3556 lines
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Entry
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- #243000 - INDIFFERENCE TO PAIN, CONGENITAL, AUTOSOMAL RECESSIVE; CIP
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- OMIM
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<p>
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<span class="h4">#243000</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/243000"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#nomenclature">Nomenclature</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="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=INDIFFERENCE TO PAIN, CONGENITAL, AUTOSOMAL RECESSIVE" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=11818&Typ=Pat" title="Congenital insensitivity to pain-anosmia-neuropathic arthropathy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Congenital insensitivity t… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=1290&Typ=Pat" title="Hereditary sensory and autonomic neuropathy type 2" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Hereditary sensory and aut… </a></div>
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<div><a href="#mimGeneReviewsFold" id="mimGeneReviewsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling."><span id="mimGeneReviewsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Gene Reviews</div>
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<div id="mimGeneReviewsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK481553/" title="Congenital Insensitivity to Pain Overview" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Congenital Insensitivity t…</a></div><div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK49247/" title="Hereditary Sensory and Autonomic Neuropathy Type II" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Hereditary Sensory and Aut…</a></div>
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</div>
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<div><a href="https://www.diseaseinfosearch.org/x/8657" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/channelopathy-associated-congenital-insensitivity-to-pain" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=243000[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=88642" title="Congenital insensitivity to pain-anosmia-neuropathic arthropathy" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Congenital insensitivity t…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=970" title="Hereditary sensory and autonomic neuropathy type 2" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Hereditary sensory and aut…</a></div>
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</div>
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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<div><a href="https://omia.org/OMIA002616/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</a>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:243000" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</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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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 88642, 970<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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243000
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</span>
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</span>
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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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INDIFFERENCE TO PAIN, CONGENITAL, AUTOSOMAL RECESSIVE; CIP
|
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</h3>
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</div>
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<div>
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<br />
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<a id="alternativeTitles" class="mim-anchor"></a>
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
|
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INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED<br />
|
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CONGENITAL ANALGESIA, AUTOSOMAL RECESSIVE<br />
|
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ASYMBOLIA FOR PAIN
|
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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>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IID, INCLUDED; HSAN2D, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
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|
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|
|
|
|
|
|
<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/2/741?start=-3&limit=10&highlight=741">
|
|
2q24.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Neuropathy, hereditary sensory and autonomic, type IID
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/243000"> 243000 </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">
|
|
SCN9A
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603415"> 603415 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/741?start=-3&limit=10&highlight=741">
|
|
2q24.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Insensitivity to pain, congenital
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/243000"> 243000 </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">
|
|
SCN9A
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603415"> 603415 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/243000" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<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/243000" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/243000" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Ears </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hearing impairment, asymmetric (in some patients with HSAN2D) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4012061&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4012061</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 <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44169009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44169009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R43.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R43.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003126&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003126</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000458" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000458</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000458" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000458</a>]</span><br /> -
|
|
Hyposmia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/83156004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">83156004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2364082&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2364082</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004409" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004409</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004409" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004409</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Mouth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Reduced numbers of tongue fungiform papilla (in some patients with HSAN2D) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4012062&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4012062</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> Bladder </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Urinary incontinence (in some patients with HSAN2D) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/165232002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">165232002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R32" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R32</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/788.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">788.30</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/788.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">788.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0042024&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0042024</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000020</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000020" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000020</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Neuropathic joints <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/67536000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">67536000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/359554008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">359554008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M14.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M14.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/713.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">713.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003892&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003892</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002821" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002821</a>]</span><br /> -
|
|
Painless fractures due to injury <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837602&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837602</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002661" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002661</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002661" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002661</a>]</span><br /> -
|
|
Bone deformities resulting from untreated fractures <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3806371&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3806371</a>]</span><br /> -
|
|
