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- #616580 - AU-KLINE SYNDROME; AUKS
- OMIM
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<span class="h4">#616580</span>
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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/616580"><strong>Clinical Synopsis</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<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="#diagnosis">Diagnosis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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=AU-KLINE SYNDROME" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22096&Typ=Pat" title="Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to 9q21.3 microdeletion" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Neurodevelopmental disorde…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=23645&Typ=Pat" title="Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Neurodevelopmental disorde…&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=23646&Typ=Pat" title="Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to a point mutation" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Neurodevelopmental disorde…&nbsp;</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK540283/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=352665" title="Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to 9q21.3 microdeletion" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Neurodevelopmental disorde…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=453499" title="Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Neurodevelopmental disorde…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=453504" title="Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to a point mutation" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Neurodevelopmental disorde…</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/92599d96-9ea3-4716-8e51-dca5458dc6f8/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>
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<a id="title" class="mim-anchor"></a>
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<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>ORPHA:</strong> 352665, 453499, 453504<br />
">ICD+</a>
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<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
616580
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<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
AU-KLINE SYNDROME; AUKS
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<a id="alternativeTitles" class="mim-anchor"></a>
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<em>Alternative titles; symbols</em>
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<h4>
<span class="mim-font">
AU-KLINE-OKAMOTO SYNDROME<br />
OKAMOTO SYNDROME<br />
HYDRONEPHROSIS, CONGENITAL, WITH CLEFT PALATE, CHARACTERISTIC FACIES, HYPOTONIA, AND MENTAL RETARDATION
</span>
</h4>
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<h4>
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
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<th>
Phenotype
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<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/9/272?start=-3&limit=10&highlight=272">
9q21.32
</a>
</span>
</td>
<td>
<span class="mim-font">
Au-Kline syndrome
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616580"> 616580 </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">
HNRNPK
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600712"> 600712 </a>
</span>
</td>
</tr>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/616580" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
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<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Head </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Dolichocephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/72239002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">72239002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221358&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221358</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000268</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000268</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=b49d4ad3bcb5a39e5263c4f1d7454a3e" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Dolichocephaly-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=b49d4ad3bcb5a39e5263c4f1d7454a3e&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Metopic ridge <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1851734&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1851734</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Long face <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836047&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836047</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000276" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000276</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000276" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000276</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=729bf273c6a346c2f07ab0965824ffb2" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Face,Long-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=729bf273c6a346c2f07ab0965824ffb2&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Underdeveloped ears <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35045004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35045004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q17.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q17.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/744.23" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">744.23</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0152423&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0152423</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008551" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008551</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008551" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008551</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Long palpebral fissures <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849340&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849340</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000637" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000637</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000637" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000637</a>]</span><br /> -
Downslanting palpebral fissures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246800008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246800008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423110&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423110</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000494" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000494</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000494" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000494</a>]</span><br /> -
Ptosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/11934000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">11934000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/29696001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">29696001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.409" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.409</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.40" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.40</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.4" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.4</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/374.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.3</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/374.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.30</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0005745&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005745</a>, <a href="https://bioportal.bioontology.org/search?q=C0033377&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0033377</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000508</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000508" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000508</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=76abf29563d4adc64d21da86221224b1" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Ptosis-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=76abf29563d4adc64d21da86221224b1&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Sparse lateral eyebrows <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857206&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857206</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005338" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005338</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005338" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005338</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Nose </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Wide nasal ridge <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4020718&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4020718</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012811" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012811</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012811" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012811</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=de766c426224c75e736ebb8d915db1c5" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Nasal_Ridge,Wide-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=de766c426224c75e736ebb8d915db1c5&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Dimple at the nasal tip <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4228315&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4228315</a>]</span><br /> -
