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<title>
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Entry
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- #605635 - HYPERALDOSTERONISM, FAMILIAL, TYPE II; HALD2
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- OMIM
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/phenotypicSeries/PS103900"> <strong>Phenotypic Series</strong> </a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#history">History</a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=(HYPERALDOSTERONISM, FAMILIAL, TYPE II) OR (CLCN2)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=8738&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605635[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=404" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:446" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/605635" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:446" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 703233008<br />
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<strong>ORPHA:</strong> 404<br />
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<strong>DO:</strong> 446<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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605635
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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HYPERALDOSTERONISM, FAMILIAL, TYPE II; HALD2
|
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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FH II
|
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</span>
|
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
|
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<span class="mim-font">
|
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<a href="/geneMap/3/918?start=-3&limit=10&highlight=918">
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3q27.1
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Hyperaldosteronism, familial, type II
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/605635"> 605635 </a>
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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CLCN2
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/600570"> 600570 </a>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/605635" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<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')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS103900" class="btn btn-info" role="button"> Phenotypic Series </a>
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<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="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
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</div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/605635" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/605635" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
|
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<span class="mim-font">
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|
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- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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</span>
|
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Vascular </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hypertension <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38341003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38341003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/401-405.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">401-405.99</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/997.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">997.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020538&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020538</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000822" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000822</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
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</div>
|
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|
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</div>
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</div>
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Increased serum aldosterone <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700633&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700633</a>]</span><br /> -
|
|
Increased aldosterone:renin ratio <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1852324&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1852324</a>]</span><br /> -
|
|
Decreased renin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0855389&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0855389</a>]</span><br /> -
|
|
Hypokalemia (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/166690008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">166690008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43339004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43339004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E87.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E87.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/276.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">276.8</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020621&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020621</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002900" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002900</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002900" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002900</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
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|
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</div>
|
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|
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</div>