Bone dysplasia (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/371521007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">371521007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0005941&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005941</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Hands </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Ulceration of digits <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4012063&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4012063</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
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<div>
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<div>
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<span class="h5 mim-font">
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<em> Feet </em>
|
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</span>
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</div>
|
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
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- Ulceration of digits <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4012063&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4012063</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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<div>
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<span class="h5 mim-font">
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<strong> SKIN, NAILS, & HAIR </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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<div>
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<span class="h5 mim-font">
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<em> Skin </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Distal painless ulcers <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4012064&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4012064</a>]</span><br /> -
|
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Hypohidrosis (in patients with HSAN2D) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/45004005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">45004005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L74.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L74.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020620&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020620</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000966" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000966</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000966" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000966</a>]</span><br /> -
|
|
Anhidrosis (in patients with HSAN2D) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14662005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14662005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39659002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39659002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L74.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L74.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/705.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">705.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003028&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003028</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000970" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000970</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000970" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000970</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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<div>
|
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<span class="h5 mim-font">
|
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<strong> NEUROLOGIC </strong>
|
|
</span>
|
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</div>
|
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<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> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Isolated absence of pain sensation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855740&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855740</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38433004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38433004</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007021" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007021</a>]</span><br /> -
|
|
Anosmia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44169009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44169009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R43.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R43.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003126&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003126</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000458" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000458</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000458" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000458</a>]</span><br /> -
|
|
Autonomic dysfunction (in patients with HSAN2D) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15241006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15241006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G90.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G90.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G90</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/337" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">337</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/337.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">337.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1145628&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1145628</a>, <a href="https://bioportal.bioontology.org/search?q=C0013363&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013363</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012332</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Peripheral Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Isolated absence of pain sensation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855740&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855740</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38433004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38433004</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007021" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007021</a>]</span><br /> -
|
|
Temperature sensation may be diminished <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4012056&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4012056</a>]</span><br /> -
|
|
All other sensory modalities are intact <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1968695&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1968695</a>]</span><br /> -
|
|
Normal peripheral nerve biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0853460&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0853460</a>]</span><br /> -
|
|
Hyporeflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/835279003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">835279003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405946002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405946002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0700078&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700078</a>, <a href="https://bioportal.bioontology.org/search?q=C0151888&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151888</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001315" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001315</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001265" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001265</a>]</span><br /> -
|
|
Loss of myelinated fibers seen in sural nerve biopsy (in patients with HSAN2D) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014944&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014944</a>]</span><br /> -
|
|
Reduced sensory nerve action potential amplitudes (in patients with HSAN2D) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4313614&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4313614</a>]</span><br /> -
|
|
Reduced sensory nerve conduction velocities (in patients with HSAN2D) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4012059&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4012059</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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<div>
|
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<span class="h5 mim-font">
|
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<strong> LABORATORY ABNORMALITIES </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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|
|
- Normal axonal flare response after intradermal histamine injection <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1855741&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1855741</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">
|
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<strong> MISCELLANEOUS </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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- Onset in infancy or childhood<br /> -
|
|
Variable severity (in patients with HSAN2D) <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 /> -
|
|
Affected individuals are highly prone to burn-related injuries<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">
|
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<strong> MOLECULAR BASIS </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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- Caused by mutation in the voltage-gated sodium channel, type IX, alpha subunit gene (SCN9A, <a href="/entry/603415#0005">603415.0005</a>)<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 class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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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="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because autosomal recessive congenital indifference to pain and autosomal recessive hereditary sensory neuropathy type IID (HSN2D) are both caused by homozygous or compound heterozygous mutations in the SCN9A gene (<a href="/entry/603415">603415</a>) on chromosome 2q24.</p>