Hypoplastic nasal alae <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834055&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834055</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000430" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000430</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000430" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000430</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">
- Open mouth <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/262016004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">262016004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240379&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240379</a>, <a href="https://bioportal.bioontology.org/search?q=C4285242&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4285242</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000194" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000194</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000194" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000194</a>]</span><br /> -
Downturned mouth <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866195&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866195</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002714" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002714</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002714" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002714</a>]</span><br /> -
Midline crease of tongue <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4228314&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4228314</a>]</span><br /> -
High-arched palate <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/27272007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">27272007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q38.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q38.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240635&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240635</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000218</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000218" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000218</a>]</span><br /> -
Bifid uvula <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/18910001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">18910001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551488&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551488</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000193" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000193</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000193" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000193</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=3c22579bdef4e88303964de87353ca6f" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Uvula,Cleft-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=3c22579bdef4e88303964de87353ca6f&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Cleft palate <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/63567004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">63567004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/87979003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">87979003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q35.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q35.5</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q35" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q35</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q35.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q35.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/749.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">749.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/749.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">749.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837218&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837218</a>, <a href="https://bioportal.bioontology.org/search?q=C2981150&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2981150</a>, <a href="https://bioportal.bioontology.org/search?q=C2240378&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2240378</a>, <a href="https://bioportal.bioontology.org/search?q=C0008925&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008925</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000175" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000175</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000175" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000175</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Teeth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Oligodontia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/787414001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">787414001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/64969001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">64969001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K00.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K00.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4082304&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4082304</a>, <a href="https://bioportal.bioontology.org/search?q=C0020608&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020608</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000668" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000668</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0000677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000677</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000677</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Neck </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Excess nuchal skin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836940&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836940</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000474" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000474</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000474" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000474</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> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cardiac malformations <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4228353&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4228353</a>]</span><br /> -
Aortic root dilation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866956&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866956</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CHEST </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Features </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Pectus excavatum <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/391987005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">391987005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/391982004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">391982004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/754.81" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">754.81</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0016842&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0016842</a>, <a href="https://bioportal.bioontology.org/search?q=C2051831&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2051831</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000767" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000767</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000767" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000767</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Breasts </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Widely spaced nipples <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/423230008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">423230008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1827524&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1827524</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006610" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006610</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006610" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006610</a>]</span><br /> -