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|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Early onset, usually before 20 years of age<br /> -
|
|
Incomplete penetrance <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836598&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836598</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span><br /> -
|
|
Variable expressivity <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861403&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861403</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003828" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003828</a>]</span><br /> -
|
|
Favorable response to spironolactone<br /> -
|
|
De novo mutation (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2985439&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2985439</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
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|
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|
|
<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 chloride channel 2 gene (CLCN2, <a href="/entry/600570#0010">600570.0010</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
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|
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|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
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|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Hyperaldosteronism
|
|
- <a href="/phenotypicSeries/PS103900">PS103900</a>
|
|
- 4 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/3/918?start=-3&limit=10&highlight=918"> 3q27.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605635"> Hyperaldosteronism, familial, type II </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/605635"> 605635 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600570"> CLCN2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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<p>A number sign (#) is used with this entry because of evidence that familial hyperaldosteronism type II (HALD2) is caused by heterozygous mutation in the CLCN2 gene (<a href="/entry/600570">600570</a>) on chromosome 3q27.</p><p>For a general phenotypic description and a discussion of genetic heterogeneity of familial hyperaldosteronism, see HALD1 (<a href="/entry/103900">103900</a>).</p>
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<p>Familial hyperaldosteronism type II (HALD2) is an autosomal dominant disorder characterized by hypertension due to increased aldosterone, often with hypokalemia. Patients usually present before age 20 years, although some may present in infancy. The disorder shows incomplete penetrance and variable expressivity; some patients may have normal blood pressure but have an increased aldosterone:renin ratio (ARR) on laboratory testing. Spironolactone is an effective treatment (summary by <a href="#3" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a general phenotypic description and a discussion of genetic heterogeneity of familial hyperaldosteronism, see HALD1 (<a href="/entry/103900">103900</a>).</p>
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<p><a href="#4" class="mim-tip-reference" title="Stowasser, M., Gordon, R. D., Tunny, T. J., Klemm, S. A., Finn, W. L., Krek, A. L. <strong>Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism.</strong> Clin. Exp. Pharm. Physiol. 19: 319-322, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1521363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1521363</a>] [<a href="https://doi.org/10.1111/j.1440-1681.1992.tb00462.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1521363">Stowasser et al. (1992)</a> reported a family (family 3) with familial hyperaldosteronism. Affected individuals had hypertension and hypokalemia. Adrenal venous sampling was consistent with bilateral production of aldosterone; none had adenomas. <a href="#3" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> provided a follow-up of the family reported by <a href="#4" class="mim-tip-reference" title="Stowasser, M., Gordon, R. D., Tunny, T. J., Klemm, S. A., Finn, W. L., Krek, A. L. <strong>Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism.</strong> Clin. Exp. Pharm. Physiol. 19: 319-322, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1521363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1521363</a>] [<a href="https://doi.org/10.1111/j.1440-1681.1992.tb00462.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1521363">Stowasser et al. (1992)</a>. There were 7 affected individuals, 6 of whom were found to have hypertension between 16 and 24 years of age. Most had increased serum aldosterone and an increased aldosterone/renin ratio (ARR) with a positive confirmatory fludrocortisone suppression test and non-lateralizing aldosterone production. Severe patients had hypokalemia. Hypertension and hypokalemia responded to treatment with spironolactone. One mutation carrier had normal blood pressure but an increased aldosterone/renin ratio, whereas another mutation carrier was normotensive with a normal aldosterone/renin ratio. These findings indicated incomplete penetrance and variable expressivity. <a href="#3" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> also identified 9 patients from 7 additional families with similar features. The age at onset ranged from childhood to young adulthood. One patient presented in infancy, but hypertension resolved by 2 years of age. <a href="#3" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> noted that the phenotype was similar to HALD4 (<a href="/entry/617027">617027</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1521363+29403011" 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="#1" class="mim-tip-reference" title="Fernandes-Rosa, F. L., Daniil, G., Orozco, I. J., Goppner, C., El Zein, R., Jain, V., Boulkroun, S., Jeunemaitre, X., Amar, L., Lefebvre, H., Schwarzmayr, T., Strom, T. M., Jentsch, T. J., Zennaro, M.-C. <strong>A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.