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</span>
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<div>
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<br />
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Congenital indifference to pain is a rare autosomal recessive disorder characterized by the complete absence of pain perception typically associated with noxious stimuli. Affected individuals are aware of a stimulus, but have lost the ability to perceive pain. Most patients are hyposmic or anosmic. Other sensory modalities are unaffected, and there is an absence of overt autonomic symptoms. Sural nerve biopsy and nerve conduction velocity studies are normal (summary by <a href="#7" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al., 2006</a>; and <a href="#16" class="mim-tip-reference" title="Goldberg, Y. P., Pimstone, S. N., Namdari, R., Price, N., Cohen, C., Sherrington, R. P., Hayden, M. R. <strong>Human mendelian pain disorders: a key to discovery and validation of novel analgesics.</strong> Clin. Genet. 82: 367-373, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22845492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22845492</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2012.01942.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22845492">Goldberg et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22845492+17167479" 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>Hereditary sensory and autonomic neuropathy type IID (HSAN2D) is an autosomal recessive disorder characterized by congenital or childhood-onset distal loss of pain and temperature sensation as well as autonomic dysfunction accompanied by hyposmia, hearing loss, hypogeusia, and sometimes bone dysplasia. The phenotype is highly variable, even within families. Two Japanese families have been reported (summary by <a href="#27" class="mim-tip-reference" title="Yuan, J., Matsuura, E., Higuchi, Y., Hashiguchi, A., Nakamura, T., Nozuma, S., Sakiyama, Y., Yoshimura, A., Izumo, S., Takashima, H. <strong>Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation.</strong> Neurology 80: 1641-1649, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23596073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23596073</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182904fdd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23596073">Yuan et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23596073" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of HSAN, see HSAN1 (<a href="/entry/162400">162400</a>).</p>
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<p><a href="#9" class="mim-tip-reference" title="Dyck, P. J., Mellinger, J. F., Reagan, T. J., Horowitz, S. J., McDonald, J. W., Litchy, W. J., Daube, J. R., Fealey, R. D., Go, V. L., Kao, P. C., Brimijoin, W. S., Lambert, E. H. <strong>Not 'indifference to pain' but varieties of hereditary sensory and autonomic neuropathy.</strong> Brain 106: 373-390, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6189547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6189547</a>] [<a href="https://doi.org/10.1093/brain/106.2.373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6189547">Dyck et al. (1983)</a> stated that congenital 'indifference' to pain is characterized by an absence of nerve pathology on histologic examination and can be distinguished from congenital 'insensitivity' to pain, which is associated with pathologic changes in peripheral nerves, as found in hereditary sensory and autonomic neuropathies, such as HSAN4 (<a href="/entry/256800">256800</a>) or HSAN5 (<a href="/entry/608654">608654</a>). Many cases reported as congenital indifference to pain or congenital analgesia were reported before the development of methods to assess the physiologic function of nerve fibers; therefore, <a href="#9" class="mim-tip-reference" title="Dyck, P. J., Mellinger, J. F., Reagan, T. J., Horowitz, S. J., McDonald, J. W., Litchy, W. J., Daube, J. R., Fealey, R. D., Go, V. L., Kao, P. C., Brimijoin, W. S., Lambert, E. H. <strong>Not 'indifference to pain' but varieties of hereditary sensory and autonomic neuropathy.</strong> Brain 106: 373-390, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6189547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6189547</a>] [<a href="https://doi.org/10.1093/brain/106.2.373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6189547">Dyck et al. (1983)</a> suggested that some of these cases may actually have been cases of HSAN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6189547" 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>Another interpretation of the distinction was provided by <a href="#7" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> who noted that the term 'indifference' implies a lack of concern to a stimulus that is received and perceived through normal sensory pathways, whereas 'insensitivity' describes the absence of painful sensation or failure to receive perception due to a detectable defect in sensory pathways. <a href="#7" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> thus suggested that congenital indifference to pain due to mutations in the SCN9A gene is actually a form of insensitivity to pain since the defect is due to a channelopathy that is not normally detected by routine histopathology. The authors proposed the term 'channelopathy-associated insensitivity to pain' for the disorder described here. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17167479" 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>Individuals with congenital indifference to pain have painless injuries beginning in infancy but otherwise normal sensory modalities. Perception of passive movement, joint position, and vibration are normal, as are tactile thresholds and light touch perception. Reflexes and autonomic responses are also normal. The axonal flare response after intradermal injection of histamine is normal, a finding that is in contrast to HSAN (<a href="#18" class="mim-tip-reference" title="Nagasako, E. M., Oaklander, A. L., Dworkin, R. H. <strong>Congenital insensitivity to pain: an update.</strong> Pain 101: 213-219, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12583863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12583863</a>] [<a href="https://doi.org/10.1016/S0304-3959(02)00482-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12583863">Nagasako et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12583863" 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>The first case of congenital analgesia is said to have been reported by <a href="#8" class="mim-tip-reference" title="Dearborn, G. <strong>A case of congenital general pure analgesia.</strong> J. Nerv. Ment. Dis. 75: 612-615, 1932."None>Dearborn (1932)</a>. The patient made a living as a human pincushion act. A crucifixion had to be called off when a woman in the audience fainted after a spike was driven through one hand.</p><p><a href="#11" class="mim-tip-reference" title="Fanconi, G., Ferrazzini, F. <strong>Kongenitale Analgie (kongenitale generalisierte Schmerzindifferenz).</strong> Helv. Paediat. Acta 12: 79-115, 1957.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13448589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13448589</a>]" pmid="13448589">Fanconi and Ferrazzini (1957)</a> described an affected brother and sister from consanguineous parents, and parental consanguinity has been noted in other cases (<a href="#20" class="mim-tip-reference" title="Ogden, T. E., Robert, F., Carmichael, E. A. <strong>Some sensory syndromes in children: indifference to pain and sensory neuropathy.</strong> J. Neurol. Neurosurg. Psychiat. 22: 267-276, 1959.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14428406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14428406</a>] [<a href="https://doi.org/10.1136/jnnp.22.4.267" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14428406">Ogden et al., 1959</a>; <a href="#4" class="mim-tip-reference" title="Bertoye, A., Carron, R., Rosenberg, D., Cotton, J.-B., Michel, M. <strong>A propos d'une observation d'indifference congenitale a la douleur (analgesie congenitale universelle): hypothese pathogenique.</strong> Pediatrie 19: 605-608, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14177235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14177235</a>]" pmid="14177235">Bertoye et al., 1964</a>; <a href="#24" class="mim-tip-reference" title="Thiemann, H. H. <strong>Analgia congenita (angeborene universelle Schmerzindifferenz).</strong> Arch. Kinderheilk. 164: 255-262, 1961.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13776331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13776331</a>]" pmid="13776331">Thiemann, 1961</a>), suggesting autosomal recessive inheritance. <a href="#23" class="mim-tip-reference" title="Silverman, F. N., Gilden, J. J. <strong>Congenital insensitivity to pain. A neurologic syndrome with bizarre skeletal lesions.</strong> Radiology 72: 176-190, 1959.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13634374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13634374</a>] [<a href="https://doi.org/10.1148/72.2.176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13634374">Silverman and Gilden (1959)</a> described a family in which 2 of 8 children of consanguineous parents were affected. <a href="#26" class="mim-tip-reference" title="Winkelmann, R. K., Lambert, E. H., Hayles, A. B. <strong>Congenital absence of pain: report of a case and experimental studies.</strong> Arch. Derm. 85: 325-339, 1962.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14007517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14007517</a>] [<a href="https://doi.org/10.1001/archderm.1962.01590030023004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14007517">Winkelmann et al. (1962)</a> reviewed the subject of absence of pain, with a useful discussion of differential diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14007517+14177235+13448589+13634374+14428406+13776331" 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="#22" class="mim-tip-reference" title="Saldanha, P. H., Schmidt, B. J., Leon, N. <strong>A genetical investigation of congenital analgesia. II. Clinico-genetical studies.</strong> Acta Genet. Statist. Med. 14: 143-158, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14209605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14209605</a>] [<a href="https://doi.org/10.1159/000151840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14209605">Saldanha et al. (1964)</a> described one family in which 3 brothers out of 10 sibs were affected and another family in which 2 sibs out of 11 were affected. The parents of the probands were normal and in 1 case were consanguineous. <a href="#14" class="mim-tip-reference" title="Gilly, R., Chevallier, G., Foray, G., Rambaud, G., Raveau, J. <strong>Indifference congenitale a la douleur: observation familiale, particularites cliniques et biologiques.</strong> Pediatrie 19: 609-614, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14177236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14177236</a>]" pmid="14177236">Gilly et al. (1964)</a> described 2 affected sibs who were born of normal parents and were of normal intelligence. <a href="#21" class="mim-tip-reference" title="Osuntokun, B. O., Odeku, E. L., Luzzatto, L. <strong>Congenital pain asymbolia and auditory imperception.</strong> J. Neurol. Neurosurg. Psychiat. 31: 291-296, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4176404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4176404</a>] [<a href="https://doi.org/10.1136/jnnp.31.3.291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4176404">Osuntokun et al. (1968)</a> described brother and half sister with congenital indifference to pain, who presumably had different fathers, both normal. They referred to the condition as 'pain asymbolia' and noted the association of auditory imperception. <a href="#13" class="mim-tip-reference" title="Gaudier, B., Bourlond, A., Nuyts, J.-P., Ryckewaert, P. H., Lefebvre, P., Ryckewaert-Sandor, L. <strong>L'indifference congenitale a la douleur. A propos de deux nouvelles observations.</strong> Arch. Franc. Pediat. 26: 1027-1040, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4190086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4190086</a>]" pmid="4190086">Gaudier et al. (1969)</a> described affected brothers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4176404+14209605+14177236+4190086" 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="Baxter, D. W., Olszewski, J. <strong>Congenital universal insensitivity to pain.</strong> Brain 83: 381-393, 1960.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13688072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13688072</a>] [<a href="https://doi.org/10.1093/brain/83.3.381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13688072">Baxter and Olszewski (1960)</a> reported no anatomic abnormalities at autopsy. In several patients with congenital indifference to pain, <a href="#2" class="mim-tip-reference" title="Becak, W., Becak, M. L., Andrade, J. D. <strong>A genetical investigation of congenital analgesia. I. Cytogenetic studies.</strong> Acta Genet. Statist. Med. 14: 133-142, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14209604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14209604</a>] [<a href="https://doi.org/10.1159/000151839" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14209604">Becak et al. (1964)</a> found mosaicism of cells with normal karyotype and cells trisomic for a chromosome in the 13-15 group; <a href="#5" class="mim-tip-reference" title="Blau, J. N., Mutton, D. E. <strong>Chromosome studies in the 'sensory syndrome'.</strong> Acta Genet. Statist. Med. 17: 226-233, 1967."None>Blau and Mutton (1967)</a> could demonstrate no chromosomal abnormality. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13688072+14209604" 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="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> described individuals from 3 Pakistani families with congenital inability to perceive any form of pain, in whom all other sensory modalities were preserved and the peripheral and central nervous systems were apparently otherwise intact. The trait was segregating as an autosomal recessive in the family. The index case was a 10-year-old child well known to the medical service after regularly performing 'street theater.' He placed knives through his arms and walked on burning coals, but experienced no pain. He died on his 14th birthday after jumping off a house roof. All affected individuals had injuries to their lips (some requiring plastic surgery) and/or tongue (with loss the distal third in 2 cases), caused by biting themselves in the first 4 years of life. The children were considered of normal intelligence by their parents and teachers. All could correctly perceive sensations of touch, warm and cold temperature, proprioception, tickle, and pressure, but not painful stimuli. <a href="#7" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> referred to the disorder as 'channelopathy-associated insensitivity to pain.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17167479" 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="Weiss, J., Pyrski, M., Jacobi, E., Bufe, B., Willnecker, V., Schick, B., Zizzari, P., Gossage, S. J., Greer, C. A., Leinders-Zufall, T., Woods, C. G., Wood, J. N., Zufall, F. <strong>Loss-of-function mutations in sodium channel NaV1.7 cause anosmia.</strong> Nature 472: 186-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21441906[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/nature09975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21441906">Weiss et al. (2011)</a> found that individuals with channelopathy-associated insensitivity to pain caused by mutations in SCN9A were completely anosmic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21441906" 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="Middleton, S. J., Perini, I., Themistocleous, A. C., Weir, G. A., McCann, K., Barry, A. M., Marshall, A., Lee, M., Mayo, L. M., Bohic, M., Baskozos, G., Morrison, I., and 12 others. <strong>Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.</strong> Brain 145: 3637-3653, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34957475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34957475</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34957475[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/10.1093/brain/awab482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34957475">Middleton et al. (2022)</a> performed psychophysiologic testing in 6 patients with CIP and found that perception of touch pleasantness, emotional reactions to touch, and the ability to discriminate between low force filaments were altered. The findings suggested that SCN9A is involved in the affective touch system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34957475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Clinical Variability</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Ebermann, I., Elsayed, S. M., Abdel-Ghaffar, T. Y., Nurnberg, G., Nurnberg, P., Elsobky, E., Bolz, H. J. <strong>Double homozygosity for mutations of AGL and SCN9A mimicking neurohepatopathy syndrome.</strong> Neurology 70: 2343-2344, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18541889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18541889</a>] [<a href="https://doi.org/10.1212/01.wnl.0000314731.65875.5c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18541889">Ebermann et al. (2008)</a> reported an 11-year-old boy, born of Egyptian consanguineous parents, with a phenotype suggestive of Navajo neurohepatopathy (MTDPS6; <a href="/entry/256810">256810</a>), including short stature, frequent painless fractures, bruises, and cuts, hepatomegaly with elevated liver enzymes, corneal ulcerations, and mild hypotonia. His 22-month-old sister had short stature, hepatomegaly, increased liver enzymes, and hypotonia. A cousin had died at age 8 years from liver failure. After genetic analysis excluded a mutation in the MPV17 gene (<a href="/entry/137960">137960</a>), <a href="#10" class="mim-tip-reference" title="Ebermann, I., Elsayed, S. M., Abdel-Ghaffar, T. Y., Nurnberg, G., Nurnberg, P., Elsobky, E., Bolz, H. J. <strong>Double homozygosity for mutations of AGL and SCN9A mimicking neurohepatopathy syndrome.</strong> Neurology 70: 2343-2344, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18541889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18541889</a>] [<a href="https://doi.org/10.1212/01.wnl.0000314731.65875.5c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18541889">Ebermann et al. (2008)</a> postulated 2 recessive diseases. Genomewide linkage analysis and gene sequencing of the proband identified a homozygous mutation in the AGL gene (<a href="/entry/610860">610860</a>), consistent with glycogen storage disease III (GSD3; <a href="/entry/232400">232400</a>), and a homozygous mutation in the SCN9A gene, consistent with congenital insensitivity to pain. His sister had the AGL mutation and GSD3 only. <a href="#10" class="mim-tip-reference" title="Ebermann, I., Elsayed, S. M., Abdel-Ghaffar, T. Y., Nurnberg, G., Nurnberg, P., Elsobky, E., Bolz, H. J. <strong>Double homozygosity for mutations of AGL and SCN9A mimicking neurohepatopathy syndrome.</strong> Neurology 70: 2343-2344, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18541889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18541889</a>] [<a href="https://doi.org/10.1212/01.wnl.0000314731.65875.5c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18541889">Ebermann et al. (2008)</a> emphasized that consanguineous matings increase the risk of homozygous genotypes and recessive diseases, which may complicate genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18541889" 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>Hereditary Sensory and Autonomic Neuropathy, Type IID</em></strong></p><p>