Inverted nipples <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/82231009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">82231009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0269269&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0269269</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003186" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003186</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003186" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003186</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Feeding difficulties <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78164000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0232466&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232466</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span><br /> -
Constipation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14760008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14760008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/564.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/564.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009806&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009806</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Genitalia (Male) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cryptorchidism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204878001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204878001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q53.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q53.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/752.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">752.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0010417&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010417</a>, <a href="https://bioportal.bioontology.org/search?q=C5441920&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5441920</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000028</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000028" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000028</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Kidneys </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hydronephrosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/43064006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">43064006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/N13.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">N13.30</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/591" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">591</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020295&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020295</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000126" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000126</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000126" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000126</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>
<div>
<span class="h5 mim-font">
<em> Skull </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Ridged metopic suture <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857949&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857949</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005487" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005487</a>]</span><br /> -
Craniosynostosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/57219006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">57219006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q75.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q75.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1421244&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1421244</a>, <a href="https://bioportal.bioontology.org/search?q=C5848303&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5848303</a>, <a href="https://bioportal.bioontology.org/search?q=C0010278&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010278</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001363" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001363</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0005458" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005458</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001363" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001363</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spine </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Vertebral segmentation defects <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/205455005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">205455005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0432163&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0432163</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003422" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003422</a>]</span><br /> -
Scoliosis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/298382003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">298382003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20944008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20944008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111266001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111266001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M41.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0559260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0559260</a>, <a href="https://bioportal.bioontology.org/search?q=C0036439&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036439</a>, <a href="https://bioportal.bioontology.org/search?q=C0700208&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700208</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</a>]</span><br /> -
Sacral dimple <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/311897005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">311897005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L05.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L05.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0426848&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0426848</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000960" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000960</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000960" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000960</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Pelvis </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hip dysplasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52781008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52781008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1328407&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1328407</a>, <a href="https://bioportal.bioontology.org/search?q=C4551649&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551649</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008807" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008807</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001385" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001385</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001385" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001385</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hands </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Postaxial polydactyly <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0220697&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220697</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100259</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100259" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100259</a>]</span><br /> -
Deep palmar creases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857539&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857539</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006191" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006191</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006191" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006191</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">
- Overlapping toes <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/203541003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">203541003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0920299&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0920299</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001845" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001845</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001845" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001845</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=95d99d9c813cf900dd135accc0aeb649" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/gn_nAzK3RwNEKgzMG_nCyxmaZctWGHcK-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=95d99d9c813cf900dd135accc0aeb649&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Deep plantar creases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1857953&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1857953</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001869" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001869</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001869" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001869</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">