</strong> Nature Genet. 50: 355-361, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403012</a>] [<a href="https://doi.org/10.1038/s41588-018-0053-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403012">Fernandes-Rosa et al. (2018)</a> reported a 9-year-old girl with HALD2 who presented with hypertension, hypokalemia, elevated serum aldosterone, and suppressed plasma renin activity. Abdominal imaging showed no adrenal abnormalities. She responded well to treatment with spironolactone and amlodipine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403012" 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>The transmission pattern of HALD2 in the family reported by <a href="#4" class="mim-tip-reference" title="Stowasser, M., Gordon, R. D., Tunny, T. J., Klemm, S. A., Finn, W. L., Krek, A. L. <strong>Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism.</strong> Clin. Exp. Pharm. Physiol. 19: 319-322, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1521363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1521363</a>] [<a href="https://doi.org/10.1111/j.1440-1681.1992.tb00462.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1521363">Stowasser et al. (1992)</a> and <a href="#3" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> was consistent with autosomal dominant inheritance with incomplete penetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1521363+29403011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of 8 unrelated families with HALD2, <a href="#3" class="mim-tip-reference" title="Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others. <strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong> Nature Genet. 50: 349-354, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-018-0048-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403011">Scholl et al. (2018)</a> identified 5 different heterozygous missense mutations in the CLCN2 gene (<a href="/entry/600570#0010">600570.0010</a>-<a href="/entry/600570#0014">600570.0014</a>). The mutation in the first family (family 3, originally reported by <a href="#4" class="mim-tip-reference" title="Stowasser, M., Gordon, R. D., Tunny, T. J., Klemm, S. A., Finn, W. L., Krek, A. L. <strong>Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism.</strong> Clin. Exp. Pharm. Physiol. 19: 319-322, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1521363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1521363</a>] [<a href="https://doi.org/10.1111/j.1440-1681.1992.tb00462.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1521363">Stowasser et al., 1992</a>) was found by exome sequencing and confirmed by Sanger sequencing. The variant segregated with the disorder in the family, although there was evidence of incomplete penetrance and variable disease expressivity. Subsequent CLCN2 mutations in the other families were found by screening the CLCN2 gene in 80 patients with a similar phenotype. In 2 patients, the CLCN2 mutation occurred de novo. One mutation (R172Q; <a href="/entry/600570#0010">600570.0010</a>) was found in 4 unrelated families, and haplotype analysis suggested independent occurrence of the mutation. In vitro functional expression studies in human HEK293 and H295R human adrenocortical cancer cells showed that all mutants shifted the activation curve of the channel to more positive voltages with higher open probabilities at the glomerulosa resting potential. All except 1 mutant (S865R; <a href="/entry/600570#0012">600570.0012</a>) modified the common gate by increasing the minimum open probability and accelerating activation, resulting in significantly larger chloride efflux compared to wildtype. The S865R variant, which likely has a regulatory function, slowed down deactivation of the gates, with a similar overall effect of increasing chloride flux. The mutations increased expression of CYP11B2 (<a href="/entry/124080">124080</a>) and its upstream regulator NR4A2 (<a href="/entry/601828">601828</a>), which increased aldosterone production. Current clamp recordings showed that the R172Q significantly amplified the depolarization of H295R-derived cells compared to wildtype. The findings demonstrated a role of anion channels in glomerulosa membrane potential determination and aldosterone production, and further showed that CLCN2 mutations can increase excitatory anion efflux by modifying the voltage dependence of channel opening, resulting in a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1521363+29403011" 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 girl with HALD2, <a href="#1" class="mim-tip-reference" title="Fernandes-Rosa, F. L., Daniil, G., Orozco, I. J., Goppner, C., El Zein, R., Jain, V., Boulkroun, S., Jeunemaitre, X., Amar, L., Lefebvre, H., Schwarzmayr, T., Strom, T. M., Jentsch, T. J., Zennaro, M.-C. <strong>A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.</strong> Nature Genet. 50: 355-361, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403012</a>] [<a href="https://doi.org/10.1038/s41588-018-0053-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29403012">Fernandes-Rosa et al. (2018)</a> identified a de novo heterozygous missense mutation in the CLCN2 gene (G24D; <a href="/entry/600570#0015">600570.0015</a>). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient was 1 of 12 patients with early-onset hypertension and hyperaldosteronism who underwent whole-exome sequencing. Expression of the mutant protein in Xenopus oocytes dramatically increased current amplitudes compared to wildtype due to a change in the voltage-dependent gating of CLCN2. Expression of the mutation into human adrenocortical cells resulted in increased expression of aldosterone synthase (CYP11B2) and increased aldosterone production, as well as robust chloride currents that lacked strong voltage dependence. Cells expressing the mutation also had increased aldosterone production after stimulation with angiotensin II compared to cells with wildtype CLCN2. Knockdown of CLCN2 in human adrenocortical cells using shRNA abolished chloride currents and decreased aldosterone production. Sequencing of exon 2 of the CLCN2 gene in 100 patients with bilateral adrenal hyperplasia identified 2 rare heterozygous variants (R66Q and P48R) in 2 patients diagnosed with hypertension at 29 and 19 years, respectively, during pregnancy. However, both variants failed to significantly change CLCN2 currents in Xenopus oocytes. The findings suggested that gain-of-function CLCN2 mutations increase chloride conductance in zona glomerulosa cells, resulting in depolarization and a subsequent increase in opening of voltage-gated calcium channels that trigger autonomous aldosterone production by increasing intracellular calcium concentrations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403012" 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="#5" class="mim-tip-reference" title="Torpy, D. J., Gordon, R. D., Lin, J. P., Huggard, P. R., Taymans, S. E., Stowasser, M., Chrousos, G. P., Stratakis, C. A. <strong>Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene.</strong> J. Clin. Endocr. Metab. 83: 3214-3218, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9745430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9745430</a>] [<a href="https://doi.org/10.1210/jcem.83.9.5086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9745430">Torpy et al. (1998)</a> reported linkage analysis on one of 17 families known to them with familial hyperaldosteronism type II. All affected individuals had negative testing for the CYP11B1/CYP11B2 hybrid gene (<a href="/entry/202010#0002">202010.0002</a>), known to be responsible for familial hyperaldosteronism type I. Linkage analysis also excluded CYP11B2 (<a href="/entry/124080">124080</a>) on chromosome 8q21 as a candidate for familial hyperaldosteronism type II. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9745430" 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="Lafferty, A. R., Torpy, D. J., Stowasser, M., Taymans, S. E., Lin, J. P., Huggard, P., Gordon, R. D., Stratakis, C. A. <strong>A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22).</strong> J. Med. Genet. 37: 831-835, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11073536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11073536</a>] [<a href="https://doi.org/10.1136/jmg.37.11.831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11073536">Lafferty et al. (2000)</a> reported further linkage analysis on the extended kindred originally reported by <a href="#5" class="mim-tip-reference" title="Torpy, D. J., Gordon, R. D., Lin, J. P., Huggard, P. R., Taymans, S. E., Stowasser, M., Chrousos, G. P., Stratakis, C. A. <strong>Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene.</strong> J. Clin. Endocr. Metab. 83: 3214-3218, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9745430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9745430</a>] [<a href="https://doi.org/10.1210/jcem.83.9.5086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9745430">Torpy et al. (1998)</a>. They found linkage between familial hyperaldosteronism type 2 and markers within cytogenetic band 7p22, with a 2-point lod score of 3.26 for markers at loci D7S511 and D7S517 (theta = 0.0) and a multipoint lod score of 3.5 between markers at loci D7S2521 and GATA24F03. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11073536+9745430" 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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Fernandes-Rosa, F. L., Daniil, G., Orozco, I. J., Goppner, C., El Zein, R., Jain, V., Boulkroun, S., Jeunemaitre, X., Amar, L., Lefebvre, H., Schwarzmayr, T., Strom, T. M., Jentsch, T. J., Zennaro, M.-C.
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<strong>A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.</strong>
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Nature Genet. 50: 355-361, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403012</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29403012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41588-018-0053-8" target="_blank">Full Text</a>]
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Lafferty, A. R., Torpy, D. J., Stowasser, M., Taymans, S. E., Lin, J. P., Huggard, P., Gordon, R. D., Stratakis, C. A.
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<strong>A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22).</strong>
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J. Med. Genet. 37: 831-835, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11073536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11073536</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11073536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others.
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<strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong>
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Nature Genet. 50: 349-354, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29403011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29403011</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29403011[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=29403011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Stowasser, M., Gordon, R. D., Tunny, T. J., Klemm, S. A., Finn, W. L., Krek, A. L.
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<strong>Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism.</strong>
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Clin. Exp. Pharm. Physiol. 19: 319-322, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1521363/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1521363</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1521363" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Torpy, D. J., Gordon, R. D., Lin, J. P., Huggard, P. R., Taymans, S. E., Stowasser, M., Chrousos, G. P., Stratakis, C. A.
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<strong>Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene.</strong>
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J. Clin. Endocr. Metab. 83: 3214-3218, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9745430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9745430</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9745430" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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carol : 08/10/2018<br>ckniffin : 08/09/2018<br>alopez : 07/12/2016<br>alopez : 12/21/2010<br>alopez : 3/19/2004<br>mcapotos : 3/13/2001<br>alopez : 2/21/2001<br>alopez : 2/21/2001<br>alopez : 2/12/2001
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HYPERALDOSTERONISM, FAMILIAL, TYPE II; HALD2
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Hyperaldosteronism, familial, type II
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<p>A number sign (#) is used with this entry because of evidence that familial hyperaldosteronism type II (HALD2) is caused by heterozygous mutation in the CLCN2 gene (600570) on chromosome 3q27.</p><p>For a general phenotypic description and a discussion of genetic heterogeneity of familial hyperaldosteronism, see HALD1 (103900).</p>
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<p>Familial hyperaldosteronism type II (HALD2) is an autosomal dominant disorder characterized by hypertension due to increased aldosterone, often with hypokalemia. Patients usually present before age 20 years, although some may present in infancy. The disorder shows incomplete penetrance and variable expressivity; some patients may have normal blood pressure but have an increased aldosterone:renin ratio (ARR) on laboratory testing. Spironolactone is an effective treatment (summary by Scholl et al., 2018). </p><p>For a general phenotypic description and a discussion of genetic heterogeneity of familial hyperaldosteronism, see HALD1 (103900).</p>
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<p>Stowasser et al. (1992) reported a family (family 3) with familial hyperaldosteronism. Affected individuals had hypertension and hypokalemia. Adrenal venous sampling was consistent with bilateral production of aldosterone; none had adenomas. Scholl et al. (2018) provided a follow-up of the family reported by Stowasser et al. (1992). There were 7 affected individuals, 6 of whom were found to have hypertension between 16 and 24 years of age. Most had increased serum aldosterone and an increased aldosterone/renin ratio (ARR) with a positive confirmatory fludrocortisone suppression test and non-lateralizing aldosterone production. Severe patients had hypokalemia. Hypertension and hypokalemia responded to treatment with spironolactone. One mutation carrier had normal blood pressure but an increased aldosterone/renin ratio, whereas another mutation carrier was normotensive with a normal aldosterone/renin ratio. These findings indicated incomplete penetrance and variable expressivity. Scholl et al. (2018) also identified 9 patients from 7 additional families with similar features. The age at onset ranged from childhood to young adulthood. One patient presented in infancy, but hypertension resolved by 2 years of age. Scholl et al. (2018) noted that the phenotype was similar to HALD4 (617027). </p><p>Fernandes-Rosa et al. (2018) reported a 9-year-old girl with HALD2 who presented with hypertension, hypokalemia, elevated serum aldosterone, and suppressed plasma renin activity. Abdominal imaging showed no adrenal abnormalities. She responded well to treatment with spironolactone and amlodipine. </p>
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<p>The transmission pattern of HALD2 in the family reported by Stowasser et al. (1992) and Scholl et al. (2018) was consistent with autosomal dominant inheritance with incomplete penetrance. </p>
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<p>In affected members of 8 unrelated families with HALD2, Scholl et al. (2018) identified 5 different heterozygous missense mutations in the CLCN2 gene (600570.0010-600570.0014). The mutation in the first family (family 3, originally reported by Stowasser et al., 1992) was found by exome sequencing and confirmed by Sanger sequencing. The variant segregated with the disorder in the family, although there was evidence of incomplete penetrance and variable disease expressivity. Subsequent CLCN2 mutations in the other families were found by screening the CLCN2 gene in 80 patients with a similar phenotype. In 2 patients, the CLCN2 mutation occurred de novo. One mutation (R172Q; 600570.0010) was found in 4 unrelated families, and haplotype analysis suggested independent occurrence of the mutation. In vitro functional expression studies in human HEK293 and H295R human adrenocortical cancer cells showed that all mutants shifted the activation curve of the channel to more positive voltages with higher open probabilities at the glomerulosa resting potential. All except 1 mutant (S865R; 600570.0012) modified the common gate by increasing the minimum open probability and accelerating activation, resulting in significantly larger chloride efflux compared to wildtype. The S865R variant, which likely has a regulatory function, slowed down deactivation of the gates, with a similar overall effect of increasing chloride flux. The mutations increased expression of CYP11B2 (124080) and its upstream regulator NR4A2 (601828), which increased aldosterone production. Current clamp recordings showed that the R172Q significantly amplified the depolarization of H295R-derived cells compared to wildtype. The findings demonstrated a role of anion channels in glomerulosa membrane potential determination and aldosterone production, and further showed that CLCN2 mutations can increase excitatory anion efflux by modifying the voltage dependence of channel opening, resulting in a gain of function. </p><p>In a girl with HALD2, Fernandes-Rosa et al. (2018) identified a de novo heterozygous missense mutation in the CLCN2 gene (G24D; 600570.0015). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient was 1 of 12 patients with early-onset hypertension and hyperaldosteronism who underwent whole-exome sequencing. Expression of the mutant protein in Xenopus oocytes dramatically increased current amplitudes compared to wildtype due to a change in the voltage-dependent gating of CLCN2. Expression of the mutation into human adrenocortical cells resulted in increased expression of aldosterone synthase (CYP11B2) and increased aldosterone production, as well as robust chloride currents that lacked strong voltage dependence. Cells expressing the mutation also had increased aldosterone production after stimulation with angiotensin II compared to cells with wildtype CLCN2. Knockdown of CLCN2 in human adrenocortical cells using shRNA abolished chloride currents and decreased aldosterone production. Sequencing of exon 2 of the CLCN2 gene in 100 patients with bilateral adrenal hyperplasia identified 2 rare heterozygous variants (R66Q and P48R) in 2 patients diagnosed with hypertension at 29 and 19 years, respectively, during pregnancy. However, both variants failed to significantly change CLCN2 currents in Xenopus oocytes. The findings suggested that gain-of-function CLCN2 mutations increase chloride conductance in zona glomerulosa cells, resulting in depolarization and a subsequent increase in opening of voltage-gated calcium channels that trigger autonomous aldosterone production by increasing intracellular calcium concentrations. </p>
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<p>Torpy et al. (1998) reported linkage analysis on one of 17 families known to them with familial hyperaldosteronism type II. All affected individuals had negative testing for the CYP11B1/CYP11B2 hybrid gene (202010.0002), known to be responsible for familial hyperaldosteronism type I. Linkage analysis also excluded CYP11B2 (124080) on chromosome 8q21 as a candidate for familial hyperaldosteronism type II. </p><p>Lafferty et al. (2000) reported further linkage analysis on the extended kindred originally reported by Torpy et al. (1998). They found linkage between familial hyperaldosteronism type 2 and markers within cytogenetic band 7p22, with a 2-point lod score of 3.26 for markers at loci D7S511 and D7S517 (theta = 0.0) and a multipoint lod score of 3.5 between markers at loci D7S2521 and GATA24F03. </p>
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<strong>REFERENCES</strong>
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Fernandes-Rosa, F. L., Daniil, G., Orozco, I. J., Goppner, C., El Zein, R., Jain, V., Boulkroun, S., Jeunemaitre, X., Amar, L., Lefebvre, H., Schwarzmayr, T., Strom, T. M., Jentsch, T. J., Zennaro, M.-C.
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<strong>A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.</strong>
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Nature Genet. 50: 355-361, 2018.
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[PubMed: 29403012]
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[Full Text: https://doi.org/10.1038/s41588-018-0053-8]
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Lafferty, A. R., Torpy, D. J., Stowasser, M., Taymans, S. E., Lin, J. P., Huggard, P., Gordon, R. D., Stratakis, C. A.
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<strong>A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22).</strong>
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J. Med. Genet. 37: 831-835, 2000.
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[PubMed: 11073536]
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[Full Text: https://doi.org/10.1136/jmg.37.11.831]
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Scholl, U. I., Stolting, G., Schewe, J., Thiel, A., Tan, H., Nelson-Williams, C., Vichot, A. A., Jin, S. C., Loring, E., Untiet, V., Yoo, T., Choi, J., and 17 others.
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<strong>CLCN2 chloride channel mutations in familial hyperaldosteronism type II.</strong>
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Nature Genet. 50: 349-354, 2018.
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[PubMed: 29403011]
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[Full Text: https://doi.org/10.1038/s41588-018-0048-5]
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Stowasser, M., Gordon, R. D., Tunny, T. J., Klemm, S. A., Finn, W. L., Krek, A. L.
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<strong>Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism.</strong>
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Clin. Exp. Pharm. Physiol. 19: 319-322, 1992.
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[PubMed: 1521363]
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[Full Text: https://doi.org/10.1111/j.1440-1681.1992.tb00462.x]
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Torpy, D. J., Gordon, R. D., Lin, J. P., Huggard, P. R., Taymans, S. E., Stowasser, M., Chrousos, G. P., Stratakis, C. A.
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<strong>Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene.</strong>
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J. Clin. Endocr. Metab. 83: 3214-3218, 1998.
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[PubMed: 9745430]
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[Full Text: https://doi.org/10.1210/jcem.83.9.5086]
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Cassandra L. Kniffin - updated : 08/09/2018
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Michael J. Wright : 2/9/2001
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carol : 02/06/2024<br>carol : 08/10/2018<br>ckniffin : 08/09/2018<br>alopez : 07/12/2016<br>alopez : 12/21/2010<br>alopez : 3/19/2004<br>mcapotos : 3/13/2001<br>alopez : 2/21/2001<br>alopez : 2/21/2001<br>alopez : 2/12/2001
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To ensure long-term funding for the OMIM project, we have diversified
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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