadotropic hypogonadism-1 with or without anosmia (HH1) is caused by mutation in the KAL1 gene (ANOS1; <a href="/entry/300836">300836</a>) on chromosome Xp22.3, sometimes in association with mutation in another gene, e.g., PROKR2 (<a href="/entry/607123">607123</a>).</p>
</span>
<div>
<br />
</div>
</div>
<div>
<a id="description" class="mim-anchor"></a>
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
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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="#38" class="mim-tip-reference" title="Raivio, T., Falardeau, J., Dwyer, A., Quinton, R., Hayes, F. J., Hughes, V. A., Cole, L. W., Pearce, S. H., Lee, H., Boepple, P., Crowley, W. F., Jr., Pitteloud, N. &lt;strong&gt;Reversal of idiopathic hypogonadotropic hypogonadism.&lt;/strong&gt; New Eng. J. Med. 357: 863-873, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17761590/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17761590&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa066494&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17761590">Raivio et al., 2007</a>). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17761590" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For information on the autosomal forms of hypogonadotropic hypogonadism with or without anosmia, see <a href="/entry/147950">147950</a>.</p>
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<p>Males with Kallmann syndrome show anosmia due to agenesis of the olfactory lobes, and hypogonadism secondary to deficiency of hypothalamic gonadotropin-releasing hormone (see GNRH1, <a href="/entry/152760">152760</a>). In the course of molecular genetic studies of X-linked Kallmann syndrome, <a href="#15" class="mim-tip-reference" title="Hardelin, J.-P., Levilliers, J., del Castillo, I., Cohen-Salmon, M., Legouis, R., Blanchard, S., Compain, S., Bouloux, P., Kirk, J., Moraine, C., Chaussain, J.-L., Weissenbach, J., Petit, C. &lt;strong&gt;X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene.&lt;/strong&gt; Proc. Nat. Acad. Sci. 89: 8190-8194, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1518845/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1518845&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.89.17.8190&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1518845">Hardelin et al. (1992)</a> found instances of renal agenesis and also pointed to mirror movements of the hands (bimanual synkinesia), pes cavus, high-arched palate, and cerebellar ataxia. Synkinesia, which is one of the more frequent findings, may be attributable to lack of inhibitory fibers connecting the 2 hemispheres through the corpus callosum (<a href="#29" class="mim-tip-reference" title="Nass, R. &lt;strong&gt;Mirror movement asymmetries in congenital hemiparesis: the inhibition hypothesis revisited.&lt;/strong&gt; Neurology 35: 1059-1062, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4010948/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4010948&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.35.7.1059&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4010948">Nass, 1985</a>). Colorblindness was also segregating in families described by <a href="#20" class="mim-tip-reference" title="Kallmann, F. J., Schoenfeld, W. A., Barrera, S. E. &lt;strong&gt;The genetic aspects of primary eunuchoidism.&lt;/strong&gt; Am. J. Ment. Defic. 48: 203-236, 1944."None>Kallmann et al. (1944)</a>; however, the information was too limited to give conclusive evidence on possible X-linkage of this syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1518845+4010948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="De Morsier, G. &lt;strong&gt;Etudes sur les dysraphies cranio-encephaliques. I. Agenesie des lobes olfactifs (telencephaloschizis lateral) et des commissures calleuse et anterieure (telencephaloschizis median): la dysplasie olfacto-genitale.&lt;/strong&gt; Schweiz. Arch. Neurol. Psychiat. 74: 309-361, 1954.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14385744/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14385744&lt;/a&gt;]" pmid="14385744">De Morsier (1954)</a> collected 28 reported cases of agenesis of the olfactory lobes in which complete autopsy was performed and found that abnormalities of the sexual organs, mainly cryptorchidism and testicular atrophy, had been noted in 14. He suggested that the genital atrophy is secondary to involvement of the hypothalamus as well as the olfactory lobes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14385744" 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="Hockaday, T. D. R. &lt;strong&gt;Hypogonadism and life-long anosmia.&lt;/strong&gt; Postgrad. Med. J. 42: 572-574, 1966.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5919183/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5919183&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/pgmj.42.491.572&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="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 (see <a href="/entry/147950">147950</a>). Anosmia must be inquired about in cases of hypogonadism since patients rarely volunteer the information. Indeed, the patient is sometimes unaware of anosmia so that tests are necessary. <a href="#35" class="mim-tip-reference" title="Pittman, J. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Boston, Mass. 1966."None>Pittman (1966)</a> found anosmia in 16 of 28 cases of hypogonadotropic hypogonadism. <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><a href="#2" class="mim-tip-reference" title="Ballabio, A. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Houston, Texas 3/11/1993."None>Ballabio (1993)</a> reported the consensus from an NIH conference on Kallmann syndrome that no patient of molecularly confirmed X-linked Kallmann syndrome has intact smell. In a single family, 1 brother was hyposmic and had normal gonadal development, whereas 2 brothers and 2 maternal cousins had the full-blown Kallmann syndrome phenotype. There was agreement that the intrafamilial variability of the phenotype in the autosomal forms of Kallmann syndrome (for which no molecular test is available) is extensive. Several families have been described in which affected individuals have either hypogonadism or anosmia or both. On the contrary, in the X-linked families, the phenotype seems to be consistent within families.</p><p><a href="#24" class="mim-tip-reference" title="Males, J. L., Townsend, J. L., Schneider, R. A. &lt;strong&gt;Hypogonadotropic hypogonadism with anosmia--Kallmann&#x27;s syndrome: a disorder of olfactory and hypothalamic function.&lt;/strong&gt; Arch. Intern. Med. 131: 501-507, 1973.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4540668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4540668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archinte.131.4.501&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4540668">Males et al. (1973)</a> studied 6 unrelated subjects, 5 males and 1 female, with hypogonadism and anosmia. All the males had small genitals and decreased sexual hair. Gynecomastia and eunuchoid habitus were seen in 4. All 6 had a radiographically normal sella turcica. Testicular biopsies of the males showed decreased numbers of germ cells and a spermatogenic state at the primary spermatocyte stage. Leydig cells were not histologically identifiable. The affected female had 2 brothers with anosmia and hypogonadism. Urine gonadotropins were low in the 2 patients tested. Basal urinary 17-hydroxycorticosteroids were normal in those tested. A metyrapone test suggested low levels of ACTH in 2. One male patient at operation showed agenesis of the olfactory bulbs and tracts. The authors stated that the Kallmann syndrome is probably the expression of a disorder of hypothalamic regulation involving the control of those releasing factors needed for effective pituitary function. Additionally, it is interesting to note that there is some evidence for a relationship between olfactory acuity (perhaps to detect pheromones) and the gonadal and adrenal system in laboratory test animals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4540668" 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>Unilateral renal agenesis has been described in several patients with Kallmann syndrome (<a href="#47" class="mim-tip-reference" title="Wegenke, J. D., Uehling, D. T., Wear, J. B., Jr., Gordon, E. S., Bargman, G. J., Deacon, J. S. R., Herrmann, J. P. R., Opitz, J. M. &lt;strong&gt;Familial Kallmann syndrome with unilateral renal aplasia.&lt;/strong&gt; Clin. Genet. 7: 368-381, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1080088/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1080088&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1975.tb00344.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1080088">Wegenke et al., 1975</a>; <a href="#17" class="mim-tip-reference" title="Hermanussen, M., Sippell, W. G. &lt;strong&gt;Heterogeneity of Kallmann&#x27;s syndrome.&lt;/strong&gt; Clin. Genet. 28: 106-111, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4042391/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4042391&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1985.tb00368.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4042391">Hermanussen and Sippell, 1985</a>). <a href="#22" class="mim-tip-reference" title="Kirk, J. M. W., Grant, D. B., Besser, G. M., Shalet, S., Quinton, R., Smith, C. S., White, M., Edwards, O., Bouloux, P.-M. G. &lt;strong&gt;Unilateral renal aplasia in X-linked Kallmann&#x27;s syndrome.&lt;/strong&gt; Clin. Genet. 46: 260-262, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7820942/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7820942&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1994.tb04238.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7820942">Kirk et al. (1994)</a> reported a systematic study of kidneys in 17 affected persons from 6 families with Kallmann syndrome, including a family with an association of Kallmann syndrome and ichthyosis and interstitial deletion within the short arm of the X chromosome. Unilateral renal agenesis was found in 6 males in 4 families. Moreover, in 2 families (including a family in which all 4 patients demonstrated normal kidneys), there were male infants who died with bilateral renal agenesis. In the family with an association of Kallmann syndrome and ichthyosis, unilateral renal agenesis was found in 2 of 4 affected persons, although all 4 had the same X-chromosome deletion. Presumably, normal renal development requires expression of the Kallmann product (Kalig1/AMDLX), but mutation or absence of this product is not invariably associated with renal agenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4042391+1080088+7820942" 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="#7" class="mim-tip-reference" title="Birnbacher, R., Wandl-Vergesslich, K., Frisch, H. &lt;strong&gt;Diagnosis of X-recessive Kallmann syndrome in early infancy: evidence of hypoplastic rhinencephalon.&lt;/strong&gt; Europ. J. Pediat. 153: 245-247, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8194555/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8194555&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF01954511&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8194555">Birnbacher et al. (1994)</a> made the diagnosis of X-linked Kallmann syndrome in a 3-month-old infant who presented with hypogonadism, a small penis, and bilateral cryptorchidism. He showed an inadequate response of luteinizing hormone and follicle stimulating hormone to the administration of luteinizing hormone-releasing hormone (LHRH; <a href="/entry/152760">152760</a>) and of testosterone to human chorionic gonadotropin. A maternal uncle had hypogonadism and anosmia and also showed an impaired LH (<a href="/entry/152780">152780</a>) and FSH (<a href="/entry/136530">136530</a>) response to LHRH. MRI showed hypoplasia of the rhinencephalon in both cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8194555" 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="Massin, N., Pecheux, C., Eloit, C., Bensimon, J.-L., Galey, J., Kuttenn, F., Hardelin, J.-P., Dode, C., Touraine, P. &lt;strong&gt;X-chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene.&lt;/strong&gt; J. Clin. Endocr. Metab. 88: 2003-2008, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12727945/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12727945&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2002-021981&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12727945">Massin et al. (2003)</a> described clinical heterogeneity in 3 brothers with Kallmann syndrome who carried a large deletion in the KAL1 gene (<a href="/entry/300386#0011">300386.0011</a>). All 3 had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain MRI showed hypoplastic olfactory bulbs in the 3 sibs, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e., unilateral renal aplasia (sibs B and C), high-arched palate (sib A), brachymetacarpalia (sib A), mirror movements (sibs A and B), and abnormal eye movements (sib C). Sib A suffered from a severe congenital hearing impairment, a feature that had been reported in Kallmann syndrome but had not yet been ascribed unambiguously to the X-linked form of the disease. The authors concluded that the variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of X-linked Kallmann syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12727945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="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. &lt;strong&gt;Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.&lt;/strong&gt; Nature Genet. 33: 463-465, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12627230/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12627230&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1122&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12627230">Dode et al. (2003)</a> stated that bimanual synkinesia had been observed in 75% of X-linked Kallmann syndrome cases; they described bimanual synkinesia, i.e., mirror movements of the hands, in 2 affected members in a family with an autosomal dominant form of Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>). Highly arched palate, which can be regarded as a mild anomaly of palatal fusion, is a common feature of KAL1. <a href="#10" 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. &lt;strong&gt;Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.&lt;/strong&gt; Nature Genet. 33: 463-465, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12627230/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12627230&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1122&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12627230">Dode et al. (2003)</a> found cleft palate or cleft lip in several individuals with HH2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12627230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Kaplan, J. D., Bernstein, J. A., Kwan, A., Hudgins, L. &lt;strong&gt;Clues to an early diagnosis of Kallmann syndrome.&lt;/strong&gt; Am. J. Med. Genet. 152A: 2796-2801, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20949504/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20949504&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33442&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20949504">Kaplan et al. (2010)</a> studied 5 patients with features of Kallmann syndrome and reviewed reported patients. Noting that the diagnosis can be difficult to make before puberty, they suggested that it should be considered when a patient presents a combination of features that includes microphallus, cryptorchidism, hearing loss, renal agenesis, and oral clefting or dental agenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20949504" 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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<div>