- Sacral dimple <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/311897005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">311897005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L05.91" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L05.91</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0426848&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0426848</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000960" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000960</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000960" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000960</a>]</span><br /> -
Deep palmar and plantar creases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5194597&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5194597</a>]</span><br />
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<strong> MUSCLE, SOFT TISSUES </strong>
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- Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br />
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- Delayed psychomotor development <span class="mim-feature-ids hidden">[SNOMEDCT: <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">[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> 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 /> -
Intellectual disability <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> 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 /> -
Poor speech <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848207&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848207</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002465" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002465</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002465" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002465</a>]</span><br /> -
High pain tolerance <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/247407006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">247407006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423726&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423726</a>]</span><br /> -
Nodular heterotopia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253151003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253151003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0431378&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0431378</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Dysmorphic features are variable<br /> -
De novo mutation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2985439&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2985439</a>]</span><br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK, <a href="/entry/600712#0001">600712.0001</a>)<br />
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
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<p>A number sign (#) is used with this entry because of evidence that Au-Kline syndrome (AUKS) is caused by heterozygous mutation in the HNRNPK gene (<a href="/entry/600712">600712</a>) on chromosome 9q21.</p>
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<strong>Description</strong>
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<p>Au-Kline syndrome (AUKS) is an autosomal dominant disorder characterized by hypotonia, global developmental delay, characteristic facies (long palpebral fissures, shallow orbits, ptosis, a broad nasal bridge, hypoplastic alae nasi, downturned corners of the mouth and a long face), congenital heart defects, genitourinary abnormalities, skeletal abnormalities, and variable other congenital malformations (summary by <a href="#3" class="mim-tip-reference" title="Choufani, S., McNiven, V., Cytrynbaum, C., Jangjoo, M., Adam, M. P., Bjornsson, H. T., Harris, J., Dyment, D. A., Graham, G. E., Nezarati, M. M., Aul, R. B., Castiglioni, C., and 50 others. &lt;strong&gt;An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 109: 1867-1884, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/36130591/&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;36130591&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=36130591[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/10.1016/j.ajhg.2022.08.014&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="36130591">Choufani et al., 2022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36130591" 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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<strong>Clinical Features</strong>
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<p><a href="#10" class="mim-tip-reference" title="Okamoto, N., Matsumoto, F., Shimada, K., Satomura, K. &lt;strong&gt;New MCA/MR syndrome with generalized hypotonia, congenital hydronephrosis, and characteristic face.&lt;/strong&gt; Am. J. Med. Genet. 68: 347-349, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9024570/&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;9024570&lt;/a&gt;]" pmid="9024570">Okamoto et al. (1997)</a> described what they considered to be a new MCA/MR syndrome in a 2-year-old Japanese girl and an unrelated 15-month-old Japanese boy. Manifestations included congenital hydronephrosis, severe mental retardation, growth failure, generalized floppiness, and cleft palate. The facies showed midface hypoplasia, hypertrichosis, long eyelashes, prominent eyes, epicanthus, low-set ears, long ear lobe, flat nasal bridge, short upturned nose, long philtrum, and webbed neck. The girl had mild aortic stenosis and regurgitation; ventricular septal defect, atrial septal defect, and patent ductus arteriosus (see <a href="/entry/607411">607411</a>) had closed. The boy had endocardial cushion defect. In both patients, the karyotype was normal, the parents were nonconsanguineous and healthy, and sibs were normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9024570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Wallerstein, R., Shih, L., Fong, M.-H., Zheng, S., Poon, E. &lt;strong&gt;A new case of Okamoto syndrome.&lt;/strong&gt; Clin. Dysmorph. 14: 85-87, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15770130/&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;15770130&lt;/a&gt;]" pmid="15770130">Wallerstein et al. (2005)</a> reported a 6-month-old Chinese American boy with congenital hydronephrosis, cleft palate, severe hypotonia, congenital heart defect, developmental delay, and characteristic facial features with an open-mouthed appearance and full lower lip. The authors considered this to be the third reported case of Okamoto syndrome. The infant also had idiopathic splenomegaly and nonspecific MRI changes in the brain, which had not been reported in the first 2 cases. <a href="#13" class="mim-tip-reference" title="Wallerstein, R., Rhoads, F. &lt;strong&gt;Natural history of a child with Okamoto syndrome.&lt;/strong&gt; Clin. Dysmorph. 22: 127-128, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23591295/&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;23591295&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/MCD.0b013e32836127d0&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="23591295">Wallerstein and Rhoads (2013)</a> provided a follow-up of this patient. At age 8 years, he had significant developmental disabilities, with a motor level of approximately 6 to 8 months and a language age of about 24 months. <a href="#4" class="mim-tip-reference" title="Conteh, F. S., Tyagi, R., Brooks, S. S. &lt;strong&gt;A new finding of a tethered cord in a patient with Okamoto syndrome.&lt;/strong&gt; Clin. Dysmorph. 26: 110-113, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/27552167/&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;27552167&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/MCD.0000000000000147&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="27552167">Conteh et al. (2017)</a> noted that the patient was diagnosed with a tethered spinal cord at age 8 years 7 months. At age 11 years and 3 months, he presented with back and leg pain with severe gait difficulty, lower extremity paresthesia, numbness, and weakness, with worsening bladder dysfunction. Following filum terminale sectioning with neuromonitoring for release of his cord, his symptoms improved and he was able to ambulate independently. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15770130+27552167+23591295" 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="Markouri, M., Karpathios, T., Dinopoulos, A., Attilakos, A., Fretzayas, A., Bakoula, C., Kitsiou-Tzeli, S. &lt;strong&gt;Okamoto syndrome in a girl of Caucasian origin.&lt;/strong&gt; Dev. Med. Child Neurol. 50: 950-952, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19046188/&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;19046188&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1469-8749.2008.03147.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="19046188">Markouri et al. (2008)</a> reported a 2-year-old Greek female with Okamoto syndrome, born to healthy, nonconsanguineous parents. The child had multiple congenital anomalies including cleft palate, stenosis of the ureteropelvic junction with hydronephrosis, and cardiac anomalies, along with generalized hypotonia, severe developmental delay, and growth failure. The distinctive facial appearance included microcephaly, midface hypoplasia, prominent eyes, epicanthal folds, long eyelashes, synophrys, low-set ears with long earlobe, flat nasal bridge with short upturned nose, open mouth appearance, full lower lip, and downturned mouth. Unlike previously reported patients, she had severe anal stenosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19046188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Taylor, J., Aftimos, S. &lt;strong&gt;A newborn with likely Okamoto syndrome.&lt;/strong&gt; Clin. Dysmorph. 19: 103-106, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20179579/&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;20179579&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1097/MCD.0b013e328337bb8d&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="20179579">Taylor and Aftimos (2010)</a> reported what they believed to be the fifth reported case of Okamoto syndrome. The female offspring of nonconsanguineous parents of mixed ethnic background had multiple congenital anomalies and characteristic facial features. Echocardiogram showed severe aortic stenosis with mildly hypoplastic left ventricle, mild mitral valve hypoplasia, and 2 small atrial septal defects. She was profoundly hypotonic and made little spontaneous movement. In the facies, she had mild supraorbital ridging and hypertrichosis of the forehead, temple, and cheeks, prominent eyes with large palpebral fissures and hypertelorism, depressed nasal bridge and infraorbital grooves, short upturned nose, tented upper lip, cleft palate, large and low-set ears, and redundancy of skin of the posterior neck. A brain MRI showed thinning of the corpus callosum and presence of germinolytic cysts within the lateral ventricles. She also had intestinal malrotation and uterine didelphyis, features not reported previously. She died at age 12 days after the withdrawal of supportive medical care. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20179579" 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="Au, P. Y. B., You, J., Caluseriu, O., Schwartzentruber, J., Majewski, J., Bernier, F. P., Ferguson, M., Care for Rare Canada Consortium, Valle, D., Parboosingh, J. S., Sobreira, N., Innes, A. M., Kline, A. D. &lt;strong&gt;GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.&lt;/strong&gt; Hum. Mutat. 36: 1009-1014, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26173930/&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;26173930&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.22837&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="26173930">Au et al. (2015)</a> reported 2 unrelated boys, aged 17 and 11 years, with a complex syndromic neurodevelopmental disorder and a mutation in the HNRNPK gene. The patients had delayed psychomotor development with moderate intellectual disability and speech impairment. One had attention deficit-hyperactivity disorder. Both had somewhat variable dysmorphic features apparent since birth, including dolichocephaly, ridged metopic suture, long face, long palpebral fissures, ptosis, broad or sparse lateral eyebrows, underdeveloped ear helices, wide nasal ridge with dip at the nasal tip, open downturned mouth, high palate, prominent midline tongue groove, missing molars, and excess nuchal skin. Both patients had cryptorchidism and skeletal anomalies, including hip dysplasia, scoliosis, and extra lumbar vertebrae; 1 had multiple vertebral segmentation defects. One patient had planovalgus feet and crowded toes, whereas the other had postaxial polydactyly and overlapping toes. Cardiac defects included 2 small ventricular septal defects in 1 patient, and bicuspid aortic valve and aortic root dilation in the other. Additional features included hypotonia, hyporeflexia, and high pain tolerance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26173930" 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="#6" class="mim-tip-reference" title="Lange, L., Pagnamenta, A. T., Lise, S., Clasper, S., Stewart, H., Akha, E. S., Quaghebeur, G., Knight, S. J. L., Keays, D. A., Taylor, J. C., Kini, U. &lt;strong&gt;A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.&lt;/strong&gt; Clin. Genet. 90: 258-262, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26954065/&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;26954065&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26954065[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/10.1111/cge.12773&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="26954065">Lange et al. (2016)</a> described a boy with a mutation in the HNRNPK gene and a complex phenotype that expanded the phenotype of AUKS. Nuchal thickening was noted at 12 weeks' gestation, but karyotype was normal. Postnatally, the child had an atrioventricular septal defect, cleft palate, renal pelvic dilatation, bilateral talipes, partial agenesis of the corpus callosum, hypotonia, and significant developmental delay. Dysmorphic features included a prominent metopic ridge, medial flare of the eyebrows, long palpebral fissures with lateral eversion of the lower eyelids, hypoplastic alae nasi, low-set prominent ears, and thick wrinkled skin in the back of the neck. He also had hypoplastic toenails, deep palmar and plantar creases, and a midline groove on his tongue. He had a shallow acetabulum and mild scoliosis. He had sagittal craniosynostosis on skull CT scan and agenesis of the corpus callosum with nodular heterotopia in the frontal horns on brain MRI. His weight and head circumference were within normal limits, but his height was above the 90th centile. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26954065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Miyake, N., Inaba, M., Mizuno, S., Shiina, M., Imagawa, E., Miyatake, S., Nakashima, M., Mizuguchi, T., Takata, A., Ogata, K., Matsumoto, N. &lt;strong&gt;A case of atypical Kabuki syndrome arising from a novel missense variant in HNRNPK. (Letter)&lt;/strong&gt; Clin. Genet. 92: 554-555, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28771707/&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;28771707&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/cge.13023&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="28771707">Miyake et al. (2017)</a> described a 4-year-old Japanese boy with AUKS who had severe developmental delay, broad and laterally sparse eyebrows, long palpebral fissures, ectropion of the lateral lower eyelids, and prominent digit pads. He also had right ureteropelvic junction stenosis, left ureteral stenosis, and bilateral hydronephrosis. Brain imaging at 2 years 8 months was normal. <a href="#9" class="mim-tip-reference" title="Miyake, N., Inaba, M., Mizuno, S., Shiina, M., Imagawa, E., Miyatake, S., Nakashima, M., Mizuguchi, T., Takata, A., Ogata, K., Matsumoto, N. &lt;strong&gt;A case of atypical Kabuki syndrome arising from a novel missense variant in HNRNPK. (Letter)&lt;/strong&gt; Clin. Genet. 92: 554-555, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28771707/&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;28771707&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/cge.13023&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="28771707">Miyake et al. (2017)</a> noted that previously reported patients with AUKS had ridged metopic sutures, long faces, long palpebral fissures, prominent ears, full cheeks, open mouths, high palates, genitourinary anomalies, various hand/foot abnormalities, hypotonia, high pain tolerance, and intellectual disabilities. Some patients with AUKS also had lateral sparse eyebrows, low-set ears, downturned mouths, prominent midline grooves of the tongue, cardiac anomalies, hip dysplasia, scoliosis, and thick/wrinkled skin on the neck. Multiple ear pits and creases of the earlobes were seen in their patient, and earlobe creases were described in a patient with AUKS by <a href="#2" class="mim-tip-reference" title="Au, P. Y. B., You, J., Caluseriu, O., Schwartzentruber, J., Majewski, J., Bernier, F. P., Ferguson, M., Care for Rare Canada Consortium, Valle, D., Parboosingh, J. S., Sobreira, N., Innes, A. M., Kline, A. D. &lt;strong&gt;GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.&lt;/strong&gt; Hum. Mutat. 36: 1009-1014, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26173930/&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;26173930&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.22837&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="26173930">Au et al. (2015)</a>. <a href="#9" class="mim-tip-reference" title="Miyake, N., Inaba, M., Mizuno, S., Shiina, M., Imagawa, E., Miyatake, S., Nakashima, M., Mizuguchi, T., Takata, A., Ogata, K., Matsumoto, N. &lt;strong&gt;A case of atypical Kabuki syndrome arising from a novel missense variant in HNRNPK. (Letter)&lt;/strong&gt; Clin. Genet. 92: 554-555, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28771707/&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;28771707&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/cge.13023&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="28771707">Miyake et al. (2017)</a> noted that although AUKS has many features in common with Kabuki syndrome (see <a href="/entry/147920">147920</a>), the AUKS features of ridged metopic sutures, long faces, full cheeks, open mouths, prominent midline grooves of the tongue, and high pain tolerance are rarely seen in Kabuki syndrome and could be helpful in differential diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28771707+26173930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Au, P. Y. B., Goedhart, C., Ferguson, M., Breckpot, J., Devriendt, K., Wierenga, K., Fanning, E., Grange, D. K., Graham, G. E., Galarreta, C., Jones, M. C., Kini, U., Stewart, H., Parboosingh, J. S., Kline, A. D., Innes, A. M., Care for Rare Canada Consortium. &lt;strong&gt;Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature.&lt;/strong&gt; Europ. J. Hum. Genet. 26: 1272-1281, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29904177/&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;29904177&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29904177[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/10.1038/s41431-018-0187-2&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="29904177">Au et al. (2018)</a> reported 6 new patients with AUKS and reviewed the clinical features of the previously reported 6 patients. Prenatal presentation was notable; 5 patients had increased nuchal translucency and 5 patients had hydronephrosis. Shared facial features included long palpebral fissures, shallow orbits, ptosis, broad nasal bridge, hypoplastic alae nasi, and a downturned mouth. Missing teeth were seen in 2 patients and malocclusion in at least 3. Craniosynostosis affecting the sagittal suture and/or metopic ridging was seen in one-third of patients, with involvement of the lambdoid suture in only 1 patient. A long face and mildly coarse facial features were also seen. Variable ear anomalies were present in many patients, and both sensorineural and conductive hearing loss were reported. Vision abnormalities were variable, with optic nerve abnormalities seen in at least 3 patients. Congenital heart defects were reported in 10 of 12 patients, with ventricular septal defects being the most common. Genitourinary anomalies were also common. Gastrointestinal malformations were rarely described, but motility issues (e.g., constipation) was common. All patients had global developmental delay, and older patients had moderate to severe intellectual disability. High pain tolerance was reported in at least 4 patients. Brain MRI findings were variable, with hypoplasia or agenesis of the corpus callosum being the most common. Skeletal findings, in particular vertebral anomalies, were common. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29904177" 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="#3" class="mim-tip-reference" title="Choufani, S., McNiven, V., Cytrynbaum, C., Jangjoo, M., Adam, M. P., Bjornsson, H. T., Harris, J., Dyment, D. A., Graham, G. E., Nezarati, M. M., Aul, R. B., Castiglioni, C., and 50 others. &lt;strong&gt;An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 109: 1867-1884, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/36130591/&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;36130591&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=36130591[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/10.1016/j.ajhg.2022.08.014&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="36130591">Choufani et al. (2022)</a> reported clinical features in a cohort of 32 patients with Au-Kline syndrome, including 6 previously reported patients. All 32 patients had global developmental delay/intellectual disability and hypotonia. Other neurologic features included CNS malformations in 50%, abnormal myelination in 10%, hypo- or areflexia in 39%, and high pain tolerance in 37%. Fifty percent of patients had metopic ridging and 23% had craniosynostosis. Sixty-two percent of patients had a congenital heart defect and 10% of patients had aortic dilation. Oral features included cleft palate in 26% of patients and a high-arched palate in 19%. Musculoskeletal involvement included scoliosis (39%), vertebral segmentation defects (10%), joint hypermobility (59%), and muscle weakness (45%). Five of 22 patients had hearing loss, 13/17 males had cryptorchidism, and 16/31 had hydronephrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36130591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Okamoto, N. &lt;strong&gt;Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation.&lt;/strong&gt; Am. J. Med. Genet. 179A: 822-826, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30793470/&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;30793470&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.61079&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="30793470">Okamoto (2019)</a> reported a 4-year-old boy, born to nonconsanguineous Japanese parents, with the initial diagnosis of Okamoto syndrome. His features were similar to those of patients with AUKS and he was found to have a mutation in the HNRNPK gene. <a href="#11" class="mim-tip-reference" title="Okamoto, N. &lt;strong&gt;Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation.&lt;/strong&gt; Am. J. Med. Genet. 179A: 822-826, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30793470/&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;30793470&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.61079&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="30793470">Okamoto (2019)</a> noted that none of the patients previously reported with Okamoto syndrome had a molecular diagnosis, including the original patients of <a href="#10" class="mim-tip-reference" title="Okamoto, N., Matsumoto, F., Shimada, K., Satomura, K. &lt;strong&gt;New MCA/MR syndrome with generalized hypotonia, congenital hydronephrosis, and characteristic face.&lt;/strong&gt; Am. J. Med. Genet. 68: 347-349, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9024570/&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;9024570&lt;/a&gt;]" pmid="9024570">Okamoto et al. (1997)</a>. <a href="#11" class="mim-tip-reference" title="Okamoto, N. &lt;strong&gt;Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation.&lt;/strong&gt; Am. J. Med. Genet. 179A: 822-826, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30793470/&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;30793470&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.61079&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="30793470">Okamoto (2019)</a> concluded that Okamoto syndrome and Au-Kline syndrome are the same disorder with the characteristic features of impaired intellectual development, distinctive facial dysmorphism, skeletal/connective tissue abnormalities, cardiac anomalies, and genitourinary anomalies. A hypotonic face and open mouth are consistent features. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9024570+30793470" 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="Maystadt, I., Deprez, M., Moortgat, S., Benoit, V., Karadurmus, D. &lt;strong&gt;A second case of Okamoto syndrome caused by HNRNPK mutation.&lt;/strong&gt; Am. J. Med. Genet. 182A: 1537-1539, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32222014/&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;32222014&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.61568&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="32222014">Maystadt et al. (2020)</a> reported a patient who presented at birth with hypotonia, posterior cleft palate, and dysmorphic features including coarse facies, dolichocephaly, low-set ears, and macroglossia. She also had a ventricular septal defect and hydronephrosis. Brain MRI showed periventricular leukomalacia and mild ventricular dilation. At 10 years of age she had severe developmental delay and joint hyperlaxity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32222014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<p>The heterozygous mutations in the HNRNPK gene that were identified in patients with AUKS by <a href="#2" class="mim-tip-reference" title="Au, P. Y. B., You, J., Caluseriu, O., Schwartzentruber, J., Majewski, J., Bernier, F. P., Ferguson, M., Care for Rare Canada Consortium, Valle, D., Parboosingh, J. S., Sobreira, N., Innes, A. M., Kline, A. D. &lt;strong&gt;GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.&lt;/strong&gt; Hum. Mutat. 36: 1009-1014, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26173930/&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;26173930&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.22837&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="26173930">Au et al. (2015)</a>, <a href="#6" class="mim-tip-reference" title="Lange, L., Pagnamenta, A. T., Lise, S., Clasper, S., Stewart, H., Akha, E. S., Quaghebeur, G., Knight, S. J. L., Keays, D. A., Taylor, J. C., Kini, U. &lt;strong&gt;A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.&lt;/strong&gt; Clin. Genet. 90: 258-262, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26954065/&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;26954065&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26954065[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/10.1111/cge.12773&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="26954065">Lange et al. (2016)</a>, and others occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26954065+26173930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
<a id="diagnosis" class="mim-anchor"></a>
<h4 href="#mimDiagnosisFold" id="mimDiagnosisToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Diagnosis</strong>
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<p><a href="#3" class="mim-tip-reference" title="Choufani, S., McNiven, V., Cytrynbaum, C., Jangjoo, M., Adam, M. P., Bjornsson, H. T., Harris, J., Dyment, D. A., Graham, G. E., Nezarati, M. M., Aul, R. B., Castiglioni, C., and 50 others. &lt;strong&gt;An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 109: 1867-1884, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/36130591/&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;36130591&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=36130591[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/10.1016/j.ajhg.2022.08.014&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="36130591">Choufani et al. (2022)</a> developed clinical diagnostic criteria for Au-Kline syndrome which required 3 major criteria for diagnosis: (1) global developmental delay or intellectual disability; (2) congenital hypotonia; and (3) 5 of 6 facial features (long facies, shallow orbits, increased length of palpebral fissures, broad nasal ridge and/or thick alae nasi with narrow nares, upper lip with exaggerated cupid's bow, and a tongue that is large or bifid and/or with a deep midline groove). <a href="#3" class="mim-tip-reference" title="Choufani, S., McNiven, V., Cytrynbaum, C., Jangjoo, M., Adam, M. P., Bjornsson, H. T., Harris, J., Dyment, D. A., Graham, G. E., Nezarati, M. M., Aul, R. B., Castiglioni, C., and 50 others. &lt;strong&gt;An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 109: 1867-1884, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/36130591/&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;36130591&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=36130591[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/10.1016/j.ajhg.2022.08.014&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="36130591">Choufani et al. (2022)</a> also defined a unique DNA methylation episignature consisting of 429 differentially methylated sites in a patient's blood compared to controls. This methylation signature was highly sensitive and specific for a diagnosis of AUKS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36130591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p>In 2 unrelated boys with Au-Kline syndrome, <a href="#2" class="mim-tip-reference" title="Au, P. Y. B., You, J., Caluseriu, O., Schwartzentruber, J., Majewski, J., Bernier, F. P., Ferguson, M., Care for Rare Canada Consortium, Valle, D., Parboosingh, J. S., Sobreira, N., Innes, A. M., Kline, A. D. &lt;strong&gt;GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.&lt;/strong&gt; Hum. Mutat. 36: 1009-1014, 2015.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26173930/&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;26173930&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.22837&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="26173930">Au et al. (2015)</a> identified 2 different de novo heterozygous putative loss-of-function mutations in the HNRNPK gene (<a href="/entry/600712#0001">600712.0001</a> and <a href="/entry/600712#0002">600712.0002</a>). The mutations were found by exome sequencing. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26173930" 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>Using trio-based whole-exome sequencing, <a href="#6" class="mim-tip-reference" title="Lange, L., Pagnamenta, A. T., Lise, S., Clasper, S., Stewart, H., Akha, E. S., Quaghebeur, G., Knight, S. J. L., Keays, D. A., Taylor, J. C., Kini, U. &lt;strong&gt;A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.&lt;/strong&gt; Clin. Genet. 90: 258-262, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26954065/&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;26954065&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26954065[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/10.1111/cge.12773&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="26954065">Lange et al. (2016)</a> identified a de novo heterozygous 2-bp insertion (c.931_932insTT; <a href="/entry/600712#0003">600712.0003</a>) in exon 11 of the HNRNPK gene in a boy with a phenotype consistent with AUKS. The variant was confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26954065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By exome sequencing, <a href="#9" class="mim-tip-reference" title="Miyake, N., Inaba, M., Mizuno, S., Shiina, M., Imagawa, E., Miyatake, S., Nakashima, M., Mizuguchi, T., Takata, A., Ogata, K., Matsumoto, N. &lt;strong&gt;A case of atypical Kabuki syndrome arising from a novel missense variant in HNRNPK. (Letter)&lt;/strong&gt; Clin. Genet. 92: 554-555, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28771707/&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;28771707&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/cge.13023&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="28771707">Miyake et al. (2017)</a> identified a de novo heterozygous missense mutation in the HNRNPK gene (L155P; <a href="/entry/600712#0005">600712.0005</a>) in a Japanese boy with AUKS. The variant was confirmed by Sanger sequencing and was not present in the ExAC, Exome Variant Server, or Human Genetic Variation databases or in an in-house database of 575 exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28771707" 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>Using whole-exome sequencing, <a href="#1" class="mim-tip-reference" title="Au, P. Y. B., Goedhart, C., Ferguson, M., Breckpot, J., Devriendt, K., Wierenga, K., Fanning, E., Grange, D. K., Graham, G. E., Galarreta, C., Jones, M. C., Kini, U., Stewart, H., Parboosingh, J. S., Kline, A. D., Innes, A. M., Care for Rare Canada Consortium. &lt;strong&gt;Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature.&lt;/strong&gt; Europ. J. Hum. Genet. 26: 1272-1281, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29904177/&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;29904177&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29904177[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/10.1038/s41431-018-0187-2&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="29904177">Au et al. (2018)</a> identified 5 patients with AUKS with de novo heterozygous loss-of-function variants in HNRNPK, including nonsense, frameshift, and canonical splice variants. In addition, they reported a girl (patient 10) with a de novo 264-kb microdeletion encompassing 9q21.32, which disrupts HNRNPK as well as 3 additional genes and a microRNA with no known human disease association. The common phenotype between the patients with HNRNPK truncating variants and the microdeletion supported haploinsufficiency of the HNRNPK gene as the pathogenic mechanism of AUKS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29904177" 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="#3" class="mim-tip-reference" title="Choufani, S., McNiven, V., Cytrynbaum, C., Jangjoo, M., Adam, M. P., Bjornsson, H. T., Harris, J., Dyment, D. A., Graham, G. E., Nezarati, M. M., Aul, R. B., Castiglioni, C., and 50 others. &lt;strong&gt;An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 109: 1867-1884, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/36130591/&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;36130591&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=36130591[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/10.1016/j.ajhg.2022.08.014&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="36130591">Choufani et al. (2022)</a> reported heterozygous mutations in the HNRNPK gene in a cohort of 32 patients with AUKS, 6 of whom had previously been reported. In the cohort, 13 patients had missense mutations (including E85K (<a href="/entry/600712#0006">600712.0006</a>), reported in 5 unrelated patients), 8 patients had nonsense mutations, 3 patients had splicing mutations, 2 patients had frameshift mutations, 4 patients had intronic mutations, 1 patient had an in-frame indel, and 1 patient had a large (264 kb) deletion that involved the HNRNPK gene. About 85% of the mutations were clustered in the K homology RNA-binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36130591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 4-year-old Japanese boy, born of nonconsanguineous parents, with AUKS, <a href="#11" class="mim-tip-reference" title="Okamoto, N. &lt;strong&gt;Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation.&lt;/strong&gt; Am. J. Med. Genet. 179A: 822-826, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/30793470/&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;30793470&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.61079&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="30793470">Okamoto (2019)</a> identified a de novo heterozygous splice site mutation in the HNRNPK gene (<a href="/entry/600713#0007">600713.0007</a>). The mutation was found by Sanger sequencing of the HNRNPK gene. The patient had originally been diagnosed with Okamoto syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30793470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 10-year-old girl, born of nonconsanguineous parents, with AUKS, <a href="#8" class="mim-tip-reference" title="Maystadt, I., Deprez, M., Moortgat, S., Benoit, V., Karadurmus, D. &lt;strong&gt;A second case of Okamoto syndrome caused by HNRNPK mutation.&lt;/strong&gt; Am. J. Med. Genet. 182A: 1537-1539, 2020.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/32222014/&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;32222014&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.61568&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="32222014">Maystadt et al. (2020)</a> identified a de novo heterozygous splice site mutation in the HNRNPK gene (<a href="/entry/600713#0008">600713.0008</a>). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32222014" 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 an 11-year-old girl with AUKS, who was initially thought to have Kabuki syndrome, <a href="#5" class="mim-tip-reference" title="Dentici, M. L., Barresi, S., Niceta, M., Pantaleoni, F., Pizzi, S., Dallapiccola, B., Tartaglia, M., Digilio, M. C. &lt;strong&gt;Clinical spectrum of Kabuki-like syndrome caused by HNRNPK haploinsufficiency.&lt;/strong&gt; Clin. Genet. 93: 401-407, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28374925/&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;28374925&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/cge.13029&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="28374925">Dentici et al. (2018)</a> identified a de novo heterozygous frameshift mutation in the HNRNPK gene (<a href="/entry/600713#0009">600713.0009</a>). mRNA analysis in patient leukocytes demonstrated lack of expression of the HNRNPK allele with the mutation, indicating that the mutation led to nonsense-mediated decay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28374925" 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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<strong>Genotype/Phenotype Correlations</strong>
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<p>Based on a molecular, clinical, and DNA methylation analysis in a cohort of 32 patients with AUKS, <a href="#3" class="mim-tip-reference" title="Choufani, S., McNiven, V., Cytrynbaum, C., Jangjoo, M., Adam, M. P., Bjornsson, H. T., Harris, J., Dyment, D. A., Graham, G. E., Nezarati, M. M., Aul, R. B., Castiglioni, C., and 50 others. &lt;strong&gt;An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 109: 1867-1884, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/36130591/&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;36130591&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=36130591[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/10.1016/j.ajhg.2022.08.014&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="36130591">Choufani et al. (2022)</a> found that individuals with missense mutations in the HNRNPK gene were more likely to have an intermediate AUKS DNA methylation episignature and a lower AUKS clinical severity score. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36130591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="references"class="mim-anchor"></a>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Au2018" class="mim-anchor"></a>
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Au, P. Y. B., Goedhart, C., Ferguson, M., Breckpot, J., Devriendt, K., Wierenga, K., Fanning, E., Grange, D. K., Graham, G. E., Galarreta, C., Jones, M. C., Kini, U., Stewart, H., Parboosingh, J. S., Kline, A. D., Innes, A. M., Care for Rare Canada Consortium.
<strong>Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature.</strong>
Europ. J. Hum. Genet. 26: 1272-1281, 2018.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29904177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29904177</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29904177[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29904177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/s41431-018-0187-2" target="_blank">Full Text</a>]
</p>
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<li>
<a id="2" class="mim-anchor"></a>
<a id="Au2015" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Au, P. Y. B., You, J., Caluseriu, O., Schwartzentruber, J., Majewski, J., Bernier, F. P., Ferguson, M., Care for Rare Canada Consortium, Valle, D., Parboosingh, J. S., Sobreira, N., Innes, A. M., Kline, A. D.
<strong>GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.</strong>
Hum. Mutat. 36: 1009-1014, 2015.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26173930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26173930</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26173930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/humu.22837" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
<a id="Choufani2022" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Choufani, S., McNiven, V., Cytrynbaum, C., Jangjoo, M., Adam, M. P., Bjornsson, H. T., Harris, J., Dyment, D. A., Graham, G. E., Nezarati, M. M., Aul, R. B., Castiglioni, C., and 50 others.
<strong>An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.</strong>
Am. J. Hum. Genet. 109: 1867-1884, 2022.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36130591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36130591</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36130591[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36130591" 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/j.ajhg.2022.08.014" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
<a id="Conteh2017" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Conteh, F. S., Tyagi, R., Brooks, S. S.
<strong>A new finding of a tethered cord in a patient with Okamoto syndrome.</strong>
Clin. Dysmorph. 26: 110-113, 2017.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27552167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27552167</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27552167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/MCD.0000000000000147" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
<a id="Dentici2018" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Dentici, M. L., Barresi, S., Niceta, M., Pantaleoni, F., Pizzi, S., Dallapiccola, B., Tartaglia, M., Digilio, M. C.
<strong>Clinical spectrum of Kabuki-like syndrome caused by HNRNPK haploinsufficiency.</strong>
Clin. Genet. 93: 401-407, 2018.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28374925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28374925</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28374925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/cge.13029" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
<a id="Lange2016" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lange, L., Pagnamenta, A. T., Lise, S., Clasper, S., Stewart, H., Akha, E. S., Quaghebeur, G., Knight, S. J. L., Keays, D. A., Taylor, J. C., Kini, U.
<strong>A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.</strong>
Clin. Genet. 90: 258-262, 2016.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26954065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26954065</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26954065[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26954065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/cge.12773" target="_blank">Full Text</a>]
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<a id="Markouri2008" class="mim-anchor"></a>
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Markouri, M., Karpathios, T., Dinopoulos, A., Attilakos, A., Fretzayas, A., Bakoula, C., Kitsiou-Tzeli, S.
<strong>Okamoto syndrome in a girl of Caucasian origin.</strong>
Dev. Med. Child Neurol. 50: 950-952, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19046188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19046188</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19046188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1469-8749.2008.03147.x" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
<a id="Maystadt2020" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Maystadt, I., Deprez, M., Moortgat, S., Benoit, V., Karadurmus, D.
<strong>A second case of Okamoto syndrome caused by HNRNPK mutation.</strong>
Am. J. Med. Genet. 182A: 1537-1539, 2020.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32222014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32222014</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32222014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.61568" target="_blank">Full Text</a>]
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<a id="Miyake2017" class="mim-anchor"></a>
<div class="">
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Miyake, N., Inaba, M., Mizuno, S., Shiina, M., Imagawa, E., Miyatake, S., Nakashima, M., Mizuguchi, T., