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Entry
- #256800 - INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS; CIPA
- OMIM
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<span class="h4">#256800</span>
<br />
<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/256800"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS162400"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#otherFeatures">Other Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS" 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>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=935&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
<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;">&#9658;</span>Gene Reviews</div>
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<div style="margin-left: 0.5em;"><a href="https://www.ncbi.nlm.nih.gov/books/NBK1769/" title="NTRK1 Congenital Insensitivity to Pain with Anhidrosis" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">NTRK1 Congenital Insensiti…</a></div><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>
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<div><a href="https://www.diseaseinfosearch.org/x/3832" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
<div><a href="https://medlineplus.gov/genetics/condition/congenital-insensitivity-to-pain-with-anhidrosis" 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.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=642" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/affa164c-14ad-44b8-8fee-9fd6ccd6eb5a/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0070146" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/256800" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://omia.org/results?search_type=advanced&omia_id=000312,001150" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:256800" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 62985007<br />
<strong>ORPHA:</strong> 642<br />
<strong>DO:</strong> 0070146<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
256800
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS; CIPA
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
NEUROPATHY, CONGENITAL SENSORY, WITH ANHIDROSIS<br />
HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY IV; HSAN4<br />
HSAN IV<br />
FAMILIAL DYSAUTONOMIA, TYPE II
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/1269?start=-3&limit=10&highlight=1269">
1q23.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Insensitivity to pain, congenital, with anhidrosis
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/256800"> 256800 </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">
NTRK1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191315"> 191315 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/256800" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS162400" class="btn btn-info" role="button"> Phenotypic Series </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/256800" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/256800" 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> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Absent corneal sensation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/373423002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">373423002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0271291&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0271291</a>]</span><br /> -
Corneal opacities <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64634000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64634000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413921009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413921009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/371.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">371.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0010038&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010038</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007957" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007957</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007957" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007957</a>]</span><br /> -
Corneal ulceration <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91514001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91514001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H16.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H16.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H16.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H16.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/370.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">370.0</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/370.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">370.00</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0010043&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010043</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012804" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012804</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012804" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012804</a>]</span><br /> -
Very poor corneal healing <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850430&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850430</a>]</span><br /> -
Corneal scarring <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95726001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95726001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349702&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349702</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000559" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000559</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000559" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000559</a>]</span><br /> -
Neurotrophic keratitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128080005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128080005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0339296&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0339296</a>]</span><br /> -
Normal lacrimation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850431&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850431</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">
- Accidental injury and ulceration of the lips and tongue due to decreased sensation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837601&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837601</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Vascular </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Postural hypotension with compensatory tachycardia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850438&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850438</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005307" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005307</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005307" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005307</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 arthropathy <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> <span class="mim-feature-ids hidden">[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 /> -
Osteomyelitis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/60168000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">60168000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M86.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M86.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M86" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M86</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/730.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">730.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/730.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">730.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0029443&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0029443</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002754" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002754</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002754" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002754</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">
- Acral ulceration and osteomyelitis leading to autoamputation of the digits <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837603&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837603</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Feet </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Acral ulceration and osteomyelitis leading to autoamputation of the digits <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837603&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837603</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Anhidrosis <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 /> -
Anhidrosis of the trunk and limbs 100% of the time <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850435&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850435</a>]</span><br /> -
Thick, calloused skin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850436&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850436</a>]</span><br /> -
Lichenification of palms <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850437&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850437</a>]</span><br /> -
Skin ulcers <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/46742003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">46742003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L98.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L98.4</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0037299&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037299</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0200042" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0200042</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Nails </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Dystrophic nails <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/87065009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">87065009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L60.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L60.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221260</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008404" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008404</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008404" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008404</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hair </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypotrichosis of the scalp <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857042&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857042</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002209</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Developmental delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
Mental retardation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a>, <a href="https://bioportal.bioontology.org/search?q=C0025362&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025362</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Peripheral Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Autonomic dysfunction <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 /> -
Pain insensitivity, diffuse (including to visceral pain) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850422&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850422</a>]</span><br /> -
Temperature insensitivity, diffuse <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850423&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850423</a>]</span><br /> -
Markedly decreased small unmyelinated nerve fibers <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850424&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850424</a>]</span><br /> -
Decreased small myelinated nerve fibers <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850425&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850425</a>]</span><br /> -
Loss of sympathetic fibers innervating eccrine sweat glands <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850426&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850426</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Behavioral Psychiatric Manifestations </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hyperactivity in 50% of patients <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850427&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850427</a>]</span><br /> -
Emotional lability in 50% of patients <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850428&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850428</a>]</span><br /> -
Susceptibility to rage in 50% of patients <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850429&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850429</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> METABOLIC FEATURES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Fever, episodic, severe <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850440</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/386661006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">386661006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/50177009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">50177009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R50.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R50.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/780.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">780.60</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001945" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001945</a>]</span><br /> -
Fever is often the presenting symptom <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850441&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850441</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> IMMUNOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Delayed wound healing with normal immune system <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850432&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850432</a>]</span><br /> -
Increased susceptibility to severe and frequent infections with Staphylococcus aureus <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4012164&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4012164</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> LABORATORY ABNORMALITIES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Absent axonal flare response to intradermal histamine injection <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1850434&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1850434</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Onset in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848924</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span><br /> -
Accidental injury to the self (mouth, digits) has been referred to by some as 'self-mutilation'<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the neurotrophic tyrosine kinase receptor, type 1, gene (NTRK1, <a href="/entry/191315#0001">191315.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Hereditary sensory and autonomic neuropathy
- <a href="/phenotypicSeries/PS162400">PS162400</a>
- 16 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/949?start=-3&limit=10&highlight=949"> 1p13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608654"> Neuropathy, hereditary sensory and autonomic, type V </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608654"> 608654 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162030"> NGF </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162030"> 162030 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/1269?start=-3&limit=10&highlight=1269"> 1q23.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/256800"> Insensitivity to pain, congenital, with anhidrosis </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/256800"> 256800 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191315"> NTRK1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/191315"> 191315 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/1177?start=-3&limit=10&highlight=1177"> 2q37.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614213"> Neuropathy, hereditary sensory, type IIC </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614213"> 614213 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601255"> KIF1A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/601255"> 601255 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/104?start=-3&limit=10&highlight=104"> 3p24-p22 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608088"> Neuropathy, hereditary sensory, type IB </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608088"> 608088 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608088"> HSN1B </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608088"> 608088 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/183?start=-3&limit=10&highlight=183"> 3p22.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615548"> Neuropathy, hereditary sensory and autonomic, type VII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615548"> 615548 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604385"> SCN11A </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604385"> 604385 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/5/67?start=-3&limit=10&highlight=67"> 5p15.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613115"> Neuropathy, hereditary sensory and autonomic, type IIB </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613115"> 613115 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613114"> RETREG1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613114"> 613114 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/611?start=-3&limit=10&highlight=611"> 6p12.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614653"> Neuropathy, hereditary sensory and autonomic, type VI </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614653"> 614653 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/113810"> DST </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/113810"> 113810 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/301?start=-3&limit=10&highlight=301"> 9q22.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162400"> Neuropathy, hereditary sensory and autonomic, type IA </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/162400"> 162400 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605712"> SPTLC1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605712"> 605712 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/397?start=-3&limit=10&highlight=397"> 9q31.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/223900"> Dysautonomia, familial </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/223900"> 223900 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603722"> ELP1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603722"> 603722 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/9/579?start=-3&limit=10&highlight=579"> 9q34.12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616488"> Neuropathy, hereditary sensory and autonomic, type VIII </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616488"> 616488 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616458"> PRDM12 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616458"> 616458 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/528?start=-3&limit=10&highlight=528"> 11q13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615632"> Neuropathy, hereditary sensory, type IF </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615632"> 615632 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609369"> ATL3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/609369"> 609369 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/10?start=-3&limit=10&highlight=10"> 12p13.33 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/201300"> Neuropathy, hereditary sensory and autonomic, type II </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/201300"> 201300 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605232"> WNK1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605232"> 605232 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/225?start=-3&limit=10&highlight=225"> 14q22.