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<a href="#27" class="mim-tip-reference" title="Yuan, J., Matsuura, E., Higuchi, Y., Hashiguchi, A., Nakamura, T., Nozuma, S., Sakiyama, Y., Yoshimura, A., Izumo, S., Takashima, H. <strong>Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation.</strong> Neurology 80: 1641-1649, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23596073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23596073</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182904fdd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23596073">Yuan et al. (2013)</a> reported 2 Japanese sibs, born of consanguineous parents, and 1 unrelated Japanese patient with hereditary sensory and autonomic neuropathy. The phenotype was somewhat variable, even between the 2 sibs. A 50-year-old man developed decreased pain and temperature perception in the hands and feet in childhood, which progressed to the proximal limbs after age 40. He also had hyposmia, lack of sweating, skin lesions, including burn marks, and unilateral asymptomatic sensorineural hearing loss. There was mild weakness in the right lower limb, resulting in a steppage gait, and areflexia. His 55-year-old older sister had a history of recurrent fractures in childhood and had bone dysplasia with deformities of the elbow, foot, and lower limbs. She had no pain or temperature sensation in her feet as an adult. Other features included mild muscle weakness in the lower limbs and anhidrosis but not hyposmia or hearing loss. An unrelated 33-year-old man had decreased pain and temperature perception since birth, resulting in digital ulceration and deformities. Hyposmia and unilateral hearing loss were noted in early childhood. Other features included occasional urinary and fecal incontinence, reduced sweating, and reduced number of fungiform papillae on the tongue, consistent with autonomic dysfunction. He also had pigmentary skin lesions and left acetabular dysplasia resulting in asymmetric leg length. Vibration and joint position remained intact in all patients. Nerve conduction studies of the 2 unrelated men showed variably slowed sensory nerve conduction velocities (NCVs) and decreased sensory nerve action potential (SNAP) amplitudes in the median nerves. However, 1 patient had normal sural NCV and SNAP values. Sural nerve biopsy showed variable loss of myelinated fibers, which did not appear to correlate with symptoms in 1 patient. Both families were from the Kagoshima prefecture, but were unrelated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23596073" 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 HSAN2D in the families reported by <a href="#27" class="mim-tip-reference" title="Yuan, J., Matsuura, E., Higuchi, Y., Hashiguchi, A., Nakamura, T., Nozuma, S., Sakiyama, Y., Yoshimura, A., Izumo, S., Takashima, H. <strong>Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation.</strong> Neurology 80: 1641-1649, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23596073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23596073</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182904fdd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23596073">Yuan et al. (2013)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23596073" 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 3 northern Pakistani families segregating autosomal recessive 'channelopathy-associated insensitivity to pain,' <a href="#7" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> mapped the trait to 2q24.3, a region containing the SCN9A gene, which encodes the alpha subunit of the voltage-gated sodium channel, Nav1.7 (2-point lod of 3.2 at theta = 0.0). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17167479" 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>By sequence analysis of the SCN9A gene in 3 northern Pakistani families segregating autosomal recessive 'channelopathy-associated insensitivity to pain,' <a href="#7" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> identified 3 distinct homozygous nonsense mutations (<a href="/entry/603415#0005">603415.0005</a>-<a href="/entry/603415#0007">603415.0007</a>). By coexpression of wildtype or mutant human Nav1.7 with sodium channel beta-1 and beta-2 subunits in cultured cells, <a href="#7" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> showed that these mutations caused loss of function of Nav1.7. In cells expressing mutant Nav1.7, the currents were no greater than background. The data suggested that SCN9A is an essential and nonredundant requirement for nociception in humans. <a href="#7" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> suggested that these findings should stimulate the search for novel analgesics to target this sodium channel subunit selectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17167479" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Goldberg, Y. P., MacFarlane, J., MacDonald, M. L., Thompson, J., Dube, M.-P., Mattice, M., Fraser, R., Young, C., Hossain, S., Pape, T., Payne, B., Radomski, C., and 18 others. <strong>Loss-of-function mutations in the Na(v)1.7 gene underlie congenital indifference to pain in multiple human populations.</strong> Clin. Genet. 71: 311-319, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17470132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17470132</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00790.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17470132">Goldberg et al. (2007)</a> identified 10 different mutations in the SCN9A gene (see, e.g., <a href="/entry/603415#0014">603415.0014</a>-<a href="/entry/603415#0015">603415.0015</a>), 9 of which were truncating mutations, in affected members of 9 different families with congenital insensitivity to pain. The families were from Canada, the U.S., and Argentina as well as various countries in Europe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17470132" 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="Weiss, J., Pyrski, M., Jacobi, E., Bufe, B., Willnecker, V., Schick, B., Zizzari, P., Gossage, S. J., Greer, C. A., Leinders-Zufall, T., Woods, C. G., Wood, J. N., Zufall, F. <strong>Loss-of-function mutations in sodium channel NaV1.7 cause anosmia.</strong> Nature 472: 186-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21441906[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/nature09975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21441906">Weiss et al. (2011)</a> studied the individual reported by <a href="#19" class="mim-tip-reference" title="Nilsen, K. B., Nicholas, A. K., Woods, C. G., Mellgren, S. I., Nebuchennykh, M., Aasly, J. <strong>Two novel SCN9A mutations causing insensitivity to pain.</strong> Pain 143: 155-158, 2009. Note: Erratum: Pain 145: 264 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19304393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19304393</a>] [<a href="https://doi.org/10.1016/j.pain.2009.02.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19304393">Nilsen et al. (2009)</a>. This individual was heterozygous for a frameshift and nonsense mutation in the NaV1.7 protein. <a href="#25" class="mim-tip-reference" title="Weiss, J., Pyrski, M., Jacobi, E., Bufe, B., Willnecker, V., Schick, B., Zizzari, P., Gossage, S. J., Greer, C. A., Leinders-Zufall, T., Woods, C. G., Wood, J. N., Zufall, F. <strong>Loss-of-function mutations in sodium channel NaV1.7 cause anosmia.</strong> Nature 472: 186-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21441906[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/nature09975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21441906">Weiss et al. (2011)</a> also studied 2 other individuals, sibs, who were compound heterozygous for nonsense and frameshift mutations. None of the affected individuals was able to smell. In the case of the sibs, both parents, who were heterozygous, had intact olfactory sensation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21441906+19304393" 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 3 Japanese patients from 2 unrelated families with HSAN2D, <a href="#27" class="mim-tip-reference" title="Yuan, J., Matsuura, E., Higuchi, Y., Hashiguchi, A., Nakamura, T., Nozuma, S., Sakiyama, Y., Yoshimura, A., Izumo, S., Takashima, H. <strong>Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation.</strong> Neurology 80: 1641-1649, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23596073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23596073</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182904fdd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23596073">Yuan et al. (2013)</a> identified a homozygous truncating mutation in the SCN9A gene (<a href="/entry/603415#0028">603415.0028</a>). The mutation was predicted to result in nonsense-mediated mRNA decay and loss of SCN9A function in nociceptive neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23596073" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Becak1963" class="mim-tip-reference" title="Becak, W., Becak, M. L., Schmidt, B. J. <strong>Chromosome trisomy of group 13-15 in two cases of generalised congenital analgesia. (Letter)</strong> Lancet 281: 664-665, 1963. Note: Originally Volume I.">Becak et al. (1963)</a>; <a href="#Bourlond1966" class="mim-tip-reference" title="Bourlond, A., Winkelmann, R. K. <strong>Study of cutaneous innervation in congenital anesthesia.</strong> Arch. Neurol. 14: 223-227, 1966.">Bourlond and Winkelmann (1966)</a>; <a href="#Ford1938" class="mim-tip-reference" title="Ford, F. R., Wilkins, L. <strong>Congenital universal indifference to pain.</strong> Bull. Johns Hopkins Hosp. 62: 448-466, 1938.">Ford and Wilkins
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Baxter, D. W., Olszewski, J.
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Brain 83: 381-393, 1960.
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[<a href="https://doi.org/10.1093/brain/83.3.381" target="_blank">Full Text</a>]
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Becak, W., Becak, M. L., Andrade, J. D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14209604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14209604</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14209604" 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/10.1159/000151839" target="_blank">Full Text</a>]
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Becak, W., Becak, M. L., Schmidt, B. J.
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<strong>Chromosome trisomy of group 13-15 in two cases of generalised congenital analgesia. (Letter)</strong>
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Lancet 281: 664-665, 1963. Note: Originally Volume I.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13970027/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13970027</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13970027" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(63)91297-2" target="_blank">Full Text</a>]
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Bertoye, A., Carron, R., Rosenberg, D., Cotton, J.-B., Michel, M.
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<strong>A propos d'une observation d'indifference congenitale a la douleur (analgesie congenitale universelle): hypothese pathogenique.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14177235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14177235</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14177235" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Blau, J. N., Mutton, D. E.
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<strong>Chromosome studies in the 'sensory syndrome'.</strong>
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Acta Genet. Statist. Med. 17: 226-233, 1967.
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Bourlond, A., Winkelmann, R. K.
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<strong>Study of cutaneous innervation in congenital anesthesia.</strong>
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Arch. Neurol. 14: 223-227, 1966.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4143709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4143709</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4143709" 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/10.1001/archneur.1966.00470080107016" target="_blank">Full Text</a>]
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Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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=17167479" 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/nature05413" target="_blank">Full Text</a>]
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Dyck, P. J., Mellinger, J. F., Reagan, T. J., Horowitz, S. J., McDonald, J. W., Litchy, W. J., Daube, J. R., Fealey, R. D., Go, V. L., Kao, P. C., Brimijoin, W. S., Lambert, E. H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6189547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6189547</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6189547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/106.2.373" target="_blank">Full Text</a>]
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Ebermann, I., Elsayed, S. M., Abdel-Ghaffar, T. Y., Nurnberg, G., Nurnberg, P., Elsobky, E., Bolz, H. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18541889/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18541889</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18541889" 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/10.1212/01.wnl.0000314731.65875.5c" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13448589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13448589</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13448589" 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="Ford1938" class="mim-anchor"></a>
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Ford, F. R., Wilkins, L.
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<strong>Congenital universal indifference to pain.</strong>
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Bull. Johns Hopkins Hosp. 62: 448-466, 1938.
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Gaudier, B., Bourlond, A., Nuyts, J.-P., Ryckewaert, P. H., Lefebvre, P., Ryckewaert-Sandor, L.
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Arch. Franc. Pediat. 26: 1027-1040, 1969.
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[<a href="https://doi.org/10.1111/j.1399-0004.2007.00790.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2012.01942.x" target="_blank">Full Text</a>]
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Middleton, S. J., Perini, I., Themistocleous, A. C., Weir, G. A., McCann, K., Barry, A. M., Marshall, A., Lee, M., Mayo, L. M., Bohic, M., Baskozos, G., Morrison, I., and 12 others.
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[<a href="https://doi.org/10.1093/brain/awab482" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0304-3959(02)00482-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.pain.2009.02.016" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jnnp.22.4.267" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jnnp.31.3.291" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000151840" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1148/72.2.176" target="_blank">Full Text</a>]
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<strong>Loss-of-function mutations in sodium channel NaV1.7 cause anosmia.</strong>
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[<a href="https://doi.org/10.1001/archderm.1962.01590030023004" target="_blank">Full Text</a>]
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<a id="Yuan2013" class="mim-anchor"></a>
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Yuan, J., Matsuura, E., Higuchi, Y., Hashiguchi, A., Nakamura, T., Nozuma, S., Sakiyama, Y., Yoshimura, A., Izumo, S., Takashima, H.
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<strong>Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23596073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23596073</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23596073" 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/10.1212/WNL.0b013e3182904fdd" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 06/26/2023
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Cassandra L. Kniffin - updated : 10/28/2014<br>Ada Hamosh - updated : 6/7/2011<br>Cassandra L. Kniffin - updated : 12/20/2010<br>Cassandra L. Kniffin - updated : 7/6/2007<br>Victor A. McKusick - updated : 12/20/2006<br>Cassandra L. Kniffin - reorganized : 5/24/2004<br>Cassandra L. Kniffin - updated : 5/17/2004
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Victor A. McKusick : 6/3/1986
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carol : 03/23/2022<br>carol : 03/22/2022<br>carol : 01/09/2018<br>carol : 04/25/2017<br>carol : 11/10/2014<br>mcolton : 10/29/2014<br>ckniffin : 10/28/2014<br>terry : 6/15/2011<br>alopez : 6/9/2011<br>terry : 6/7/2011<br>ckniffin : 12/20/2010<br>ckniffin : 10/18/2010<br>terry : 3/4/2009<br>wwang : 7/12/2007<br>ckniffin : 7/6/2007<br>carol : 1/2/2007<br>ckniffin : 12/29/2006<br>carol : 12/22/2006<br>terry : 12/20/2006<br>ckniffin : 5/24/2004<br>carol : 5/24/2004<br>carol : 5/24/2004<br>carol : 5/24/2004<br>ckniffin : 5/17/2004<br>joanna : 3/18/2004<br>terry : 6/14/1994<br>mimadm : 2/19/1994<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/26/1989<br>marie : 3/25/1988
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<h3>
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<span class="mim-font">
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<strong>#</strong> 243000
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</h3>
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<h3>
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<span class="mim-font">
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INDIFFERENCE TO PAIN, CONGENITAL, AUTOSOMAL RECESSIVE; CIP
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</h3>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED<br />
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CONGENITAL ANALGESIA, AUTOSOMAL RECESSIVE<br />
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ASYMBOLIA FOR PAIN
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</p>
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<span class="h3 mim-font">
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NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IID, INCLUDED; HSAN2D, INCLUDED
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<strong>ORPHA:</strong> 88642, 970;
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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<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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Gene/Locus <br /> MIM number
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<tbody>
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<span class="mim-font">
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2q24.3
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<span class="mim-font">
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Neuropathy, hereditary sensory and autonomic, type IID
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<span class="mim-font">
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243000
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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SCN9A
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<span class="mim-font">
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603415
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<span class="mim-font">
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2q24.3
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<span class="mim-font">
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Insensitivity to pain, congenital
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</td>
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<span class="mim-font">
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243000
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<td>
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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SCN9A
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<span class="mim-font">
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603415
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</table>
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<span class="mim-font">
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<strong>TEXT</strong>
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</h4>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because autosomal recessive congenital indifference to pain and autosomal recessive hereditary sensory neuropathy type IID (HSN2D) are both caused by homozygous or compound heterozygous mutations in the SCN9A gene (603415) on chromosome 2q24.</p>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>Congenital indifference to pain is a rare autosomal recessive disorder characterized by the complete absence of pain perception typically associated with noxious stimuli. Affected individuals are aware of a stimulus, but have lost the ability to perceive pain. Most patients are hyposmic or anosmic. Other sensory modalities are unaffected, and there is an absence of overt autonomic symptoms. Sural nerve biopsy and nerve conduction velocity studies are normal (summary by Cox et al., 2006; and Goldberg et al., 2012). </p><p>Hereditary sensory and autonomic neuropathy type IID (HSAN2D) is an autosomal recessive disorder characterized by congenital or childhood-onset distal loss of pain and temperature sensation as well as autonomic dysfunction accompanied by hyposmia, hearing loss, hypogeusia, and sometimes bone dysplasia. The phenotype is highly variable, even within families. Two Japanese families have been reported (summary by Yuan et al., 2013). </p><p>For a discussion of genetic heterogeneity of HSAN, see HSAN1 (162400).</p>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</strong>
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</h4>
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<span class="mim-text-font">
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<p>Dyck et al. (1983) stated that congenital 'indifference' to pain is characterized by an absence of nerve pathology on histologic examination and can be distinguished from congenital 'insensitivity' to pain, which is associated with pathologic changes in peripheral nerves, as found in hereditary sensory and autonomic neuropathies, such as HSAN4 (256800) or HSAN5 (608654). Many cases reported as congenital indifference to pain or congenital analgesia were reported before the development of methods to assess the physiologic function of nerve fibers; therefore, Dyck et al. (1983) suggested that some of these cases may actually have been cases of HSAN. </p><p>Another interpretation of the distinction was provided by Cox et al. (2006) who noted that the term 'indifference' implies a lack of concern to a stimulus that is received and perceived through normal sensory pathways, whereas 'insensitivity' describes the absence of painful sensation or failure to receive perception due to a detectable defect in sensory pathways. Cox et al. (2006) thus suggested that congenital indifference to pain due to mutations in the SCN9A gene is actually a form of insensitivity to pain since the defect is due to a channelopathy that is not normally detected by routine histopathology. The authors proposed the term 'channelopathy-associated insensitivity to pain' for the disorder described here. </p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Individuals with congenital indifference to pain have painless injuries beginning in infancy but otherwise normal sensory modalities. Perception of passive movement, joint position, and vibration are normal, as are tactile thresholds and light touch perception. Reflexes and autonomic responses are also normal. The axonal flare response after intradermal injection of histamine is normal, a finding that is in contrast to HSAN (Nagasako et al., 2003). </p><p>The first case of congenital analgesia is said to have been reported by Dearborn (1932). The patient made a living as a human pincushion act. A crucifixion had to be called off when a woman in the audience fainted after a spike was driven through one hand.</p><p>Fanconi and Ferrazzini (1957) described an affected brother and sister from consanguineous parents, and parental consanguinity has been noted in other cases (Ogden et al., 1959; Bertoye et al., 1964; Thiemann, 1961), suggesting autosomal recessive inheritance. Silverman and Gilden (1959) described a family in which 2 of 8 children of consanguineous parents were affected. Winkelmann et al. (1962) reviewed the subject of absence of pain, with a useful discussion of differential diagnosis. </p><p>Saldanha et al. (1964) described one family in which 3 brothers out of 10 sibs were affected and another family in which 2 sibs out of 11 were affected. The parents of the probands were normal and in 1 case were consanguineous. Gilly et al. (1964) described 2 affected sibs who were born of normal parents and were of normal intelligence. Osuntokun et al. (1968) described brother and half sister with congenital indifference to pain, who presumably had different fathers, both normal. They referred to the condition as 'pain asymbolia' and noted the association of auditory imperception. Gaudier et al. (1969) described affected brothers. </p><p>Baxter and Olszewski (1960) reported no anatomic abnormalities at autopsy. In several patients with congenital indifference to pain, Becak et al. (1964) found mosaicism of cells with normal karyotype and cells trisomic for a chromosome in the 13-15 group; Blau and Mutton (1967) could demonstrate no chromosomal abnormality. </p><p>Cox et al. (2006) described individuals from 3 Pakistani families with congenital inability to perceive any form of pain, in whom all other sensory modalities were preserved and the peripheral and central nervous systems were apparently otherwise intact. The trait was segregating as an autosomal recessive in the family. The index case was a 10-year-old child well known to the medical service after regularly performing 'street theater.' He placed knives through his arms and walked on burning coals, but experienced no pain. He died on his 14th birthday after jumping off a house roof. All affected individuals had injuries to their lips (some requiring plastic surgery) and/or tongue (with loss the distal third in 2 cases), caused by biting themselves in the first 4 years of life. The children were considered of normal intelligence by their parents and teachers. All could correctly perceive sensations of touch, warm and cold temperature, proprioception, tickle, and pressure, but not painful stimuli. Cox et al. (2006) referred to the disorder as 'channelopathy-associated insensitivity to pain.' </p><p>Weiss et al. (2011) found that individuals with channelopathy-associated insensitivity to pain caused by mutations in SCN9A were completely anosmic. </p><p>Middleton et al. (2022) performed psychophysiologic testing in 6 patients with CIP and found that perception of touch pleasantness, emotional reactions to touch, and the ability to discriminate between low force filaments were altered. The findings suggested that SCN9A is involved in the affective touch system. </p><p><strong><em>Clinical Variability</em></strong></p><p>
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Ebermann et al. (2008) reported an 11-year-old boy, born of Egyptian consanguineous parents, with a phenotype suggestive of Navajo neurohepatopathy (MTDPS6; 256810), including short stature, frequent painless fractures, bruises, and cuts, hepatomegaly with elevated liver enzymes, corneal ulcerations, and mild hypotonia. His 22-month-old sister had short stature, hepatomegaly, increased liver enzymes, and hypotonia. A cousin had died at age 8 years from liver failure. After genetic analysis excluded a mutation in the MPV17 gene (137960), Ebermann et al. (2008) postulated 2 recessive diseases. Genomewide linkage analysis and gene sequencing of the proband identified a homozygous mutation in the AGL gene (610860), consistent with glycogen storage disease III (GSD3; 232400), and a homozygous mutation in the SCN9A gene, consistent with congenital insensitivity to pain. His sister had the AGL mutation and GSD3 only. Ebermann et al. (2008) emphasized that consanguineous matings increase the risk of homozygous genotypes and recessive diseases, which may complicate genetic counseling. </p><p><strong><em>Hereditary Sensory and Autonomic Neuropathy, Type IID</em></strong></p><p>
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Yuan et al. (2013) reported 2 Japanese sibs, born of consanguineous parents, and 1 unrelated Japanese patient with hereditary sensory and autonomic neuropathy. The phenotype was somewhat variable, even between the 2 sibs. A 50-year-old man developed decreased pain and temperature perception in the hands and feet in childhood, which progressed to the proximal limbs after age 40. He also had hyposmia, lack of sweating, skin lesions, including burn marks, and unilateral asymptomatic sensorineural hearing loss. There was mild weakness in the right lower limb, resulting in a steppage gait, and areflexia. His 55-year-old older sister had a history of recurrent fractures in childhood and had bone dysplasia with deformities of the elbow, foot, and lower limbs. She had no pain or temperature sensation in her feet as an adult. Other features included mild muscle weakness in the lower limbs and anhidrosis but not hyposmia or hearing loss. An unrelated 33-year-old man had decreased pain and temperature perception since birth, resulting in digital ulceration and deformities. Hyposmia and unilateral hearing loss were noted in early childhood. Other features included occasional urinary and fecal incontinence, reduced sweating, and reduced number of fungiform papillae on the tongue, consistent with autonomic dysfunction. He also had pigmentary skin lesions and left acetabular dysplasia resulting in asymmetric leg length. Vibration and joint position remained intact in all patients. Nerve conduction studies of the 2 unrelated men showed variably slowed sensory nerve conduction velocities (NCVs) and decreased sensory nerve action potential (SNAP) amplitudes in the median nerves. However, 1 patient had normal sural NCV and SNAP values. Sural nerve biopsy showed variable loss of myelinated fibers, which did not appear to correlate with symptoms in 1 patient. Both families were from the Kagoshima prefecture, but were unrelated. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Inheritance</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The transmission pattern of HSAN2D in the families reported by Yuan et al. (2013) was consistent with autosomal recessive inheritance. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 3 northern Pakistani families segregating autosomal recessive 'channelopathy-associated insensitivity to pain,' Cox et al. (2006) mapped the trait to 2q24.3, a region containing the SCN9A gene, which encodes the alpha subunit of the voltage-gated sodium channel, Nav1.7 (2-point lod of 3.2 at theta = 0.0). </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By sequence analysis of the SCN9A gene in 3 northern Pakistani families segregating autosomal recessive 'channelopathy-associated insensitivity to pain,' Cox et al. (2006) identified 3 distinct homozygous nonsense mutations (603415.0005-603415.0007). By coexpression of wildtype or mutant human Nav1.7 with sodium channel beta-1 and beta-2 subunits in cultured cells, Cox et al. (2006) showed that these mutations caused loss of function of Nav1.7. In cells expressing mutant Nav1.7, the currents were no greater than background. The data suggested that SCN9A is an essential and nonredundant requirement for nociception in humans. Cox et al. (2006) suggested that these findings should stimulate the search for novel analgesics to target this sodium channel subunit selectively. </p><p>Goldberg et al. (2007) identified 10 different mutations in the SCN9A gene (see, e.g., 603415.0014-603415.0015), 9 of which were truncating mutations, in affected members of 9 different families with congenital insensitivity to pain. The families were from Canada, the U.S., and Argentina as well as various countries in Europe. </p><p>Weiss et al. (2011) studied the individual reported by Nilsen et al. (2009). This individual was heterozygous for a frameshift and nonsense mutation in the NaV1.7 protein. Weiss et al. (2011) also studied 2 other individuals, sibs, who were compound heterozygous for nonsense and frameshift mutations. None of the affected individuals was able to smell. In the case of the sibs, both parents, who were heterozygous, had intact olfactory sensation. </p><p>In 3 Japanese patients from 2 unrelated families with HSAN2D, Yuan et al. (2013) identified a homozygous truncating mutation in the SCN9A gene (603415.0028). The mutation was predicted to result in nonsense-mediated mRNA decay and loss of SCN9A function in nociceptive neurons. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Becak et al. (1963); Bourlond and Winkelmann (1966); Ford and Wilkins
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(1938)
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Baxter, D. W., Olszewski, J.
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<strong>Congenital universal insensitivity to pain.</strong>
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Brain 83: 381-393, 1960.
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[PubMed: 13688072]
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[Full Text: https://doi.org/10.1093/brain/83.3.381]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Becak, W., Becak, M. L., Andrade, J. D.
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<strong>A genetical investigation of congenital analgesia. I. Cytogenetic studies.</strong>
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Acta Genet. Statist. Med. 14: 133-142, 1964.
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[PubMed: 14209604]
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[Full Text: https://doi.org/10.1159/000151839]
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</p>
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</li>
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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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