<a id="biochemicalFeatures" class="mim-anchor"></a>
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<strong>Biochemical Features</strong>
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<p><a href="#3" class="mim-tip-reference" title="Bardin, C. W., Ross, G. T., Rifkind, A. B., Cargille, C. M., Lipsett, M. B. &lt;strong&gt;Studies of the pituitary Leydig cell axis in young men with hypogonadotropic hypogonadism and hyposmia: comparison with normal men, prepubertal boys, and hypo-pituitary patients.&lt;/strong&gt; J. Clin. Invest. 48: 2046-2056, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4390462/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4390462&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1172/JCI106170&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4390462">Bardin et al. (1969)</a> concluded that patients with Kallmann syndrome have a defect in both pituitary and Leydig cell function. They demonstrated impaired secretion of FSH and LH and thought there to be Leydig cell insensitivity to gonadotropin. Treatment with chorionic gonadotropin can correct cryptorchidism and establish fertility, even in adult males. <a href="#43" class="mim-tip-reference" title="Schroffner, W. G., Furth, E. D. &lt;strong&gt;Hypogonadotropic hypogonadism with anosmia (Kallmann&#x27;s syndrome) unresponsive to clomiphene citrate.&lt;/strong&gt; J. Clin. Endocr. 31: 267-270, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5453324/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5453324&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem-31-3-267&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5453324">Schroffner and Furth (1970)</a> found failure of response to clomiphene, as measured by plasma levels of gonadotropins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5453324+4390462" 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>With respect to neuroendocrine phenotype, <a href="#30" 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. &lt;strong&gt;The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 1532-1538, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11297579/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11297579&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.4.7420&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11297579">Oliveira et al. (2001)</a> observed that 8 Kallmann syndrome men with documented KAL1 (<a href="/entry/300836">300836</a>) mutations had completely apulsatile LH secretion, whereas those with autosomal modes of inheritance demonstrated a more variable spectrum with evidence of enfeebled (but present) GnRH-induced LH pulses. They concluded that patients with KAL1 mutations have apulsatile LH secretion consistent with a complete absence of GnRH migration of GnRH cells into the hypothalamus, whereas evidence of enfeebled GnRH-induced LH pulses may be present in autosomal Kallmann syndrome cases. <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>
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<div>
<a id="inheritance" class="mim-anchor"></a>
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<strong>Inheritance</strong>
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<p><a href="#45" class="mim-tip-reference" title="Sparkes, R. S., Simpson, R. W., Paulsen, C. A. &lt;strong&gt;Familial hypogonadotropic hypogonadism with anosmia.&lt;/strong&gt; Arch. Intern. Med. 121: 534-538, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5652405/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5652405&lt;/a&gt;]" pmid="5652405">Sparkes et al. (1968)</a> described X-linked inheritance of hypogonadotropic hypogonadism with anosmia in 2 brothers and their half sister. The 3 affected sibs had the same mother who, despite having minor signs of the disorder (late menarche and irregular menses), had 9 liveborn children. The affected girl had no menses or breast development at age 18 and her ovaries were histologically exactly like those of the fetus. The father had anosmia. This may have been an autosomal recessive form with heterozygous expression in the father or an autosomal dominant form (see <a href="/entry/147950">147950</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5652405" 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="Hermanussen, M., Sippell, W. G. &lt;strong&gt;Heterogeneity of Kallmann&#x27;s syndrome.&lt;/strong&gt; Clin. Genet. 28: 106-111, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4042391/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4042391&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1985.tb00368.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4042391">Hermanussen and Sippell (1985)</a> reported a presumably X-linked recessive kindred. All carrier females had normal sexual and olfactory function. <a href="#18" class="mim-tip-reference" title="Hipkin, L. J., Casson, I. F., Davis, J. C. &lt;strong&gt;Identical twins discordant for Kallmann&#x27;s syndrome.&lt;/strong&gt; J. Med. Genet. 27: 198-199, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2325096/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2325096&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.27.3.198&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2325096">Hipkin et al. (1990)</a> described male twins who were identical by DNA fingerprinting; one had full-blown manifestations of Kallmann syndrome, whereas the other showed normal sexual development and only hyposmia. In a second family, <a href="#17" class="mim-tip-reference" title="Hermanussen, M., Sippell, W. G. &lt;strong&gt;Heterogeneity of Kallmann&#x27;s syndrome.&lt;/strong&gt; Clin. Genet. 28: 106-111, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4042391/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4042391&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1985.tb00368.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4042391">Hermanussen and Sippell (1985)</a> observed 16-year-old twin sisters of whom one had retarded pubertal development and total anosmia, and the other, proven to be monozygotic by blood grouping and HLA typing, had undergone a normal menarche but showed total anosmia. The authors pointed out that sporadic cases of Kallmann syndrome have appeared only in families in which isolated anosmia (see <a href="/entry/301700">301700</a>, <a href="/entry/107200">107200</a>) is present. They suggested that there is an acquired hypothalamic GnRH deficiency on the basis of preexisting anosmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4042391+2325096" 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="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. &lt;strong&gt;The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 1532-1538, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11297579/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11297579&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.4.7420&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11297579">Oliveira et al. (2001)</a> observed that of their X-linked cases confirmed by mutation analysis, only 1 of 3 pedigrees appeared X-linked by inspection, whereas the other 2 contained only affected brothers. Female members of 3 known KAL1 mutation families exhibited no reproductive phenotype and were not anosmic, whereas 3 families with anosmic women were not found to carry KAL1 mutations. The authors concluded that obligate female carriers in families with KAL1 mutations have no discernible phenotype. <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>
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<a id="populationGenetics" class="mim-anchor"></a>
<h4 href="#mimPopulationGeneticsFold" id="mimPopulationGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Population Genetics</strong>
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<p><a href="#33" class="mim-tip-reference" title="Pawlowitzki, I. H., Diekstall, P., Schadel, A., Miny, P. &lt;strong&gt;Estimating frequency of Kallmann syndrome among hypogonadic and among anosmic patients.&lt;/strong&gt; Am. J. Med. Genet. 26: 473-479, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3101500/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3101500&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320260226&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3101500">Pawlowitzki et al. (1987)</a> attempted to estimate the frequency of the Kallmann syndrome, which they referred to by the acronym HHA for hypogonadotropic hypogonadism and anosmia. Among 791 hypogonadal males, they found 19 persons with HHA. They reported that HHA is about one-tenth as common as the Klinefelter syndrome. Among 24 patients presenting with anosmia, they found one hitherto undiagnosed case of HHA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3101500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="clinicalManagement" class="mim-anchor"></a>
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<strong>Clinical Management</strong>
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<p>The mean age at diagnosis in the patients of <a href="#33" class="mim-tip-reference" title="Pawlowitzki, I. H., Diekstall, P., Schadel, A., Miny, P. &lt;strong&gt;Estimating frequency of Kallmann syndrome among hypogonadic and among anosmic patients.&lt;/strong&gt; Am. J. Med. Genet. 26: 473-479, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3101500/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3101500&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320260226&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3101500">Pawlowitzki et al. (1987)</a> and in those reported in the literature was 24.8 and 24.9 years, respectively. Since therapeutic success with substitution therapy, leading to endogenous sex-steroid secretion and even reproduction, is probably age dependent (<a href="#39" class="mim-tip-reference" title="Rogol, A., Mittal, K., White, B. J., McGinnis, M. H., Lieblich, J. M., Rosen, S. W. &lt;strong&gt;HLA-compatible paternity in two &#x27;fertile eunuchs&#x27; with congenital hypogonadotrophic hypogonadism and anosmia (the Kallmann syndrome).&lt;/strong&gt; J. Clin. Endocr. Metab. 51: 275-279, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6772660/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6772660&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem-51-2-275&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6772660">Rogol et al., 1980</a>), early diagnosis is important. In a 28-year-old man with Kallmann syndrome, <a href="#31" class="mim-tip-reference" title="Oppermann, D., Happ, J., Mayr, W. R. &lt;strong&gt;Stimulation of spermatogenesis and biological paternity by intranasal (low dose) gonadotropin-releasing hormone (GnRH) in a male with Kallmann&#x27;s syndrome: intraindividual comparison of GnRH and gonadotropins for stimulation of spermatogenesis.&lt;/strong&gt; J. Clin. Endocr. Metab. 65: 1060-1066, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3312278/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3312278&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem-65-5-1060&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3312278">Oppermann et al. (1987)</a> caused the induction and maintenance of spermatogenesis and biologic paternity by intranasal administration of gonadotropin-releasing hormone (<a href="/entry/152760">152760</a>) in low dose. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3101500+3312278+6772660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="cytogenetics" class="mim-anchor"></a>
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<strong>Cytogenetics</strong>
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<p><a href="#13" class="mim-tip-reference" title="Guioli, S., Incerti, B., Zanaria, E., Bardoni, B., Franco, B., Taylor, K., Ballabio, A., Camerino, G. &lt;strong&gt;Kallmann syndrome due to a translocation resulting in an X/Y fusion gene.&lt;/strong&gt; Nature Genet. 1: 337-340, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1302031/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1302031&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0892-337&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1302031">Guioli et al. (1992)</a> described a patient with Kallmann syndrome who carried an X;Y translocation resulting from abnormal pairing and recombination between the X-linked Kallmann syndrome gene and its homolog on the Y. The translocation created a recombinant, nonfunctional KAL gene identical to the normal X-linked gene with the exception of the 3-prime end that was derived from the Y. The findings indicated that the 3-prime portion of the Kallmann syndrome gene is essential for its function and cannot be substituted by the Y-derived homologous region, although a 'position effect' remained a formal possibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302031" 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="#26" class="mim-tip-reference" title="Maya-Nunez, G., Cuevas-Covarrubias, S., Zenteno, J. C., Ulloa-Aguirre, A., Kofman-Alfaro, S., Mendez, J. P. &lt;strong&gt;Contiguous gene syndrome due to deletion of the first three exons of the Kallmann gene and complete deletion of the steroid sulphatase gene.&lt;/strong&gt; Clin. Endocr. 48: 713-718, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9713559/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9713559&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1046/j.1365-2265.1998.00406.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9713559">Maya-Nunez et al. (1998)</a> described a contiguous gene syndrome due to deletion of the first 3 exons of the KAL1 gene and complete deletion of the steroid sulfatase gene (<a href="/entry/300747">300747</a>). The 20-year-old subject had hypogonadism, anosmia, and generalized ichthyosis. They found reports of complete deletion of both the STS and the KAL genes in 6 families, and 1 previous description of 3 sibs with complete deletion of the STS gene and partial deletion of the KAL gene. The KAL gene is proximal to the STS gene, with its 3-prime end oriented toward the telomere. It was therefore surprising that the 5-prime end of the KAL gene was deleted. This was said to be the first report of a deletion (or a point mutation) in this region of the KAL gene. The involvement of the conserved cysteine-rich N-terminal region which corresponds to the whey acidic protein motif of the KAL gene demonstrated the importance of this specific region for the function of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9713559" 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 clinical assessment and molecular analysis of KAL1 and FGFR1 (<a href="/entry/136350">136350</a>, mutations in which cause KS (HH2), <a href="/entry/147950">147950</a>) in 28 patients with Kallmann syndrome, <a href="#42" 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. &lt;strong&gt;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.&lt;/strong&gt; J. Clin. Endocr. Metab. 89: 1079-1088, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15001591/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15001591&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2003-030476&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15001591">Sato et al. (2004)</a> found submicroscopic deletions at Xp22.3 involving VCXA (<a href="/entry/300533">300533</a>), STS (<a href="/entry/300747">300747</a>), KAL1, and OA1 (<a href="/entry/300808">300808</a>) in 3 familial cases and 1 sporadic male case affected by a contiguous gene syndrome. <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>
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<div>
<a id="pathogenesis" class="mim-anchor"></a>
<h4 href="#mimPathogenesisFold" id="mimPathogenesisToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimPathogenesisToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
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<div id="mimPathogenesisFold" class="collapse in mimTextToggleFold">
<span class="mim-text-font">
<p><a href="#4" class="mim-tip-reference" title="Bick, D., Curry, C. J. R., McGill, J. R., Schorderet, D. F., Bux, R. C., Moore, C. M. &lt;strong&gt;Male infant with ichthyosis, Kallmann syndrome, chondrodysplasia punctata, and an Xp chromosome deletion.&lt;/strong&gt; Am. J. Med. Genet. 33: 100-107, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2750777/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2750777&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320330114&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2750777">Bick et al. (1989)</a> described a male infant with the combination of ichthyosis, Kallmann syndrome, and chondrodysplasia punctata as a contiguous gene syndrome due to deletion of the terminal part of Xp, with the breakpoint at Xp22.31. The mother showed the same deletion of one X chromosome. <a href="#6" class="mim-tip-reference" title="Bick, D. P., Schwanzel-Fukuda, M., Pfaff, D. W., Schorderet, D. F., Price, P. A., Campbell, L., Huff, R. W., Moore, C. M. &lt;strong&gt;Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata, ichthyosis and Kallmann syndrome due to an Xp deletion: evidence for a neuronal migration defect in Kallmann syndrome. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 45 (suppl.): A252, 1989."None>Bick et al. (1989)</a> studied an 18-week-old male fetus from this mother affected with the deletion syndrome (contiguous gene syndrome) that included steroid sulfatase deficiency, chondrodysplasia punctata, and Kallmann syndrome. The olfactory bulbs and tracts were absent and a horseshoe kidney was found. <a href="#48" class="mim-tip-reference" title="Wray, S., Grant, P., Gainer, H. &lt;strong&gt;Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode.&lt;/strong&gt; Proc. Nat. Acad. Sci. 86: 8132-8136, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2682637/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2682637&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.86.20.8132&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2682637">Wray et al. (1989)</a> presented results of studies in the mouse supporting the hypothesis that all luteinizing-hormone-releasing hormone (LHRH) cells in the central nervous system arise from a discrete group of progenitor cells in the olfactory placode and that a subpopulation of these cells migrate into forebrain areas where they subsequently establish an adult-like distribution. During normal embryologic development, the olfactory placode in the nose gives rise to the olfactory nerve and nervus terminalis. LHRH-secreting cells of the hypothalamus arise from the nervus terminalis and migrate from the nose through the cribriform plate along the olfactory tract to the hypothalamus. In the aborted fetus, <a href="#6" class="mim-tip-reference" title="Bick, D. P., Schwanzel-Fukuda, M., Pfaff, D. W., Schorderet, D. F., Price, P. A., Campbell, L., Huff, R. W., Moore, C. M. &lt;strong&gt;Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata, ichthyosis and Kallmann syndrome due to an Xp deletion: evidence for a neuronal migration defect in Kallmann syndrome. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 45 (suppl.): A252, 1989."None>Bick et al. (1989)</a> showed by immunocytochemical analysis that the LHRH-immunoreactive cells and the olfactory nerve failed to reach their normal position, ending prematurely at the meninges. Absence of LHRH-secreting cells in the hypothalamus explains the deficiency of this hormone in Kallmann syndrome. Failure of the olfactory nerve to induce the formation of the olfactory bulb and tract explains the absence of the latter structures. Thus, <a href="#6" class="mim-tip-reference" title="Bick, D. P., Schwanzel-Fukuda, M., Pfaff, D. W., Schorderet, D. F., Price, P. A., Campbell, L., Huff, R. W., Moore, C. M. &lt;strong&gt;Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata, ichthyosis and Kallmann syndrome due to an Xp deletion: evidence for a neuronal migration defect in Kallmann syndrome. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 45 (suppl.): A252, 1989."None>Bick et al. (1989)</a> appear to have demonstrated that Kallmann syndrome is a defect in neuronal migration. See also <a href="#44" class="mim-tip-reference" title="Schwanzel-Fukuda, M., Bick, D., Pfaff, D. W. &lt;strong&gt;Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome.&lt;/strong&gt; Brain Res. Molec. Brain Res. 6: 311-326, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2687610/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2687610&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0169-328x(89)90076-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2687610">Schwanzel-Fukuda et al. (1989)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2750777+2687610+2682637" 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="#23" class="mim-tip-reference" title="Krams, M., Quinton, R., Ashburner, J., Friston, K. J., Frackowiak, R. S. J., Bouloux, P.-M. G., Passingham, R. E. &lt;strong&gt;Kallmann&#x27;s syndrome: mirror movements associated with bilateral corticospinal tract hypertrophy.&lt;/strong&gt; Neurology 52: 816-822, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10078733/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10078733&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.52.4.816&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10078733">Krams et al. (1999)</a> used a quantitative MRI protocol to determine if the mirror movements characteristic of X-linked Kallmann syndrome result from loss of transcallosal inhibition, as proposed by <a href="#29" class="mim-tip-reference" title="Nass, R. &lt;strong&gt;Mirror movement asymmetries in congenital hemiparesis: the inhibition hypothesis revisited.&lt;/strong&gt; Neurology 35: 1059-1062, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4010948/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4010948&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.35.7.1059&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4010948">Nass (1985)</a>, or from an abnormal ipsilateral corticospinal tract, as suggested by electrophysiologic studies. Volumetric comparisons were made of men with X-linked Kallmann syndrome, all of whom had mirror movements, with normal controls, and men with autosomal Kallmann syndrome (<a href="/entry/147950">147950</a>, <a href="/entry/244200">244200</a>), which is not associated with mirror movements. Bilateral hypertrophy of the corticospinal tracts was found in the X-linked patients only. Hypertrophy of the corpus callosum was found in both the X-linked and autosomal Kallmann syndrome patients. The findings of <a href="#23" class="mim-tip-reference" title="Krams, M., Quinton, R., Ashburner, J., Friston, K. J., Frackowiak, R. S. J., Bouloux, P.-M. G., Passingham, R. E. &lt;strong&gt;Kallmann&#x27;s syndrome: mirror movements associated with bilateral corticospinal tract hypertrophy.&lt;/strong&gt; Neurology 52: 816-822, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10078733/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10078733&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.52.4.816&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10078733">Krams et al. (1999)</a> supported the hypothesis that the mirror movements seen in X-linked Kallmann syndrome result from abnormal development of ipsilateral corticospinal tracts. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4010948+10078733" 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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<div>
<a id="mapping" class="mim-anchor"></a>
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Mapping</strong>
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</h4>
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<div id="mimMappingFold" class="collapse in mimTextToggleFold">
<span class="mim-text-font">
<p><a href="#1" class="mim-tip-reference" title="Ballabio, A., Parenti, G., Tippett, P., Mondello, C., Di Maio, S., Tenore, A., Andria, G. &lt;strong&gt;X-linked ichthyosis, due to steroid sulphatase deficiency, associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia): linkage relationships with Xg and cloned DNA sequences from the distal short arm of the X chromosome.&lt;/strong&gt; Hum. Genet. 72: 237-240, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3007328/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3007328&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00291885&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3007328">Ballabio et al. (1986)</a> studied a large Italian pedigree in which 5 males had a syndrome, following a pattern of X-linked inheritance, characterized by steroid sulfatase-deficient ichthyosis (<a href="/entry/308100">308100</a>) and Kallmann syndrome. No crossing-over with Xg or with the probe DXS143 was found. No evidence of deletion was found in the probe studies. Thus, the Kallmann locus appears to be in the distal region of Xp, although <a href="#1" class="mim-tip-reference" title="Ballabio, A., Parenti, G., Tippett, P., Mondello, C., Di Maio, S., Tenore, A., Andria, G. &lt;strong&gt;X-linked ichthyosis, due to steroid sulphatase deficiency, associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia): linkage relationships with Xg and cloned DNA sequences from the distal short arm of the X chromosome.&lt;/strong&gt; Hum. Genet. 72: 237-240, 1986.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3007328/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3007328&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00291885&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3007328">Ballabio et al. (1986)</a> did not reject the possibility that the Kallmann syndrome in their family was due to an allele at the STS locus. By linkage to the hypervariable repeat sequence CRI-S232 (DXS278), <a href="#27" class="mim-tip-reference" title="Meitinger, T., Heye, B., Petit, C., Levilliers, J., Golla, A., Moraine, C., Dalla Piccola, B., Sippell, W. G., Murken, J., Ballabio, A. &lt;strong&gt;Definitive localization of X-linked Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) to Xp22.3: close linkage to the hypervariable repeat sequence CRI-S232.&lt;/strong&gt; Am. J. Hum. Genet. 47: 664-669, 1990. Note: Erratum: Am. J. Hum. Genet. 47: 883 only, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1977309/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1977309&lt;/a&gt;]" pmid="1977309">Meitinger et al. (1990)</a> narrowed the location of the KAL1 gene to Xp22.3; maximum lod score = 6.5 at theta = 0.03. Using pulsed field gel analysis of DNAs from patients with terminal deletions of Xp, <a href="#34" class="mim-tip-reference" title="Petit, C., Levilliers, J., Weissenbach, J. &lt;strong&gt;Long-range restriction map of the terminal part of the short arm of the human X chromosome.&lt;/strong&gt; Proc. Nat. Acad. Sci. 87: 3680-3684, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2339111/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2339111&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.87.10.3680&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2339111">Petit et al. (1990)</a> mapped the Kallmann syndrome locus to a deletion interval of 350 kb at most, located between 8,600 and 8,950 kb from Xpter. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2339111+1977309+3007328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
<h4 href="#mimMolecularGeneticsFold" id="mimMolecularGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Molecular Genetics</strong>
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<p>In a patient and his brother with Kallmann syndrome, <a href="#5" class="mim-tip-reference" title="Bick, D., Franco, B., Sherins, R. J., Heye, B., Pike, L., Crawford, J., Maddalena, A., Incerti, B., Pragliola, A., Meitinger, T., Ballabio, A. &lt;strong&gt;Brief report: intragenic deletion of the KALIG-1 gene in Kallmann&#x27;s syndrome.&lt;/strong&gt; New Eng. J. Med. 326: 1752-1755, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1594017/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1594017&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199206253262606&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1594017">Bick et al. (1992)</a> detected a 3,300-bp deletion in the KAL1 gene (<a href="/entry/300836#0001">300836.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1594017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Hardelin, J.-P., Levilliers, J., Blanchard, S., Carel, J.-C., Leutenegger, M., Pinard-Bertelletto, J.-P., Bouloux, P., Petit, C. &lt;strong&gt;Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome.&lt;/strong&gt; Hum. Molec. Genet. 2: 373-377, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8504298/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8504298&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/2.4.373&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8504298">Hardelin et al. (1993)</a> reported results of a mutation search of the KAL gene (<a href="/entry/300836">300836</a>) in 21 unrelated males with familial Kallmann syndrome. In 2 families, large Xp22.3 deletions that included the entire KAL gene were detected by Southern blot analysis. By sequencing each of the 14 coding exons and splice site junctions in the other 19 patients, they found 9 point mutations at separate locations in 4 exons and 1 splice site. They emphasized the high frequency of unilateral renal aplasia in X-linked Kallmann patients; 6 of 11 males with identified alterations of the KAL gene showed this feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8504298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Parenti, G., Rizzolo, M. G., Ghezzi, M., Di Maio, S., Sperandeo, M. P., Incerti, B., Franco, B., Ballabio, A., Andria, G. &lt;strong&gt;Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene.&lt;/strong&gt; Am. J. Med. Genet. 57: 476-478, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7677154/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7677154&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320570323&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7677154">Parenti et al. (1995)</a> reported the cases of 3 brothers with X-linked ichthyosis and variable expression of Kallmann syndrome. All 3 had the same deletion, which spared the first exon of the KAL1 gene; however, 1 brother had only mild hyposomia and normal pubertal progression, whereas the others were severely affected. The reason for the variability was unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7677154" 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="Georgopoulos, N. A., Pralong, F. P., Seidman, C. E., Seidman, J. G., Crowley, W. F., Jr., Vallejo, M. &lt;strong&gt;Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency.&lt;/strong&gt; J. Clin. Endocr. Metab. 82: 213-217, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8989261/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8989261&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.82.1.3692&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8989261">Georgopoulos et al. (1997)</a> determined the frequency of KAL1 gene mutations in subjects with sporadic GNRH deficiency. Only 1 of 21 (5%) with sporadic GNRH deficiency had a KAL1 gene mutation (a deletion of 14 bases starting at codon 464). In each of 3 different patients with an X-linked mode of inheritance, 3 mutations were detected. These were a single-base substitution introducing a stop codon at position 328, another encoding a phe517-to-leu substitution and a 9-base deletion at the 3-prime exon-intron splice site of exon 8. These data indicated that the incidence of mutations in the coding region of the KAL1 gene in patients with sporadic GNRH deficiency is low. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8989261" 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="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. &lt;strong&gt;The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 1532-1538, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11297579/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11297579&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.4.7420&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11297579">Oliveira et al. (2001)</a> examined 101 individuals with idiopathic hypogonadotropic hypogonadism with or without anosmia and their families to determine their modes of inheritance, incidence of KAL1 mutations, genotype-phenotype correlations, and, in a subset of 38 individuals, their neuroendocrine phenotype. Of the 101 patients, 59 had true Kallmann syndrome (hypogonadotropic hypogonadism and anosmia/hyposmia), whereas, in the remaining 42, no anosmia was evident in the patients or their families. Of the 59 Kallmann syndrome patients, 21 were familial and 38 were sporadic cases. Mutations in the coding sequence of KAL1 were identified in only 3 familial cases (14%) and 4 of the sporadic cases (11%). <a href="#30" 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. &lt;strong&gt;The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics.&lt;/strong&gt; J. Clin. Endocr. Metab. 86: 1532-1538, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11297579/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11297579&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.86.4.7420&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="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="#42" 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. &lt;strong&gt;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.&lt;/strong&gt; J. Clin. Endocr. Metab. 89: 1079-1088, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15001591/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15001591&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2003-030476&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15001591">Sato et al. (2004)</a> studied 25 male and 3 female Japanese individuals with Kallmann syndrome aged 10 to 53 years. Ten males were from 5 families, and the remaining 15 males and 3 females were apparently sporadic cases. Sequencing all exons of the KAL1 and FGFR1 (<a href="/entry/136350">136350</a>) genes showed 6 novel and 2 recurrent intragenic KAL1 mutations in 7 familial and 4 sporadic male cases and 2 novel intragenic FGFR1 mutations in 2 sporadic male cases. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in 2 males and right-side dominant renal lesion in 7 males, in addition to variable degrees of hypogonadotropic hypogonadism in all the 15 males and olfactory dysfunction in 13 males. 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 dental 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="#11" class="mim-tip-reference" title="Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. &lt;strong&gt;Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.&lt;/strong&gt; PLoS Genet. 2: e175, 2006. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17054399/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17054399&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1371/journal.pgen.0020175&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17054399">Dode et al. (2006)</a> described a patient with Kallmann syndrome who was heterozygous for 2 mutations: one in the KAL1 gene (<a href="/entry/300836#0012">300836.0012</a>) and the other in the PROKR2 gene (<a href="/entry/607123#0001">607123.0001</a>), raising the possibility of digenic inheritance. <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="#46" class="mim-tip-reference" title="Trarbach, E. B., Costa, E. M. F., Versiani, B., de Castro, M., Baptista, M. T. M., Garmes, H. M., de Mendonca, B. B., Latronico, A. C. &lt;strong&gt;Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.&lt;/strong&gt; J. Clin. Endocr. Metab. 91: 4006-4012, 2006. Note: Erratum: J. Clin. Endocr. Metab. 93: 2013 only, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16882753/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16882753&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2005-2793&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16882753">Trarbach et al. (2006)</a> investigated 80 Brazilian patients with isolated hypogonadotropic hypogonadism (IHH), 46 of whom had olfactory abnormalities, for mutations in the KAL1 and FGFR1 genes. Two novel mutations in the KAL1 gene were found among the 46 patients with Kallmann syndrome (<a href="/entry/300386#0013">300386.0013</a> and <a href="/entry/300386#0014">300386.0014</a>). Eight novel FGFR1 mutations were found in 8 patients with Kallmann syndrome and in 1 with IHH and normal olfactory status. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16882753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Possible Association with Functional Hypothalamic Amenorrhea in Carrier Females</em></strong></p><p>
<a href="#8" class="mim-tip-reference" title="Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., Seminara, S. B., Boepple, P. A., Sidis, Y., Crowley, W. F., Jr., Martin, K. A., Hall, J. E., Pitteloud, N. &lt;strong&gt;A genetic basis for functional hypothalamic amenorrhea.&lt;/strong&gt; New Eng. J. Med. 364: 215-225, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21247312/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21247312&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21247312[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa0911064&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21247312">Caronia et al. (2011)</a> studied 55 women with functional hypothalamic amenorrhea, who had all completed puberty spontaneously and had a history of secondary amenorrhea for 6 months or more, with low or normal gonadotropin levels and low serum estradiol levels. All had 1 or more predisposing factors, including excessive exercise, loss of more than 15% of body weight, and/or a subclinical eating disorder, and all had normal results on neuroimaging. The authors screened 7 HH-associated genes in the 55 affected women and identified 7 patients from 6 families who carried heterozygous mutations, including 1 in KAL1, 2 in FGFR1, 2 in PROKR2, and 1 in the GNRHR gene. Since these women with mutations resumed regular menses after discontinuing hormone-replacement therapy, <a href="#8" class="mim-tip-reference" title="Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., Seminara, S. B., Boepple, P. A., Sidis, Y., Crowley, W. F., Jr., Martin, K. A., Hall, J. E., Pitteloud, N. &lt;strong&gt;A genetic basis for functional hypothalamic amenorrhea.&lt;/strong&gt; New Eng. J. Med. 364: 215-225, 2011.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/21247312/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;21247312&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=21247312[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa0911064&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="21247312">Caronia et al. (2011)</a> concluded that the genetic component of hypothalamic amenorrhea predisposes patients to, but is not sufficient to cause, GnRH deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21247312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#37" class="mim-tip-reference" title="Quinton, R., Duke, V. M., de Zoysa, P. A., Platts, A. D., Valentine, A., Kendall, B., Pickman, S., Kirk, J. M. W., Besser, G. M., Jacobs, H. S., Bouloux, P. M. G. &lt;strong&gt;The neuroradiology of Kallmann&#x27;s syndrome: a genotypic and phenotypic analysis.&lt;/strong&gt; J. Clin. Endocr. Metab. 81: 3010-3017, 1996. Note: Erratum: J. Clin. Endocr. Metab. 81: 3614 only, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8768867/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8768867&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.81.8.8768867&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8768867">Quinton et al. (1996)</a> performed detailed neurologic examinations of Kallmann syndrome subjects for phenotype-genotype correlation. They studied 27 Kallmann syndrome subjects, including 12 males with X-linked disease and 3 females; 6 male and 2 female normosmics with isolated GnRH (<a href="/entry/152760">152760</a>) deficiency; 1 male with a KMS variant; and 1 obligate female carrier. Evidence for X-linked disease came from pedigree analysis and mutation analysis of the KAL locus. All 8 normosmics, 3 males with KMS, and the female carrier had normal olfactory bulbs and sulci. Three new mutations at the KAL locus were identified, including 2 single exon deletions and 1 point mutation. No coding sequence mutations were found in 2 pedigrees with clear X-linked inheritance, suggesting that these cases may be due to mutations in pKAL, the 5-prime promoter region. No clear phenotype-genotype relationship was made between specific phenotypic anomalies and KAL mutations. Involuntary mirror movements of the upper limbs were present in 10 of 12 cases of X-linked KMS but in none of the other subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8768867" 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 a mental or intellectual disturbance was described in the original report of Kallmann syndrome (<a href="#20" class="mim-tip-reference" title="Kallmann, F. J., Schoenfeld, W. A., Barrera, S. E. &lt;strong&gt;The genetic aspects of primary eunuchoidism.&lt;/strong&gt; Am. J. Ment. Defic. 48: 203-236, 1944."None>Kallmann et al., 1944</a>), analyses of the genotype-phenotype relationship showed that Kallmann syndrome patients with mental disorders have large deletions on Xp22.3 that extend beyond the KAL1 locus (<a href="#28" class="mim-tip-reference" title="Nagata, K., Yamamoto, T., Chikumi, H., Ikeda, T., Yamamoto, H., Hashimoto, K., Yoneda, K., Nanba, E., Ninomiya, H., Ishitobi, K. &lt;strong&gt;A novel interstitial deletion of KAL1 in a Japanese family with Kallmann syndrome.&lt;/strong&gt; J. Hum. Genet. 45: 237-240, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10944855/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10944855&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s100380070033&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10944855">Nagata et al., 2000</a>). In contrast, almost all patients with mutations restricted to the KAL1 locus are free of mental disturbance. <a href="#36" class="mim-tip-reference" title="Prager, D., Braunstein, G. D. &lt;strong&gt;X-chromosome-linked Kallmann&#x27;s syndrome: pathology at the molecular level.&lt;/strong&gt; J. Clin. Endocr. Metab. 76: 824-826, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8473390/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8473390&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jcem.76.4.8473390&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8473390">Prager and Braunstein (1993)</a> speculated that another gene located close to KAL1 is responsible for the mental disturbance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10944855+8473390" 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="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. &lt;strong&gt;Kallmann&#x27;s syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations.&lt;/strong&gt; J. Clin. Endocr. Metab. 93: 758-763, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18160472/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18160472&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2007-1168&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18160472">Salenave et al. (2008)</a> studied the endocrine features reflecting gonadotropic-testicular axis function in 39 men; 21 had mutations in KAL1 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 (CHH). Three with FGFR1 (KAL2) mutations had normal puberty, were eugonadal, and had normal testosterone and gonadotropin levels. Cryptorchidism was more frequent and testicular volume was smaller in CHH 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 CHH subjects with KAL1 mutations and 7 subjects with FGFR1/KAL2 mutations; LH secretion was nonpulsatile in all the subjects, but mean LH levels were lower in those with KAL1 mutations. <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>
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<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>See Also:</strong>
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<a href="#Henkin1967" class="mim-tip-reference" title="Henkin, R. I. &lt;strong&gt;Abnormalities of taste and olfaction in patients with chromatin negative gonadal dysgenesis.&lt;/strong&gt; J. Clin. Endocr. 27: 1436-1440, 1967.">Henkin (1967)</a>; <a href="#Rowe1983" class="mim-tip-reference" title="Rowe, R. C., Schroeder, M.-L., Faiman, C. &lt;strong&gt;Testosterone-induced fertility in a patient with previously untreated Kallmann&#x27;s syndrome.&lt;/strong&gt; Fertil. Steril. 40: 400-401, 1983.">Rowe et al. (1983)</a>
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<a id="references"class="mim-anchor"></a>
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<strong>REFERENCES</strong>
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<a id="Ballabio1986" class="mim-anchor"></a>
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Ballabio, A., Parenti, G., Tippett, P., Mondello, C., Di Maio, S., Tenore, A., Andria, G.
<strong>X-linked ichthyosis, due to steroid sulphatase deficiency, associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia): linkage relationships with Xg and cloned DNA sequences from the distal short arm of the X chromosome.</strong>
Hum. Genet. 72: 237-240, 1986.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3007328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3007328</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3007328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00291885" target="_blank">Full Text</a>]
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<a id="Ballabio1993" class="mim-anchor"></a>
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Ballabio, A.
<strong>Personal Communication.</strong>
Houston, Texas 3/11/1993.
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<a id="Bardin1969" class="mim-anchor"></a>
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Bardin, C. W., Ross, G. T., Rifkind, A. B., Cargille, C. M., Lipsett, M. B.
<strong>Studies of the pituitary Leydig cell axis in young men with hypogonadotropic hypogonadism and hyposmia: comparison with normal men, prepubertal boys, and hypo-pituitary patients.</strong>
J. Clin. Invest. 48: 2046-2056, 1969.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4390462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4390462</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4390462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1172/JCI106170" target="_blank">Full Text</a>]
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<a id="Bick1989" class="mim-anchor"></a>
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Bick, D., Curry, C. J. R., McGill, J. R., Schorderet, D. F., Bux, R. C., Moore, C. M.
<strong>Male infant with ichthyosis, Kallmann syndrome, chondrodysplasia punctata, and an Xp chromosome deletion.</strong>
Am. J. Med. Genet. 33: 100-107, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2750777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2750777</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2750777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320330114" target="_blank">Full Text</a>]
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<a id="Bick1992" class="mim-anchor"></a>
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Bick, D., Franco, B., Sherins, R. J., Heye, B., Pike, L., Crawford, J., Maddalena, A., Incerti, B., Pragliola, A., Meitinger, T., Ballabio, A.
<strong>Brief report: intragenic deletion of the KALIG-1 gene in Kallmann's syndrome.</strong>
New Eng. J. Med. 326: 1752-1755, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1594017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1594017</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1594017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199206253262606" target="_blank">Full Text</a>]
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<a id="Bick1989" class="mim-anchor"></a>
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Bick, D. P., Schwanzel-Fukuda, M., Pfaff, D. W., Schorderet, D. F., Price, P. A., Campbell, L., Huff, R. W., Moore, C. M.
<strong>Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata, ichthyosis and Kallmann syndrome due to an Xp deletion: evidence for a neuronal migration defect in Kallmann syndrome. (Abstract)</strong>
Am. J. Hum. Genet. 45 (suppl.): A252, 1989.
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<a id="Birnbacher1994" class="mim-anchor"></a>
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Birnbacher, R., Wandl-Vergesslich, K., Frisch, H.
<strong>Diagnosis of X-recessive Kallmann syndrome in early infancy: evidence of hypoplastic rhinencephalon.</strong>
Europ. J. Pediat. 153: 245-247, 1994.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8194555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8194555</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8194555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF01954511" target="_blank">Full Text</a>]
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<a id="Caronia2011" class="mim-anchor"></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.
<strong>A genetic basis for functional hypothalamic amenorrhea.</strong>
New Eng. J. Med. 364: 215-225, 2011.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21247312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21247312</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21247312[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21247312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa0911064" target="_blank">Full Text</a>]
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<a id="De Morsier1954" class="mim-anchor"></a>
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De Morsier, G.
<strong>Etudes sur les dysraphies cranio-encephaliques. I. Agenesie des lobes olfactifs (telencephaloschizis lateral) et des commissures calleuse et anterieure (telencephaloschizis median): la dysplasie olfacto-genitale.</strong>
Schweiz. Arch. Neurol. Psychiat. 74: 309-361, 1954.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14385744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14385744</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14385744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Dode2003" class="mim-anchor"></a>
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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://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12627230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng1122" target="_blank">Full Text</a>]
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<a id="Dode2006" class="mim-anchor"></a>
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Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P.
<strong>Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.</strong>
PLoS Genet. 2: e175, 2006. Note: Electronic Article.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17054399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17054399</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17054399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1371/journal.pgen.0020175" target="_blank">Full Text</a>]
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<a id="Georgopoulos1997" class="mim-anchor"></a>
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Georgopoulos, N. A., Pralong, F. P., Seidman, C. E., Seidman, J. G., Crowley, W. F., Jr., Vallejo, M.
<strong>Genetic heterogeneity evidenced by low incidence of KAL-1 gene mutations in sporadic cases of gonadotropin-releasing hormone deficiency.</strong>
J. Clin. Endocr. Metab. 82: 213-217, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8989261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8989261</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8989261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem.82.1.3692" target="_blank">Full Text</a>]
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<a id="Guioli1992" class="mim-anchor"></a>
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Guioli, S., Incerti, B., Zanaria, E., Bardoni, B., Franco, B., Taylor, K., Ballabio, A., Camerino, G.
<strong>Kallmann syndrome due to a translocation resulting in an X/Y fusion gene.</strong>
Nature Genet. 1: 337-340, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302031</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng0892-337" target="_blank">Full Text</a>]
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<a id="Hardelin1993" class="mim-anchor"></a>
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Hardelin, J.-P., Levilliers, J., Blanchard, S., Carel, J.-C., Leutenegger, M., Pinard-Bertelletto, J.-P., Bouloux, P., Petit, C.
<strong>Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome.</strong>
Hum. Molec. Genet. 2: 373-377, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8504298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8504298</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8504298" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/2.4.373" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.89.17.8190" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem-27-10-1436" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1985.tb00368.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.27.3.198" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/pgmj.42.491.572" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.33442" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1994.tb04238.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.52.4.816" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archinte.131.4.501" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2002-021981" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1365-2265.1998.00406.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s100380070033" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.35.7.1059" 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/10.1210/jcem-65-5-1060" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320570323" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320260226" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.87.10.3680" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.76.4.8473390" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.81.8.8768867" target="_blank">Full Text</a>]
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New Eng. J. Med. 357: 863-873, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17761590/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17761590</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17761590" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJMoa066494" target="_blank">Full Text</a>]
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<a id="39" class="mim-anchor"></a>
<a id="Rogol1980" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Rogol, A., Mittal, K., White, B. J., McGinnis, M. H., Lieblich, J. M., Rosen, S. W.
<strong>HLA-compatible paternity in two 'fertile eunuchs' with congenital hypogonadotrophic hypogonadism and anosmia (the Kallmann syndrome).</strong>
J. Clin. Endocr. Metab. 51: 275-279, 1980.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6772660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6772660</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6772660" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem-51-2-275" target="_blank">Full Text</a>]
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<a id="Rowe1983" class="mim-anchor"></a>
<div class="">
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Rowe, R. C., Schroeder, M.-L., Faiman, C.
<strong>Testosterone-induced fertility in a patient with previously untreated Kallmann's syndrome.</strong>
Fertil. Steril. 40: 400-401, 1983.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6411501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6411501</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6411501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0015-0282(16)47310-3" target="_blank">Full Text</a>]
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<a id="Salenave2008" class="mim-anchor"></a>
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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://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'})">related citations</a>]
[<a href="https://doi.org/10.1210/jc.2007-1168" target="_blank">Full Text</a>]
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<a id="Sato2004" class="mim-anchor"></a>
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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://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'})">related citations</a>]
[<a href="https://doi.org/10.1210/jc.2003-030476" target="_blank">Full Text</a>]
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<a id="Schroffner1970" class="mim-anchor"></a>
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Schroffner, W. G., Furth, E. D.
<strong>Hypogonadotropic hypogonadism with anosmia (Kallmann's syndrome) unresponsive to clomiphene citrate.</strong>
J. Clin. Endocr. 31: 267-270, 1970.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5453324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5453324</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5453324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jcem-31-3-267" target="_blank">Full Text</a>]
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<a id="Schwanzel-Fukuda1989" class="mim-anchor"></a>
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Schwanzel-Fukuda, M., Bick, D., Pfaff, D. W.
<strong>Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome.</strong>
Brain Res. Molec. Brain Res. 6: 311-326, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2687610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2687610</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2687610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0169-328x(89)90076-4" target="_blank">Full Text</a>]
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<a id="Sparkes1968" class="mim-anchor"></a>
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Sparkes, R. S., Simpson, R. W., Paulsen, C. A.
<strong>Familial hypogonadotropic hypogonadism with anosmia.</strong>
Arch. Intern. Med. 121: 534-538, 1968.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5652405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5652405</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5652405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="46" class="mim-anchor"></a>
<a id="Trarbach2006" class="mim-anchor"></a>
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Trarbach, E. B., Costa, E. M. F., Versiani, B., de Castro, M., Baptista, M. T. M., Garmes, H. M., de Mendonca, B. B., Latronico, A. C.
<strong>Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.</strong>
J. Clin. Endocr. Metab. 91: 4006-4012, 2006. Note: Erratum: J. Clin. Endocr. Metab. 93: 2013 only, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882753</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16882753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jc.2005-2793" target="_blank">Full Text</a>]
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<a id="47" class="mim-anchor"></a>
<a id="Wegenke1975" class="mim-anchor"></a>
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<p class="mim-text-font">
Wegenke, J. D., Uehling, D. T., Wear, J. B., Jr., Gordon, E. S., Bargman, G. J., 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://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1080088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.1975.tb00344.x" target="_blank">Full Text</a>]
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<a id="48" class="mim-anchor"></a>
<a id="Wray1989" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wray, S., Grant, P., Gainer, H.
<strong>Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode.</strong>
Proc. Nat. Acad. Sci. 86: 8132-8136, 1989.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2682637/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2682637</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2682637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.86.20.8132" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 04/06/2017
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Marla J. F. O'Neill - updated : 02/09/2016<br>Marla J. F. O'Neill - updated : 2/26/2013<br>Marla J. F. O'Neill - updated : 9/25/2012<br>John A. Phillips, III - updated : 4/27/2009<br>John A. Phillips, III - updated : 7/13/2007<br>George E. Tiller - updated : 5/22/2007<br>Victor A. McKusick - updated : 11/21/2006<br>John A. Phillips, III - updated : 3/31/2005<br>John A. Phillips, III - updated : 7/21/2004<br>John A. Phillips, III - updated : 4/8/2003<br>Victor A. McKusick - updated : 3/19/2003<br>Victor A. McKusick - updated : 6/6/2002<br>Stylianos E. Antonarakis - updated : 5/3/2002<br>John A. Phillips, III - updated : 11/8/2001<br>Victor A. McKusick - updated : 8/31/2000<br>Orest Hurko - updated : 6/14/1999<br>Victor A. McKusick - updated : 10/8/1998<br>John A. Phillips, III - updated : 7/16/1998<br>Victor A. McKusick - updated : 9/12/1997<br>John A. Phillips, III - updated : 1/18/1997<br>John A. Phillips, III - updated : 9/22/1996<br>Iosif W. Lurie - updated : 9/7/1996<br>Moyra Smith - updated : 9/6/1996
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Creation Date:
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Victor A. McKusick : 6/4/1986
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alopez : 08/09/2023
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carol : 03/08/2022<br>carol : 12/23/2019<br>carol : 04/06/2017<br>carol : 02/09/2016<br>carol : 12/30/2013<br>carol : 3/26/2013<br>carol : 2/26/2013<br>carol : 10/1/2012<br>carol : 9/28/2012<br>carol : 9/27/2012<br>carol : 9/25/2012<br>terry : 9/7/2012<br>terry : 8/8/2012<br>alopez : 3/10/2011<br>alopez : 3/10/2011<br>mgross : 11/9/2009<br>carol : 7/14/2009<br>terry : 7/14/2009<br>alopez : 4/27/2009<br>carol : 10/31/2008<br>alopez : 7/13/2007<br>wwang : 5/30/2007<br>terry : 5/22/2007<br>carol : 12/5/2006<br>terry : 11/21/2006<br>alopez : 3/31/2005<br>alopez : 7/21/2004<br>terry : 6/3/2004<br>carol : 3/17/2004<br>tkritzer : 4/15/2003<br>tkritzer : 4/11/2003<br>terry : 4/8/2003<br>alopez : 4/2/2003<br>alopez : 3/20/2003<br>terry : 3/19/2003<br>mgross : 6/10/2002<br>terry : 6/6/2002<br>mgross : 5/3/2002<br>alopez : 11/8/2001<br>alopez : 11/8/2001<br>mcapotos : 9/18/2000<br>mcapotos : 9/11/2000<br>terry : 8/31/2000<br>carol : 9/10/1999<br>terry : 6/16/1999<br>terry : 6/14/1999<br>terry : 6/14/1999<br>terry : 6/14/1999<br>carol : 10/13/1998<br>carol : 10/12/1998<br>terry : 10/8/1998<br>carol : 7/20/1998<br>dholmes : 7/17/1998<br>dholmes : 7/16/1998<br>terry : 12/11/1997<br>mark : 9/22/1997<br>terry : 9/12/1997<br>jenny : 6/3/1997<br>jenny : 5/28/1997<br>jenny : 5/27/1997<br>jenny : 5/27/1997<br>carol : 9/22/1996<br>randy : 9/7/1996<br>mark : 9/6/1996<br>carol : 8/16/1996<br>mark : 1/19/1996<br>mark : 10/23/1995<br>davew : 7/6/1994<br>jason : 6/28/1994<br>carol : 5/31/1994<br>warfield : 4/20/1994<br>mimadm : 4/14/1994
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<strong>#</strong> 308700
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HYPOGONADOTROPIC HYPOGONADISM 1 WITH OR WITHOUT ANOSMIA; HH1
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<em>Alternative titles; symbols</em>
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KALLMANN SYNDROME 1; KAL1<br />
KMS<br />
HYPOGONADOTROPIC HYPOGONADISM AND ANOSMIA; HHA<br />
DYSPLASIA OLFACTOGENITALIS OF DE MORSIER<br />
ANOSMIC HYPOGONADISM
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<strong>SNOMEDCT:</strong> 93559003; &nbsp;
<strong>ICD10CM:</strong> E23.0; &nbsp;
<strong>ORPHA:</strong> 432, 478; &nbsp;
<strong>DO:</strong> 0090094; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
Xp22.31
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Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1)
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308700
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X-linked recessive
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3
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ANOS1
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300836
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because hypogonadotropic hypogonadism-1 with or without anosmia (HH1) is caused by mutation in the KAL1 gene (ANOS1; 300836) on chromosome Xp22.3, sometimes in association with mutation in another gene, e.g., PROKR2 (607123).</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.' </p><p>For information on the autosomal forms of hypogonadotropic hypogonadism with or without anosmia, see 147950.</p>
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<strong>Clinical Features</strong>
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<p>Males with Kallmann syndrome show anosmia due to agenesis of the olfactory lobes, and hypogonadism secondary to deficiency of hypothalamic gonadotropin-releasing hormone (see GNRH1, 152760). In the course of molecular genetic studies of X-linked Kallmann syndrome, Hardelin et al. (1992) found instances of renal agenesis and also pointed to mirror movements of the hands (bimanual synkinesia), pes cavus, high-arched palate, and cerebellar ataxia. Synkinesia, which is one of the more frequent findings, may be attributable to lack of inhibitory fibers connecting the 2 hemispheres through the corpus callosum (Nass, 1985). Colorblindness was also segregating in families described by Kallmann et al. (1944); however, the information was too limited to give conclusive evidence on possible X-linkage of this syndrome. </p><p>De Morsier (1954) collected 28 reported cases of agenesis of the olfactory lobes in which complete autopsy was performed and found that abnormalities of the sexual organs, mainly cryptorchidism and testicular atrophy, had been noted in 14. He suggested that the genital atrophy is secondary to involvement of the hypothalamus as well as the olfactory lobes. </p><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 (see 147950). Anosmia must be inquired about in cases of hypogonadism since patients rarely volunteer the information. Indeed, the patient is sometimes unaware of anosmia so that tests are necessary. Pittman (1966) found anosmia in 16 of 28 cases of hypogonadotropic hypogonadism. </p><p>Ballabio (1993) reported the consensus from an NIH conference on Kallmann syndrome that no patient of molecularly confirmed X-linked Kallmann syndrome has intact smell. In a single family, 1 brother was hyposmic and had normal gonadal development, whereas 2 brothers and 2 maternal cousins had the full-blown Kallmann syndrome phenotype. There was agreement that the intrafamilial variability of the phenotype in the autosomal forms of Kallmann syndrome (for which no molecular test is available) is extensive. Several families have been described in which affected individuals have either hypogonadism or anosmia or both. On the contrary, in the X-linked families, the phenotype seems to be consistent within families.</p><p>Males et al. (1973) studied 6 unrelated subjects, 5 males and 1 female, with hypogonadism and anosmia. All the males had small genitals and decreased sexual hair. Gynecomastia and eunuchoid habitus were seen in 4. All 6 had a radiographically normal sella turcica. Testicular biopsies of the males showed decreased numbers of germ cells and a spermatogenic state at the primary spermatocyte stage. Leydig cells were not histologically identifiable. The affected female had 2 brothers with anosmia and hypogonadism. Urine gonadotropins were low in the 2 patients tested. Basal urinary 17-hydroxycorticosteroids were normal in those tested. A metyrapone test suggested low levels of ACTH in 2. One male patient at operation showed agenesis of the olfactory bulbs and tracts. The authors stated that the Kallmann syndrome is probably the expression of a disorder of hypothalamic regulation involving the control of those releasing factors needed for effective pituitary function. Additionally, it is interesting to note that there is some evidence for a relationship between olfactory acuity (perhaps to detect pheromones) and the gonadal and adrenal system in laboratory test animals. </p><p>Unilateral renal agenesis has been described in several patients with Kallmann syndrome (Wegenke et al., 1975; Hermanussen and Sippell, 1985). Kirk et al. (1994) reported a systematic study of kidneys in 17 affected persons from 6 families with Kallmann syndrome, including a family with an association of Kallmann syndrome and ichthyosis and interstitial deletion within the short arm of the X chromosome. Unilateral renal agenesis was found in 6 males in 4 families. Moreover, in 2 families (including a family in which all 4 patients demonstrated normal kidneys), there were male infants who died with bilateral renal agenesis. In the family with an association of Kallmann syndrome and ichthyosis, unilateral renal agenesis was found in 2 of 4 affected persons, although all 4 had the same X-chromosome deletion. Presumably, normal renal development requires expression of the Kallmann product (Kalig1/AMDLX), but mutation or absence of this product is not invariably associated with renal agenesis. </p><p>Birnbacher et al. (1994) made the diagnosis of X-linked Kallmann syndrome in a 3-month-old infant who presented with hypogonadism, a small penis, and bilateral cryptorchidism. He showed an inadequate response of luteinizing hormone and follicle stimulating hormone to the administration of luteinizing hormone-releasing hormone (LHRH; 152760) and of testosterone to human chorionic gonadotropin. A maternal uncle had hypogonadism and anosmia and also showed an impaired LH (152780) and FSH (136530) response to LHRH. MRI showed hypoplasia of the rhinencephalon in both cases. </p><p>Massin et al. (2003) described clinical heterogeneity in 3 brothers with Kallmann syndrome who carried a large deletion in the KAL1 gene (300386.0011). All 3 had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain MRI showed hypoplastic olfactory bulbs in the 3 sibs, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e., unilateral renal aplasia (sibs B and C), high-arched palate (sib A), brachymetacarpalia (sib A), mirror movements (sibs A and B), and abnormal eye movements (sib C). Sib A suffered from a severe congenital hearing impairment, a feature that had been reported in Kallmann syndrome but had not yet been ascribed unambiguously to the X-linked form of the disease. The authors concluded that the variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of X-linked Kallmann syndrome. </p><p>Dode et al. (2003) stated that bimanual synkinesia had been observed in 75% of X-linked Kallmann syndrome cases; they described bimanual synkinesia, i.e., mirror movements of the hands, in 2 affected members in a family with an autosomal dominant form of Kallmann syndrome (HH2; 147950). Highly arched palate, which can be regarded as a mild anomaly of palatal fusion, is a common feature of KAL1. Dode et al. (2003) found cleft palate or cleft lip in several individuals with HH2. </p><p>Kaplan et al. (2010) studied 5 patients with features of Kallmann syndrome and reviewed reported patients. Noting that the diagnosis can be difficult to make before puberty, they suggested that it should be considered when a patient presents a combination of features that includes microphallus, cryptorchidism, hearing loss, renal agenesis, and oral clefting or dental agenesis. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Biochemical Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Bardin et al. (1969) concluded that patients with Kallmann syndrome have a defect in both pituitary and Leydig cell function. They demonstrated impaired secretion of FSH and LH and thought there to be Leydig cell insensitivity to gonadotropin. Treatment with chorionic gonadotropin can correct cryptorchidism and establish fertility, even in adult males. Schroffner and Furth (1970) found failure of response to clomiphene, as measured by plasma levels of gonadotropins. </p><p>With respect to neuroendocrine phenotype, Oliveira et al. (2001) observed that 8 Kallmann syndrome men with documented KAL1 (300836) mutations had completely apulsatile LH secretion, whereas those with autosomal modes of inheritance demonstrated a more variable spectrum with evidence of enfeebled (but present) GnRH-induced LH pulses. They concluded that patients with KAL1 mutations have apulsatile LH secretion consistent with a complete absence of GnRH migration of GnRH cells into the hypothalamus, whereas evidence of enfeebled GnRH-induced LH pulses may be present in autosomal Kallmann syndrome cases. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Sparkes et al. (1968) described X-linked inheritance of hypogonadotropic hypogonadism with anosmia in 2 brothers and their half sister. The 3 affected sibs had the same mother who, despite having minor signs of the disorder (late menarche and irregular menses), had 9 liveborn children. The affected girl had no menses or breast development at age 18 and her ovaries were histologically exactly like those of the fetus. The father had anosmia. This may have been an autosomal recessive form with heterozygous expression in the father or an autosomal dominant form (see 147950). </p><p>Hermanussen and Sippell (1985) reported a presumably X-linked recessive kindred. All carrier females had normal sexual and olfactory function. Hipkin et al. (1990) described male twins who were identical by DNA fingerprinting; one had full-blown manifestations of Kallmann syndrome, whereas the other showed normal sexual development and only hyposmia. In a second family, Hermanussen and Sippell (1985) observed 16-year-old twin sisters of whom one had retarded pubertal development and total anosmia, and the other, proven to be monozygotic by blood grouping and HLA typing, had undergone a normal menarche but showed total anosmia. The authors pointed out that sporadic cases of Kallmann syndrome have appeared only in families in which isolated anosmia (see 301700, 107200) is present. They suggested that there is an acquired hypothalamic GnRH deficiency on the basis of preexisting anosmia. </p><p>Oliveira et al. (2001) observed that of their X-linked cases confirmed by mutation analysis, only 1 of 3 pedigrees appeared X-linked by inspection, whereas the other 2 contained only affected brothers. Female members of 3 known KAL1 mutation families exhibited no reproductive phenotype and were not anosmic, whereas 3 families with anosmic women were not found to carry KAL1 mutations. The authors concluded that obligate female carriers in families with KAL1 mutations have no discernible phenotype. </p>
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<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Population Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Pawlowitzki et al. (1987) attempted to estimate the frequency of the Kallmann syndrome, which they referred to by the acronym HHA for hypogonadotropic hypogonadism and anosmia. Among 791 hypogonadal males, they found 19 persons with HHA. They reported that HHA is about one-tenth as common as the Klinefelter syndrome. Among 24 patients presenting with anosmia, they found one hitherto undiagnosed case of HHA. </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Clinical Management</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>The mean age at diagnosis in the patients of Pawlowitzki et al. (1987) and in those reported in the literature was 24.8 and 24.9 years, respectively. Since therapeutic success with substitution therapy, leading to endogenous sex-steroid secretion and even reproduction, is probably age dependent (Rogol et al., 1980), early diagnosis is important. In a 28-year-old man with Kallmann syndrome, Oppermann et al. (1987) caused the induction and maintenance of spermatogenesis and biologic paternity by intranasal administration of gonadotropin-releasing hormone (152760) in low dose. </p>
</span>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Cytogenetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Guioli et al. (1992) described a patient with Kallmann syndrome who carried an X;Y translocation resulting from abnormal pairing and recombination between the X-linked Kallmann syndrome gene and its homolog on the Y. The translocation created a recombinant, nonfunctional KAL gene identical to the normal X-linked gene with the exception of the 3-prime end that was derived from the Y. The findings indicated that the 3-prime portion of the Kallmann syndrome gene is essential for its function and cannot be substituted by the Y-derived homologous region, although a 'position effect' remained a formal possibility. </p><p>Maya-Nunez et al. (1998) described a contiguous gene syndrome due to deletion of the first 3 exons of the KAL1 gene and complete deletion of the steroid sulfatase gene (300747). The 20-year-old subject had hypogonadism, anosmia, and generalized ichthyosis. They found reports of complete deletion of both the STS and the KAL genes in 6 families, and 1 previous description of 3 sibs with complete deletion of the STS gene and partial deletion of the KAL gene. The KAL gene is proximal to the STS gene, with its 3-prime end oriented toward the telomere. It was therefore surprising that the 5-prime end of the KAL gene was deleted. This was said to be the first report of a deletion (or a point mutation) in this region of the KAL gene. The involvement of the conserved cysteine-rich N-terminal region which corresponds to the whey acidic protein motif of the KAL gene demonstrated the importance of this specific region for the function of the gene. </p><p>In a clinical assessment and molecular analysis of KAL1 and FGFR1 (136350, mutations in which cause KS (HH2), 147950) in 28 patients with Kallmann syndrome, Sato et al. (2004) found submicroscopic deletions at Xp22.3 involving VCXA (300533), STS (300747), KAL1, and OA1 (300808) in 3 familial cases and 1 sporadic male case affected by a contiguous gene syndrome. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Bick et al. (1989) described a male infant with the combination of ichthyosis, Kallmann syndrome, and chondrodysplasia punctata as a contiguous gene syndrome due to deletion of the terminal part of Xp, with the breakpoint at Xp22.31. The mother showed the same deletion of one X chromosome. Bick et al. (1989) studied an 18-week-old male fetus from this mother affected with the deletion syndrome (contiguous gene syndrome) that included steroid sulfatase deficiency, chondrodysplasia punctata, and Kallmann syndrome. The olfactory bulbs and tracts were absent and a horseshoe kidney was found. Wray et al. (1989) presented results of studies in the mouse supporting the hypothesis that all luteinizing-hormone-releasing hormone (LHRH) cells in the central nervous system arise from a discrete group of progenitor cells in the olfactory placode and that a subpopulation of these cells migrate into forebrain areas where they subsequently establish an adult-like distribution. During normal embryologic development, the olfactory placode in the nose gives rise to the olfactory nerve and nervus terminalis. LHRH-secreting cells of the hypothalamus arise from the nervus terminalis and migrate from the nose through the cribriform plate along the olfactory tract to the hypothalamus. In the aborted fetus, Bick et al. (1989) showed by immunocytochemical analysis that the LHRH-immunoreactive cells and the olfactory nerve failed to reach their normal position, ending prematurely at the meninges. Absence of LHRH-secreting cells in the hypothalamus explains the deficiency of this hormone in Kallmann syndrome. Failure of the olfactory nerve to induce the formation of the olfactory bulb and tract explains the absence of the latter structures. Thus, Bick et al. (1989) appear to have demonstrated that Kallmann syndrome is a defect in neuronal migration. See also Schwanzel-Fukuda et al. (1989). </p><p>Krams et al. (1999) used a quantitative MRI protocol to determine if the mirror movements characteristic of X-linked Kallmann syndrome result from loss of transcallosal inhibition, as proposed by Nass (1985), or from an abnormal ipsilateral corticospinal tract, as suggested by electrophysiologic studies. Volumetric comparisons were made of men with X-linked Kallmann syndrome, all of whom had mirror movements, with normal controls, and men with autosomal Kallmann syndrome (147950, 244200), which is not associated with mirror movements. Bilateral hypertrophy of the corticospinal tracts was found in the X-linked patients only. Hypertrophy of the corpus callosum was found in both the X-linked and autosomal Kallmann syndrome patients. The findings of Krams et al. (1999) supported the hypothesis that the mirror movements seen in X-linked Kallmann syndrome result from abnormal development of ipsilateral corticospinal tracts. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Ballabio et al. (1986) studied a large Italian pedigree in which 5 males had a syndrome, following a pattern of X-linked inheritance, characterized by steroid sulfatase-deficient ichthyosis (308100) and Kallmann syndrome. No crossing-over with Xg or with the probe DXS143 was found. No evidence of deletion was found in the probe studies. Thus, the Kallmann locus appears to be in the distal region of Xp, although Ballabio et al. (1986) did not reject the possibility that the Kallmann syndrome in their family was due to an allele at the STS locus. By linkage to the hypervariable repeat sequence CRI-S232 (DXS278), Meitinger et al. (1990) narrowed the location of the KAL1 gene to Xp22.3; maximum lod score = 6.5 at theta = 0.03. Using pulsed field gel analysis of DNAs from patients with terminal deletions of Xp, Petit et al. (1990) mapped the Kallmann syndrome locus to a deletion interval of 350 kb at most, located between 8,600 and 8,950 kb from Xpter. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>In a patient and his brother with Kallmann syndrome, Bick et al. (1992) detected a 3,300-bp deletion in the KAL1 gene (300836.0001). </p><p>Hardelin et al. (1993) reported results of a mutation search of the KAL gene (300836) in 21 unrelated males with familial Kallmann syndrome. In 2 families, large Xp22.3 deletions that included the entire KAL gene were detected by Southern blot analysis. By sequencing each of the 14 coding exons and splice site junctions in the other 19 patients, they found 9 point mutations at separate locations in 4 exons and 1 splice site. They emphasized the high frequency of unilateral renal aplasia in X-linked Kallmann patients; 6 of 11 males with identified alterations of the KAL gene showed this feature. </p><p>Parenti et al. (1995) reported the cases of 3 brothers with X-linked ichthyosis and variable expression of Kallmann syndrome. All 3 had the same deletion, which spared the first exon of the KAL1 gene; however, 1 brother had only mild hyposomia and normal pubertal progression, whereas the others were severely affected. The reason for the variability was unclear. </p><p>Georgopoulos et al. (1997) determined the frequency of KAL1 gene mutations in subjects with sporadic GNRH deficiency. Only 1 of 21 (5%) with sporadic GNRH deficiency had a KAL1 gene mutation (a deletion of 14 bases starting at codon 464). In each of 3 different patients with an X-linked mode of inheritance, 3 mutations were detected. These were a single-base substitution introducing a stop codon at position 328, another encoding a phe517-to-leu substitution and a 9-base deletion at the 3-prime exon-intron splice site of exon 8. These data indicated that the incidence of mutations in the coding region of the KAL1 gene in patients with sporadic GNRH deficiency is low. </p><p>Oliveira et al. (2001) examined 101 individuals with idiopathic hypogonadotropic hypogonadism with or without anosmia and their families to determine their modes of inheritance, incidence of KAL1 mutations, genotype-phenotype correlations, and, in a subset of 38 individuals, their neuroendocrine phenotype. Of the 101 patients, 59 had true Kallmann syndrome (hypogonadotropic hypogonadism and anosmia/hyposmia), whereas, in the remaining 42, no anosmia was evident in the patients or their families. Of the 59 Kallmann syndrome patients, 21 were familial and 38 were sporadic cases. Mutations in the coding sequence of KAL1 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>Sato et al. (2004) studied 25 male and 3 female Japanese individuals with Kallmann syndrome aged 10 to 53 years. Ten males were from 5 families, and the remaining 15 males and 3 females were apparently sporadic cases. Sequencing all exons of the KAL1 and FGFR1 (136350) genes showed 6 novel and 2 recurrent intragenic KAL1 mutations in 7 familial and 4 sporadic male cases and 2 novel intragenic FGFR1 mutations in 2 sporadic male cases. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in 2 males and right-side dominant renal lesion in 7 males, in addition to variable degrees of hypogonadotropic hypogonadism in all the 15 males and olfactory dysfunction in 13 males. 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 dental agenesis with perceptive deafness in 1 male each, in addition to a variable extent of hypogonadotropic hypogonadism and olfactory dysfunction. </p><p>Dode et al. (2006) described a patient with Kallmann syndrome who was heterozygous for 2 mutations: one in the KAL1 gene (300836.0012) and the other in the PROKR2 gene (607123.0001), raising the possibility of digenic inheritance. </p><p>Trarbach et al. (2006) investigated 80 Brazilian patients with isolated hypogonadotropic hypogonadism (IHH), 46 of whom had olfactory abnormalities, for mutations in the KAL1 and FGFR1 genes. Two novel mutations in the KAL1 gene were found among the 46 patients with Kallmann syndrome (300386.0013 and 300386.0014). Eight novel FGFR1 mutations were found in 8 patients with Kallmann syndrome and in 1 with IHH and normal olfactory status. </p><p><strong><em>Possible Association with Functional Hypothalamic Amenorrhea in Carrier Females</em></strong></p><p>
Caronia et al. (2011) studied 55 women with functional hypothalamic amenorrhea, who had all completed puberty spontaneously and had a history of secondary amenorrhea for 6 months or more, with low or normal gonadotropin levels and low serum estradiol levels. All had 1 or more predisposing factors, including excessive exercise, loss of more than 15% of body weight, and/or a subclinical eating disorder, and all had normal results on neuroimaging. The authors screened 7 HH-associated genes in the 55 affected women and identified 7 patients from 6 families who carried heterozygous mutations, including 1 in KAL1, 2 in FGFR1, 2 in PROKR2, and 1 in the GNRHR gene. Since these women with mutations resumed regular menses after discontinuing hormone-replacement therapy, Caronia et al. (2011) concluded that the genetic component of hypothalamic amenorrhea predisposes patients to, but is not sufficient to cause, GnRH deficiency. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Genotype/Phenotype Correlations</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Quinton et al. (1996) performed detailed neurologic examinations of Kallmann syndrome subjects for phenotype-genotype correlation. They studied 27 Kallmann syndrome subjects, including 12 males with X-linked disease and 3 females; 6 male and 2 female normosmics with isolated GnRH (152760) deficiency; 1 male with a KMS variant; and 1 obligate female carrier. Evidence for X-linked disease came from pedigree analysis and mutation analysis of the KAL locus. All 8 normosmics, 3 males with KMS, and the female carrier had normal olfactory bulbs and sulci. Three new mutations at the KAL locus were identified, including 2 single exon deletions and 1 point mutation. No coding sequence mutations were found in 2 pedigrees with clear X-linked inheritance, suggesting that these cases may be due to mutations in pKAL, the 5-prime promoter region. No clear phenotype-genotype relationship was made between specific phenotypic anomalies and KAL mutations. Involuntary mirror movements of the upper limbs were present in 10 of 12 cases of X-linked KMS but in none of the other subjects. </p><p>Although a mental or intellectual disturbance was described in the original report of Kallmann syndrome (Kallmann et al., 1944), analyses of the genotype-phenotype relationship showed that Kallmann syndrome patients with mental disorders have large deletions on Xp22.3 that extend beyond the KAL1 locus (Nagata et al., 2000). In contrast, almost all patients with mutations restricted to the KAL1 locus are free of mental disturbance. Prager and Braunstein (1993) speculated that another gene located close to KAL1 is responsible for the mental disturbance. </p><p>Salenave et al. (2008) studied the endocrine features reflecting gonadotropic-testicular axis function in 39 men; 21 had mutations in KAL1 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 (CHH). Three with FGFR1 (KAL2) mutations had normal puberty, were eugonadal, and had normal testosterone and gonadotropin levels. Cryptorchidism was more frequent and testicular volume was smaller in CHH 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 CHH subjects with KAL1 mutations and 7 subjects with FGFR1/KAL2 mutations; LH secretion was nonpulsatile in all the subjects, but mean LH levels were lower in those with KAL1 mutations. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Henkin (1967); Rowe et al. (1983)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Ballabio, A., Parenti, G., Tippett, P., Mondello, C., Di Maio, S., Tenore, A., Andria, G.
<strong>X-linked ichthyosis, due to steroid sulphatase deficiency, associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia): linkage relationships with Xg and cloned DNA sequences from the distal short arm of the X chromosome.</strong>
Hum. Genet. 72: 237-240, 1986.
[PubMed: 3007328]
[Full Text: https://doi.org/10.1007/BF00291885]
</p>
</li>
<li>
<p class="mim-text-font">
Ballabio, A.
<strong>Personal Communication.</strong>
Houston, Texas 3/11/1993.
</p>
</li>
<li>
<p class="mim-text-font">
Bardin, C. W., Ross, G. T., Rifkind, A. B., Cargille, C. M., Lipsett, M. B.
<strong>Studies of the pituitary Leydig cell axis in young men with hypogonadotropic hypogonadism and hyposmia: comparison with normal men, prepubertal boys, and hypo-pituitary patients.</strong>
J. Clin. Invest. 48: 2046-2056, 1969.
[PubMed: 4390462]
[Full Text: https://doi.org/10.1172/JCI106170]
</p>
</li>
<li>
<p class="mim-text-font">
Bick, D., Curry, C. J. R., McGill, J. R., Schorderet, D. F., Bux, R. C., Moore, C. M.
<strong>Male infant with ichthyosis, Kallmann syndrome, chondrodysplasia punctata, and an Xp chromosome deletion.</strong>
Am. J. Med. Genet. 33: 100-107, 1989.
[PubMed: 2750777]
[Full Text: https://doi.org/10.1002/ajmg.1320330114]
</p>
</li>
<li>
<p class="mim-text-font">
Bick, D., Franco, B., Sherins, R. J., Heye, B., Pike, L., Crawford, J., Maddalena, A., Incerti, B., Pragliola, A., Meitinger, T., Ballabio, A.
<strong>Brief report: intragenic deletion of the KALIG-1 gene in Kallmann&#x27;s syndrome.</strong>
New Eng. J. Med. 326: 1752-1755, 1992.
[PubMed: 1594017]
[Full Text: https://doi.org/10.1056/NEJM199206253262606]
</p>
</li>
<li>
<p class="mim-text-font">
Bick, D. P., Schwanzel-Fukuda, M., Pfaff, D. W., Schorderet, D. F., Price, P. A., Campbell, L., Huff, R. W., Moore, C. M.
<strong>Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata, ichthyosis and Kallmann syndrome due to an Xp deletion: evidence for a neuronal migration defect in Kallmann syndrome. (Abstract)</strong>
Am. J. Hum. Genet. 45 (suppl.): A252, 1989.
</p>
</li>
<li>
<p class="mim-text-font">
Birnbacher, R., Wandl-Vergesslich, K., Frisch, H.
<strong>Diagnosis of X-recessive Kallmann syndrome in early infancy: evidence of hypoplastic rhinencephalon.</strong>
Europ. J. Pediat. 153: 245-247, 1994.
[PubMed: 8194555]
[Full Text: https://doi.org/10.1007/BF01954511]
</p>
</li>
<li>
<p class="mim-text-font">
Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., Seminara, S. B., Boepple, P. A., Sidis, Y., Crowley, W. F., Jr., Martin, K. A., Hall, J. E., Pitteloud, N.
<strong>A genetic basis for functional hypothalamic amenorrhea.</strong>
New Eng. J. Med. 364: 215-225, 2011.
[PubMed: 21247312]
[Full Text: https://doi.org/10.1056/NEJMoa0911064]
</p>
</li>
<li>
<p class="mim-text-font">
De Morsier, G.
<strong>Etudes sur les dysraphies cranio-encephaliques. I. Agenesie des lobes olfactifs (telencephaloschizis lateral) et des commissures calleuse et anterieure (telencephaloschizis median): la dysplasie olfacto-genitale.</strong>
Schweiz. Arch. Neurol. Psychiat. 74: 309-361, 1954.
[PubMed: 14385744]
</p>
</li>
<li>
<p class="mim-text-font">
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: 12627230]
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