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613708"> Neuropathy, hereditary sensory, type ID </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613708"> 613708 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606439"> ATL1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606439"> 606439 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/419?start=-3&limit=10&highlight=419"> 14q24.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613640"> Neuropathy, hereditary sensory and autonomic, type IC </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613640"> 613640 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605713"> SPTLC2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/605713"> 605713 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/14/564?start=-3&limit=10&highlight=564"> 14q32.31 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615031"> Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615031"> 615031 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615000"> TECPR2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/615000"> 615000 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/260?start=-3&limit=10&highlight=260"> 19p13.2 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614116"> Neuropathy, hereditary sensory, type IE </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/614116"> 614116 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/126375"> DNMT1 </a>
</span>
</td>
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<span class="mim-font">
<a href="/entry/126375"> 126375 </a>
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<p>A number sign (#) is used with this entry because congenital insensitivity to pain with anhidrosis (CIPA) is caused by homozygous or compound heterozygous mutation in the NTRK1 gene (<a href="/entry/191315">191315</a>) on chromosome 1q23.</p><p>For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (<a href="/entry/162400">162400</a>).</p>
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<strong>Clinical Features</strong>
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<p>Swanson et al. (<a href="#18" class="mim-tip-reference" title="Swanson, A. G., Buchan, G. C., Alvord, E. C., Jr. &lt;strong&gt;Absence of Lissauer&#x27;s tract and small dorsal root axons in familial, congenital, universal insensitivity to pain.&lt;/strong&gt; Trans. Am. Neurol. Assoc. 88: 99-103, 1963.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14272277/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14272277&lt;/a&gt;]" pmid="14272277">1963</a>, <a href="#19" class="mim-tip-reference" title="Swanson, A. G., Buchan, G. C., Alvord, E. C., Jr. &lt;strong&gt;Anatomic changes in congenital insensitivity to pain: absence of small primary sensory neurons in ganglia, roots and Lissauer&#x27;s tract.&lt;/strong&gt; Arch. Neurol. 12: 12-18, 1965.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14224855/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14224855&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1965.00460250016002&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14224855">1965</a>) described 2 brothers with congenital insensitivity to pain and anhidrosis, despite normal-appearing sweat glands on skin biopsy. Temperature sensation was also defective. One of the brothers died after a 24-hour illness during which his temperature reached 109 degrees F. Almost complete absence of the first order afferent system considered responsible for pain and temperature was found at autopsy (<a href="#19" class="mim-tip-reference" title="Swanson, A. G., Buchan, G. C., Alvord, E. C., Jr. &lt;strong&gt;Anatomic changes in congenital insensitivity to pain: absence of small primary sensory neurons in ganglia, roots and Lissauer&#x27;s tract.&lt;/strong&gt; Arch. Neurol. 12: 12-18, 1965.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14224855/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14224855&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1965.00460250016002&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14224855">Swanson et al., 1965</a>). <a href="#13" class="mim-tip-reference" title="Pinsky, L., DiGeorge, A. M. &lt;strong&gt;Congenital familial sensory neuropathy with anhidrosis.&lt;/strong&gt; J. Pediat. 68: 1-13, 1966.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4158991/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4158991&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(66)80417-1&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4158991">Pinsky and DiGeorge (1966)</a> described the same disorder in 3 mentally retarded children, 2 of whom were sibs, with recurrent episodes of unexplained fever, repeated traumatic and thermal injuries, and self-mutilating behavior. Sweating could not be elicited by thermal, painful, emotional, or chemical stimuli, and histamine evoked no axonal flare. Subcutaneous administration of mecholyl or neostigmine in doses capable of producing lacrimation in normal children failed to do so in these patients, despite their occasional spontaneous lacrimation. <a href="#23" class="mim-tip-reference" title="Wolfe, S. M., Henkin, R. I. &lt;strong&gt;Absence of taste in type II familial dysautonomia: unresponsiveness to methacholine despite the presence of taste buds.&lt;/strong&gt; J. Pediat. 77: 103-108, 1970.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5450270/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5450270&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(70)80051-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5450270">Wolfe and Henkin (1970)</a>, who referred to the disorder in Pinsky and DiGeorge's sibs as type II familial dysautonomia, described unresponsiveness to methacholine despite the presence of taste buds. They suggested that it is the same as the disorder reported in 2 sibs of each of 2 families by <a href="#20" class="mim-tip-reference" title="Swanson, A. G. &lt;strong&gt;Congenital insensitivity to pain with anhidrosis: a unique syndrome in two male siblings.&lt;/strong&gt; Arch. Neurol. 8: 299-306, 1963.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13979626/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13979626&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archneur.1963.00460030083008&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="13979626">Swanson (1963)</a> and by <a href="#21" class="mim-tip-reference" title="Vassella, F., Emrich, H. M., Kraus-Ruppert, R., Aufdermaur, F., Tonz, O. &lt;strong&gt;Congenital sensory neuropathy with anhidrosis.&lt;/strong&gt; Arch. Dis. Child. 43: 124-130, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4171106/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4171106&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/adc.43.227.124&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4171106">Vassella et al. (1968)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4158991+5450270+14224855+13979626+14272277+4171106" 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="Yanagida, H. &lt;strong&gt;Congenital insensitivity and naloxone. (Letter)&lt;/strong&gt; Lancet 312: 520-521, 1978. Note: Originally Volume II.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/79883/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;79883&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0140-6736(78)92238-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="79883">Yanagida (1978)</a> found that naloxone, a specific antagonist of opiate receptors, was effective in CIPA, suggesting that overproduction of brain endorphins is involved in the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=79883" 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="Ishii, N., Kawaguchi, H., Miyakawa, K., Nakajima, H. &lt;strong&gt;Congenital sensory neuropathy with anhidrosis.&lt;/strong&gt; Arch. Derm. 124: 564-566, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3281596/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3281596&lt;/a&gt;]" pmid="3281596">Ishii et al. (1988)</a> described a Japanese girl with CIPA who died at the age of 21 months. During the first few months of life, she suffered from recurrent episodes of unexplained high fever without sweating and hard breathing, and was found to lack sensation to pain. After the establishment of dentition, she bit off the apical part of her tongue and began self-mutilating her lips and the tips of her fingers. <a href="#4" class="mim-tip-reference" title="Courtney, K. B., Freedenberg, D. L. &lt;strong&gt;A new variant of hereditary sensory neuropathy type IV: anhidrosis, pain insensitivity, and normal intelligence. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 47 (suppl.): A53 only, 1990."None>Courtney and Freedenberg (1990)</a> described a patient who appeared to have HSAN4, but did not have developmental delay. <a href="#15" class="mim-tip-reference" title="Rosemberg, S., Nagahashi Marie, S. K., Kliemann, S. &lt;strong&gt;Congenital insensitivity to pain with anhidrosis (hereditary sensory and autonomic neuropathy type IV).&lt;/strong&gt; Pediat. Neurol. 11: 50-56, 1994."None>Rosemberg et al. (1994)</a> presented a 4-year-old girl, the second child of consanguineous parents, who had typical HSAN4. They provided a useful review of the literature, which included 31 patients, noting that 20% of the patients succumbed to hyperpyrexia, most of them before age 3. Most of the children were mentally retarded, with IQs varying from 41 to 78, the majority being in the 60s. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3281596" 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="#8" class="mim-tip-reference" title="Ismail, E. A. R., Al-Shammari, N., Anim, J. T., Moosa, A. &lt;strong&gt;Congenital insensitivity to pain with anhidrosis: lack of eccrine sweat gland innervation confirmed.&lt;/strong&gt; J. Child Neurol. 13: 243-246, 1998. Note: Erratum: J. Child Neurol. 13: 632 only, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9620018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9620018&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1177/088307389801300511&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9620018">Ismail et al. (1998)</a> described an 8-year-old girl who was 1 of 2 affected sibs from healthy first-cousin Kuwaiti parents. She first presented at the age of 24 hours with fever, which persisted for 8 weeks. Extensive investigations revealed no cause for the fever. Recurrent febrile convulsions occurred, with fever of 42 degrees C induced by environmental temperature in Kuwait. She had mild hypotonia and hyporeflexia, did not cry during blood sampling, had never sweated, and never developed sphincter control. Pictures of the child demonstrated severe mutilation of the hands and feet as well as of the tongue and lips. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9620018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Yagev, R., Levy, J., Shorer, Z., Lifshitz, T. &lt;strong&gt;Congenital insensitivity to pain with anhidrosis: ocular and systemic manifestations.&lt;/strong&gt; Am. J. Ophthal. 127: 322-326, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10088743/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10088743&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0002-9394(98)00370-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10088743">Yagev et al. (1999)</a> studied 15 Bedouin children with CIPA and found that all had absent corneal sensation, which led to corneal opacities in 10 (67%). Active corneal ulcers were found in 7 of the 15 children; 2 children had bilateral ulcers and 3 of the ulcers were recurrent. These corneal ulcers were characterized by very poor healing, and some required surgical interventions including lateral tarsorrhaphy, corneal patch graft, and/or penetrating keratoplasty. The authors concluded that congenital insensitivity to pain and anhidrosis, although rare, should be considered in the differential diagnosis of neurotrophic keratitis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10088743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bonkowsky, J. L., Johnson, J., Carey, J. C., Smith, A. G., Swoboda, K. J. &lt;strong&gt;An infant with primary tooth loss and palmar hyperkeratosis: a novel mutation in the NTRK1 gene causing congenital insensitivity to pain with anhidrosis.&lt;/strong&gt; Pediatrics 112: e237-e241, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12949319/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12949319&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1542/peds.112.3.e237&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12949319">Bonkowsky et al. (2003)</a> studied a 1-year-old male with an atypical presentation of CIPA, whose diagnosis was confirmed by molecular analysis. The clinical features included an abnormally high pain threshold and heat intolerance, normal nerve conduction, and the absence of epidermal and sweat gland innervation in a skin biopsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12949319" 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="#5" class="mim-tip-reference" title="Hepburn, L., Prajsnar, T. K., Klapholz, C., Moreno, P., Loynes, C. A., Ogryzko, N. V., Brown, K., Schiebler, M., Hegyi, K., Antrobus, R., Hammond, K. L., Connolly, J., and 20 others. &lt;strong&gt;A Spaetzle-like role for nerve growth factor-beta in vertebrate immunity to Staphylococcus aureus.&lt;/strong&gt; Science 346: 641-646, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25359976/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25359976&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25359976[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1258705&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25359976">Hepburn et al. (2014)</a> reported 4 patients from 3 unrelated families with genetically confirmed HSAN4, including 2 consanguineous Pakistani families. In addition to absent pain and temperature sensation and the presence of learning difficulties, all patients had a history of frequent severe Staphylococcus aureus infections of the skin, bone, or teeth, suggesting a pathogen-specific immune defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25359976" 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>Pathologic Findings</em></strong></p><p>
In a biopsy of the cutaneous branch of the radial nerve from a 9-year old girl with CIPA, <a href="#14" class="mim-tip-reference" title="Rafel, E., Alberca, R., Bautista, J., Navarrete, M., Lazo, J. &lt;strong&gt;Congenital insensitivity to pain with anhidrosis.&lt;/strong&gt; Muscle Nerve 3: 216-220, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6154886/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6154886&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/mus.880030305&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6154886">Rafel et al. (1980)</a> found complete absence of small myelinated and unmyelinated fibers. They suggested that the disorder was not a hereditary sensory neuropathy, but rather a developmental defect. In a sural nerve biopsy from a 2-month-old boy with CIPA, <a href="#12" class="mim-tip-reference" title="Matsuo, M., Kurokawa, T., Goya, N., Ohta, M. &lt;strong&gt;Congenital insensitivity to pain with anhidrosis in a 2-month-old boy.&lt;/strong&gt; Neurology 31: 1190-1192, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6167904/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6167904&lt;/a&gt;]" pmid="6167904">Matsuo et al. (1981)</a> found that unmyelinated fibers were essentially lacking, and that the number of small myelinated fibers was decreased. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6154886+6167904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Langer, J., Goebel, H. H., Veit, S. &lt;strong&gt;Eccrine sweat glands are not innervated in hereditary sensory neuropathy type IV: an electron- microscopic study.&lt;/strong&gt; Acta Neuropath. 54: 199-202, 1981.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6167137/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6167137&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00687742&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6167137">Langer et al. (1981)</a> and <a href="#8" class="mim-tip-reference" title="Ismail, E. A. R., Al-Shammari, N., Anim, J. T., Moosa, A. &lt;strong&gt;Congenital insensitivity to pain with anhidrosis: lack of eccrine sweat gland innervation confirmed.&lt;/strong&gt; J. Child Neurol. 13: 243-246, 1998. Note: Erratum: J. Child Neurol. 13: 632 only, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9620018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9620018&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1177/088307389801300511&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9620018">Ismail et al. (1998)</a> demonstrated absence of eccrine sweat gland innervation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6167137+9620018" 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 immunohistochemical studies of skin biopsies from a 10-year-old girl with CIPA, <a href="#22" class="mim-tip-reference" title="Verze, L., Viglietti-Panzica, C., Plumari, L., Calcagni, M., Stella, M., Schrama, L. H., Panzica, G. C. &lt;strong&gt;Cutaneous innervation in hereditary sensory and autonomic neuropathy type IV.&lt;/strong&gt; Neurology 55: 126-128, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10891921/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10891921&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.55.1.126&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10891921">Verze et al. (2000)</a> found greatly reduced numbers of nerve fibers compared to normal controls. In particular, the epidermis was free of nerve branches or endings, whereas rare nerve fibers were present in the dermis. No autonomic nerve fibers were visible around sweat glands or hair follicles, and blood vessel walls were completely devoid of nerve fibers. Degenerative changes were not found. <a href="#22" class="mim-tip-reference" title="Verze, L., Viglietti-Panzica, C., Plumari, L., Calcagni, M., Stella, M., Schrama, L. H., Panzica, G. C. &lt;strong&gt;Cutaneous innervation in hereditary sensory and autonomic neuropathy type IV.&lt;/strong&gt; Neurology 55: 126-128, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10891921/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10891921&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1212/wnl.55.1.126&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10891921">Verze et al. (2000)</a> concluded that HSAN4 patients have a hereditary developmental defect of nerve outgrowth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10891921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Kilic, S. S., Ozturk, R., Sarisozen, B., Rotthier, A., Baets, J., Timmerman, V. &lt;strong&gt;Humoral immunodeficiency in congenital insensitivity to pain with anhidrosis.&lt;/strong&gt; Neurogenetics 10: 161-165, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19089473/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19089473&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-008-0165-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19089473">Kilic et al. (2009)</a> reported a Turkish girl with HSAN4 confirmed by genetic analysis. In addition to the classic features, she had a humoral immune defect, with recurrent infections and decreased serum immunoglobulins. The infections responded well to intravenous Ig therapy. <a href="#9" class="mim-tip-reference" title="Kilic, S. S., Ozturk, R., Sarisozen, B., Rotthier, A., Baets, J., Timmerman, V. &lt;strong&gt;Humoral immunodeficiency in congenital insensitivity to pain with anhidrosis.&lt;/strong&gt; Neurogenetics 10: 161-165, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19089473/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19089473&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s10048-008-0165-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19089473">Kilic et al. (2009)</a> postulated a role for the NTRK1 gene in B lymphocyte signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19089473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Shatzky, S., Moses, S., Levy, J., Pinsk, V., Hershkovitz, E., Herzog, L., Shorer, Z., Luder, A., Parvari, R. &lt;strong&gt;Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies.&lt;/strong&gt; Am. J. Med. Genet. 92: 353-360, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10861667/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10861667&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(20000619)92:5&lt;353::aid-ajmg12&gt;3.0.co;2-c&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10861667">Shatzky et al. (2000)</a> studied CIPA in consanguineous Israeli-Bedouin groups in which the disorder has a relatively high prevalence. They reported clinical studies of 28 patients. Using the linkage approach, they found that 9 of 10 unrelated families with CIPA were linked to the NTRK1 gene, which had been mapped to chromosome 1q23-q24; in 1 family, linkage was excluded, implying genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861667" 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 CIPA in the families reported by <a href="#6" class="mim-tip-reference" title="Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., Matsuda, I. &lt;strong&gt;Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.&lt;/strong&gt; Nature Genet. 13: 485-488, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8696348/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8696348&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0896-485&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8696348">Indo et al. (1996)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8696348" 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>Based on the phenotypic features of a mouse model lacking the gene encoding the receptor tyrosine kinase (NTRK1; <a href="/entry/191315">191315</a>) for nerve growth factor (NGF; <a href="/entry/162030">162030</a>) (<a href="#17" class="mim-tip-reference" title="Smeyne, R. J., Klein, R., Schnapp, A., Long, L. K., Bryant, S., Lewin, A., Lira, S. A., Barbacid, M. &lt;strong&gt;Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene.&lt;/strong&gt; Nature 368: 246-249, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8145823/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8145823&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/368246a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8145823">Smeyne et al., 1994</a>), <a href="#6" class="mim-tip-reference" title="Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., Matsuda, I. &lt;strong&gt;Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.&lt;/strong&gt; Nature Genet. 13: 485-488, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8696348/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8696348&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0896-485&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8696348">Indo et al. (1996)</a> studied human NTRK1 as a candidate gene for the site of the mutation in CIPA. In 3 unrelated patients with CIPA, each of whom had consanguineous parents, <a href="#6" class="mim-tip-reference" title="Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., Matsuda, I. &lt;strong&gt;Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.&lt;/strong&gt; Nature Genet. 13: 485-488, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8696348/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8696348&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0896-485&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8696348">Indo et al. (1996)</a> identified a deletion (<a href="/entry/191315#0001">191315.0001</a>), a splice site aberration (<a href="/entry/191315#0002">191315.0002</a>), and a missense mutation (<a href="/entry/191315#0003">191315.0003</a>) in the tyrosine kinase domain of NTRK1. Their findings strongly suggested that defects in NTRK1 cause CIPA and that the NGF-NTRK system has a crucial role in the development and function of the nociceptive reception system, as well as establishment of thermal regulation via sweating in humans. The results also implicated genes encoding other TRK and neurotrophin family members as candidates for developmental defects of the nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8145823+8696348" 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 patients with CIPA from an isolate of Bedouins in northern Israel, <a href="#16" class="mim-tip-reference" title="Shatzky, S., Moses, S., Levy, J., Pinsk, V., Hershkovitz, E., Herzog, L., Shorer, Z., Luder, A., Parvari, R. &lt;strong&gt;Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies.&lt;/strong&gt; Am. J. Med. Genet. 92: 353-360, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10861667/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10861667&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/1096-8628(20000619)92:5&lt;353::aid-ajmg12&gt;3.0.co;2-c&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10861667">Shatzky et al. (2000)</a> identified 2 mutations (<a href="/entry/191315#0010">191315.0010</a>; <a href="/entry/191315#0011">191315.0011</a>) in the NTRK1 gene. They made the prenatal diagnosis in 8 cases, 2 by linkage analysis and 6 by direct checking for one of the novel mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861667" 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="#Axelrod1983" class="mim-tip-reference" title="Axelrod, F. B., Pearson, J., Tepperberg, J., Ackerman, B. D. &lt;strong&gt;Congenital sensory neuropathy with skeletal dysplasia.&lt;/strong&gt; J. Pediat. 102: 727-730, 1983.">Axelrod et al. (1983)</a>; <a href="#Brown1966" class="mim-tip-reference" title="Brown, J. W., Podosin, R. &lt;strong&gt;A syndrome of the neural crest.&lt;/strong&gt; Arch. Neurol. 15: 294-301, 1966.">Brown and Podosin (1966)</a>; <a href="#Lee1976" class="mim-tip-reference" title="Lee, E. L., Oh, G. C., Lam, K. L., Parameswaran, N. &lt;strong&gt;Congenital sensory neuropathy with anhidrosis: a case report.&lt;/strong&gt; Pediatrics 57: 259-261, 1976.">Lee et al. (1976)</a>
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Axelrod, F. B., Pearson, J., Tepperberg, J., Ackerman, B. D.
<strong>Congenital sensory neuropathy with skeletal dysplasia.</strong>
J. Pediat. 102: 727-730, 1983.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6573468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6573468</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6573468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/s0022-3476(83)80246-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1542/peds.112.3.e237" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1966.00470150072012" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1258705" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0896-485" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1177/088307389801300511" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-008-0165-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00687742" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(66)80417-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/mus.880030305" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/1096-8628(20000619)92:5&lt;353::aid-ajmg12&gt;3.0.co;2-c" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/368246a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1965.00460250016002" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.1963.00460030083008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/adc.43.227.124" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/wnl.55.1.126" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(70)80051-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0002-9394(98)00370-5" target="_blank">Full Text</a>]
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<p class="mim-text-font">
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[<a href="https://doi.org/10.1016/s0140-6736(78)92238-9" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 5/14/2009<br>Cassandra L. Kniffin - updated : 5/21/2004<br>Cassandra L. Kniffin - updated : 5/18/2004<br>Natalie E. Krasikov - updated : 3/12/2004<br>Victor A. McKusick - updated : 6/7/2000<br>Jane Kelly - updated : 8/25/1999<br>Victor A. McKusick - updated : 10/7/1998
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Victor A. McKusick : 6/4/1986
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carol : 11/19/2014<br>ckniffin : 11/19/2014<br>wwang : 5/21/2009<br>ckniffin : 5/14/2009<br>terry : 3/13/2009<br>mgross : 8/10/2005<br>ckniffin : 5/24/2004<br>carol : 5/24/2004<br>carol : 5/21/2004<br>ckniffin : 5/18/2004<br>carol : 3/16/2004<br>terry : 3/12/2004<br>carol : 6/9/2000<br>terry : 6/7/2000<br>carol : 8/25/1999<br>mgross : 6/8/1999<br>dkim : 10/16/1998<br>carol : 10/13/1998<br>terry : 10/7/1998<br>alopez : 9/14/1998<br>dkim : 9/10/1998<br>mark : 8/7/1996<br>terry : 8/5/1996<br>carol : 9/27/1994<br>mimadm : 3/11/1994<br>supermim : 3/17/1992<br>carol : 10/25/1990<br>carol : 10/11/1990<br>supermim : 3/20/1990
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<span class="mim-font">
<strong>#</strong> 256800
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<span class="mim-font">
INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS; CIPA
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<em>Alternative titles; symbols</em>
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NEUROPATHY, CONGENITAL SENSORY, WITH ANHIDROSIS<br />
HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY IV; HSAN4<br />
HSAN IV<br />
FAMILIAL DYSAUTONOMIA, TYPE II
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<strong>SNOMEDCT:</strong> 62985007; &nbsp;
<strong>ORPHA:</strong> 642; &nbsp;
<strong>DO:</strong> 0070146; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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1q23.1
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Insensitivity to pain, congenital, with anhidrosis
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256800
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Autosomal recessive
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3
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NTRK1
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191315
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because congenital insensitivity to pain with anhidrosis (CIPA) is caused by homozygous or compound heterozygous mutation in the NTRK1 gene (191315) on chromosome 1q23.</p><p>For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).</p>
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<strong>Clinical Features</strong>
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<p>Swanson et al. (1963, 1965) described 2 brothers with congenital insensitivity to pain and anhidrosis, despite normal-appearing sweat glands on skin biopsy. Temperature sensation was also defective. One of the brothers died after a 24-hour illness during which his temperature reached 109 degrees F. Almost complete absence of the first order afferent system considered responsible for pain and temperature was found at autopsy (Swanson et al., 1965). Pinsky and DiGeorge (1966) described the same disorder in 3 mentally retarded children, 2 of whom were sibs, with recurrent episodes of unexplained fever, repeated traumatic and thermal injuries, and self-mutilating behavior. Sweating could not be elicited by thermal, painful, emotional, or chemical stimuli, and histamine evoked no axonal flare. Subcutaneous administration of mecholyl or neostigmine in doses capable of producing lacrimation in normal children failed to do so in these patients, despite their occasional spontaneous lacrimation. Wolfe and Henkin (1970), who referred to the disorder in Pinsky and DiGeorge's sibs as type II familial dysautonomia, described unresponsiveness to methacholine despite the presence of taste buds. They suggested that it is the same as the disorder reported in 2 sibs of each of 2 families by Swanson (1963) and by Vassella et al. (1968). </p><p>Yanagida (1978) found that naloxone, a specific antagonist of opiate receptors, was effective in CIPA, suggesting that overproduction of brain endorphins is involved in the disorder. </p><p>Ishii et al. (1988) described a Japanese girl with CIPA who died at the age of 21 months. During the first few months of life, she suffered from recurrent episodes of unexplained high fever without sweating and hard breathing, and was found to lack sensation to pain. After the establishment of dentition, she bit off the apical part of her tongue and began self-mutilating her lips and the tips of her fingers. Courtney and Freedenberg (1990) described a patient who appeared to have HSAN4, but did not have developmental delay. Rosemberg et al. (1994) presented a 4-year-old girl, the second child of consanguineous parents, who had typical HSAN4. They provided a useful review of the literature, which included 31 patients, noting that 20% of the patients succumbed to hyperpyrexia, most of them before age 3. Most of the children were mentally retarded, with IQs varying from 41 to 78, the majority being in the 60s. </p><p>Ismail et al. (1998) described an 8-year-old girl who was 1 of 2 affected sibs from healthy first-cousin Kuwaiti parents. She first presented at the age of 24 hours with fever, which persisted for 8 weeks. Extensive investigations revealed no cause for the fever. Recurrent febrile convulsions occurred, with fever of 42 degrees C induced by environmental temperature in Kuwait. She had mild hypotonia and hyporeflexia, did not cry during blood sampling, had never sweated, and never developed sphincter control. Pictures of the child demonstrated severe mutilation of the hands and feet as well as of the tongue and lips. </p><p>Yagev et al. (1999) studied 15 Bedouin children with CIPA and found that all had absent corneal sensation, which led to corneal opacities in 10 (67%). Active corneal ulcers were found in 7 of the 15 children; 2 children had bilateral ulcers and 3 of the ulcers were recurrent. These corneal ulcers were characterized by very poor healing, and some required surgical interventions including lateral tarsorrhaphy, corneal patch graft, and/or penetrating keratoplasty. The authors concluded that congenital insensitivity to pain and anhidrosis, although rare, should be considered in the differential diagnosis of neurotrophic keratitis. </p><p>Bonkowsky et al. (2003) studied a 1-year-old male with an atypical presentation of CIPA, whose diagnosis was confirmed by molecular analysis. The clinical features included an abnormally high pain threshold and heat intolerance, normal nerve conduction, and the absence of epidermal and sweat gland innervation in a skin biopsy. </p><p>Hepburn et al. (2014) reported 4 patients from 3 unrelated families with genetically confirmed HSAN4, including 2 consanguineous Pakistani families. In addition to absent pain and temperature sensation and the presence of learning difficulties, all patients had a history of frequent severe Staphylococcus aureus infections of the skin, bone, or teeth, suggesting a pathogen-specific immune defect. </p><p><strong><em>Pathologic Findings</em></strong></p><p>
In a biopsy of the cutaneous branch of the radial nerve from a 9-year old girl with CIPA, Rafel et al. (1980) found complete absence of small myelinated and unmyelinated fibers. They suggested that the disorder was not a hereditary sensory neuropathy, but rather a developmental defect. In a sural nerve biopsy from a 2-month-old boy with CIPA, Matsuo et al. (1981) found that unmyelinated fibers were essentially lacking, and that the number of small myelinated fibers was decreased. </p><p>Langer et al. (1981) and Ismail et al. (1998) demonstrated absence of eccrine sweat gland innervation. </p><p>In immunohistochemical studies of skin biopsies from a 10-year-old girl with CIPA, Verze et al. (2000) found greatly reduced numbers of nerve fibers compared to normal controls. In particular, the epidermis was free of nerve branches or endings, whereas rare nerve fibers were present in the dermis. No autonomic nerve fibers were visible around sweat glands or hair follicles, and blood vessel walls were completely devoid of nerve fibers. Degenerative changes were not found. Verze et al. (2000) concluded that HSAN4 patients have a hereditary developmental defect of nerve outgrowth. </p>
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<span class="mim-font">
<strong>Other Features</strong>
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<p>Kilic et al. (2009) reported a Turkish girl with HSAN4 confirmed by genetic analysis. In addition to the classic features, she had a humoral immune defect, with recurrent infections and decreased serum immunoglobulins. The infections responded well to intravenous Ig therapy. Kilic et al. (2009) postulated a role for the NTRK1 gene in B lymphocyte signaling. </p>
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<strong>Mapping</strong>
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<p>Shatzky et al. (2000) studied CIPA in consanguineous Israeli-Bedouin groups in which the disorder has a relatively high prevalence. They reported clinical studies of 28 patients. Using the linkage approach, they found that 9 of 10 unrelated families with CIPA were linked to the NTRK1 gene, which had been mapped to chromosome 1q23-q24; in 1 family, linkage was excluded, implying genetic heterogeneity. </p>
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<strong>Inheritance</strong>
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<p>The transmission pattern of CIPA in the families reported by Indo et al. (1996) was consistent with autosomal recessive inheritance. </p>
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<strong>Molecular Genetics</strong>
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<p>Based on the phenotypic features of a mouse model lacking the gene encoding the receptor tyrosine kinase (NTRK1; 191315) for nerve growth factor (NGF; 162030) (Smeyne et al., 1994), Indo et al. (1996) studied human NTRK1 as a candidate gene for the site of the mutation in CIPA. In 3 unrelated patients with CIPA, each of whom had consanguineous parents, Indo et al. (1996) identified a deletion (191315.0001), a splice site aberration (191315.0002), and a missense mutation (191315.0003) in the tyrosine kinase domain of NTRK1. Their findings strongly suggested that defects in NTRK1 cause CIPA and that the NGF-NTRK system has a crucial role in the development and function of the nociceptive reception system, as well as establishment of thermal regulation via sweating in humans. The results also implicated genes encoding other TRK and neurotrophin family members as candidates for developmental defects of the nervous system. </p><p>In patients with CIPA from an isolate of Bedouins in northern Israel, Shatzky et al. (2000) identified 2 mutations (191315.0010; 191315.0011) in the NTRK1 gene. They made the prenatal diagnosis in 8 cases, 2 by linkage analysis and 6 by direct checking for one of the novel mutations. </p>
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<h4>
<span class="mim-font">
<strong>See Also:</strong>
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</h4>
<span class="mim-text-font">
Axelrod et al. (1983); Brown and Podosin (1966); Lee et al. (1976)
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<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
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</h4>
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</div>
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<ol>
<li>
<p class="mim-text-font">
Axelrod, F. B., Pearson, J., Tepperberg, J., Ackerman, B. D.
<strong>Congenital sensory neuropathy with skeletal dysplasia.</strong>
J. Pediat. 102: 727-730, 1983.
[PubMed: 6573468]
[Full Text: https://doi.org/10.1016/s0022-3476(83)80246-7]
</p>
</li>
<li>
<p class="mim-text-font">
Bonkowsky, J. L., Johnson, J., Carey, J. C., Smith, A. G., Swoboda, K. J.
<strong>An infant with primary tooth loss and palmar hyperkeratosis: a novel mutation in the NTRK1 gene causing congenital insensitivity to pain with anhidrosis.</strong>
Pediatrics 112: e237-e241, 2003.
[PubMed: 12949319]
[Full Text: https://doi.org/10.1542/peds.112.3.e237]
</p>
</li>
<li>
<p class="mim-text-font">
Brown, J. W., Podosin, R.
<strong>A syndrome of the neural crest.</strong>
Arch. Neurol. 15: 294-301, 1966.
[PubMed: 4161748]
[Full Text: https://doi.org/10.1001/archneur.1966.00470150072012]
</p>
</li>
<li>
<p class="mim-text-font">
Courtney, K. B., Freedenberg, D. L.
<strong>A new variant of hereditary sensory neuropathy type IV: anhidrosis, pain insensitivity, and normal intelligence. (Abstract)</strong>
Am. J. Hum. Genet. 47 (suppl.): A53 only, 1990.
</p>
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<li>
<p class="mim-text-font">
Hepburn, L., Prajsnar, T. K., Klapholz, C., Moreno, P., Loynes, C. A., Ogryzko, N. V., Brown, K., Schiebler, M., Hegyi, K., Antrobus, R., Hammond, K. L., Connolly, J., and 20 others.
<strong>A Spaetzle-like role for nerve growth factor-beta in vertebrate immunity to Staphylococcus aureus.</strong>
Science 346: 641-646, 2014.
[PubMed: 25359976]
[Full Text: https://doi.org/10.1126/science.1258705]
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<li>
<p class="mim-text-font">
Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., Matsuda, I.
<strong>Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.</strong>
Nature Genet. 13: 485-488, 1996.
[PubMed: 8696348]
[Full Text: https://doi.org/10.1038/ng0896-485]
</p>
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<li>
<p class="mim-text-font">
Ishii, N., Kawaguchi, H., Miyakawa, K., Nakajima, H.
<strong>Congenital sensory neuropathy with anhidrosis.</strong>
Arch. Derm. 124: 564-566, 1988.
[PubMed: 3281596]
</p>
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<li>
<p class="mim-text-font">
Ismail, E. A. R., Al-Shammari, N., Anim, J. T., Moosa, A.
<strong>Congenital insensitivity to pain with anhidrosis: lack of eccrine sweat gland innervation confirmed.</strong>
J. Child Neurol. 13: 243-246, 1998. Note: Erratum: J. Child Neurol. 13: 632 only, 1998.
[PubMed: 9620018]
[Full Text: https://doi.org/10.1177/088307389801300511]
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<li>
<p class="mim-text-font">
Kilic, S. S., Ozturk, R., Sarisozen, B., Rotthier, A., Baets, J., Timmerman, V.
<strong>Humoral immunodeficiency in congenital insensitivity to pain with anhidrosis.</strong>
Neurogenetics 10: 161-165, 2009.
[PubMed: 19089473]
[Full Text: https://doi.org/10.1007/s10048-008-0165-x]
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<li>
<p class="mim-text-font">
Langer, J., Goebel, H. H., Veit, S.
<strong>Eccrine sweat glands are not innervated in hereditary sensory neuropathy type IV: an electron- microscopic study.</strong>
Acta Neuropath. 54: 199-202, 1981.
[PubMed: 6167137]
[Full Text: https://doi.org/10.1007/BF00687742]
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<li>
<p class="mim-text-font">
Lee, E. L., Oh, G. C., Lam, K. L., Parameswaran, N.
<strong>Congenital sensory neuropathy with anhidrosis: a case report.</strong>
Pediatrics 57: 259-261, 1976.
[PubMed: 1250661]
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<li>
<p class="mim-text-font">
Matsuo, M., Kurokawa, T., Goya, N., Ohta, M.
<strong>Congenital insensitivity to pain with anhidrosis in a 2-month-old boy.</strong>
Neurology 31: 1190-1192, 1981.
[PubMed: 6167904]
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<li>
<p class="mim-text-font">
Pinsky, L., DiGeorge, A. M.
<strong>Congenital familial sensory neuropathy with anhidrosis.</strong>
J. Pediat. 68: 1-13, 1966.
[PubMed: 4158991]
[Full Text: https://doi.org/10.1016/s0022-3476(66)80417-1]
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<li>
<p class="mim-text-font">
Rafel, E., Alberca, R., Bautista, J., Navarrete, M., Lazo, J.
<strong>Congenital insensitivity to pain with anhidrosis.</strong>
Muscle Nerve 3: 216-220, 1980.
[PubMed: 6154886]
[Full Text: https://doi.org/10.1002/mus.880030305]
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<li>
<p class="mim-text-font">
Rosemberg, S., Nagahashi Marie, S. K., Kliemann, S.
<strong>Congenital insensitivity to pain with anhidrosis (hereditary sensory and autonomic neuropathy type IV).</strong>
Pediat. Neurol. 11: 50-56, 1994.
</p>
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<li>
<p class="mim-text-font">
Shatzky, S., Moses, S., Levy, J., Pinsk, V., Hershkovitz, E., Herzog, L., Shorer, Z., Luder, A., Parvari, R.
<strong>Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies.</strong>
Am. J. Med. Genet. 92: 353-360, 2000.
[PubMed: 10861667]
[Full Text: https://doi.org/10.1002/1096-8628(20000619)92:5&lt;353::aid-ajmg12&gt;3.0.co;2-c]
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<li>
<p class="mim-text-font">
Smeyne, R. J., Klein, R., Schnapp, A., Long, L. K., Bryant, S., Lewin, A., Lira, S. A., Barbacid, M.
<strong>Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene.</strong>
Nature 368: 246-249, 1994.
[PubMed: 8145823]
[Full Text: https://doi.org/10.1038/368246a0]
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<li>
<p class="mim-text-font">
Swanson, A. G., Buchan, G. C., Alvord, E. C., Jr.
<strong>Absence of Lissauer&#x27;s tract and small dorsal root axons in familial, congenital, universal insensitivity to pain.</strong>
Trans. Am. Neurol. Assoc. 88: 99-103, 1963.
[PubMed: 14272277]
</p>
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<li>
<p class="mim-text-font">
Swanson, A. G., Buchan, G. C., Alvord, E. C., Jr.
<strong>Anatomic changes in congenital insensitivity to pain: absence of small primary sensory neurons in ganglia, roots and Lissauer&#x27;s tract.</strong>
Arch. Neurol. 12: 12-18, 1965.
[PubMed: 14224855]
[Full Text: https://doi.org/10.1001/archneur.1965.00460250016002]
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<li>
<p class="mim-text-font">
Swanson, A. G.
<strong>Congenital insensitivity to pain with anhidrosis: a unique syndrome in two male siblings.</strong>
Arch. Neurol. 8: 299-306, 1963.
[PubMed: 13979626]
[Full Text: https://doi.org/10.1001/archneur.1963.00460030083008]
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</li>
<li>
<p class="mim-text-font">
Vassella, F., Emrich, H. M., Kraus-Ruppert, R., Aufdermaur, F., Tonz, O.
<strong>Congenital sensory neuropathy with anhidrosis.</strong>
Arch. Dis. Child. 43: 124-130, 1968.
[PubMed: 4171106]
[Full Text: https://doi.org/10.1136/adc.43.227.124]
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</li>
<li>
<p class="mim-text-font">
Verze, L., Viglietti-Panzica, C., Plumari, L., Calcagni, M., Stella, M., Schrama, L. H., Panzica, G. C.
<strong>Cutaneous innervation in hereditary sensory and autonomic neuropathy type IV.</strong>
Neurology 55: 126-128, 2000.
[PubMed: 10891921]
[Full Text: https://doi.org/10.1212/wnl.55.1.126]
</p>
</li>
<li>
<p class="mim-text-font">
Wolfe, S. M., Henkin, R. I.
<strong>Absence of taste in type II familial dysautonomia: unresponsiveness to methacholine despite the presence of taste buds.</strong>
J. Pediat. 77: 103-108, 1970.
[PubMed: 5450270]
[Full Text: https://doi.org/10.1016/s0022-3476(70)80051-8]
</p>
</li>
<li>
<p class="mim-text-font">
Yagev, R., Levy, J., Shorer, Z., Lifshitz, T.
<strong>Congenital insensitivity to pain with anhidrosis: ocular and systemic manifestations.</strong>
Am. J. Ophthal. 127: 322-326, 1999.
[PubMed: 10088743]
[Full Text: https://doi.org/10.1016/s0002-9394(98)00370-5]
</p>
</li>
<li>
<p class="mim-text-font">
Yanagida, H.
<strong>Congenital insensitivity and naloxone. (Letter)</strong>
Lancet 312: 520-521, 1978. Note: Originally Volume II.
[PubMed: 79883]
[Full Text: https://doi.org/10.1016/s0140-6736(78)92238-9]
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</li>
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<span class="text-nowrap mim-text-font">
Contributors:
</span>
</div>
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Cassandra L. Kniffin - updated : 11/19/2014<br>Cassandra L. Kniffin - updated : 5/14/2009<br>Cassandra L. Kniffin - updated : 5/21/2004<br>Cassandra L. Kniffin - updated : 5/18/2004<br>Natalie E. Krasikov - updated : 3/12/2004<br>Victor A. McKusick - updated : 6/7/2000<br>Jane Kelly - updated : 8/25/1999<br>Victor A. McKusick - updated : 10/7/1998
</span>
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Victor A. McKusick : 6/4/1986
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carol : 07/30/2024<br>carol : 11/19/2014<br>ckniffin : 11/19/2014<br>wwang : 5/21/2009<br>ckniffin : 5/14/2009<br>terry : 3/13/2009<br>mgross : 8/10/2005<br>ckniffin : 5/24/2004<br>carol : 5/24/2004<br>carol : 5/21/2004<br>ckniffin : 5/18/2004<br>carol : 3/16/2004<br>terry : 3/12/2004<br>carol : 6/9/2000<br>terry : 6/7/2000<br>carol : 8/25/1999<br>mgross : 6/8/1999<br>dkim : 10/16/1998<br>carol : 10/13/1998<br>terry : 10/7/1998<br>alopez : 9/14/1998<br>dkim : 9/10/1998<br>mark : 8/7/1996<br>terry : 8/5/1996<br>carol : 9/27/1994<br>mimadm : 3/11/1994<br>supermim : 3/17/1992<br>carol : 10/25/1990<br>carol : 10/11/1990<br>supermim : 3/20/1990
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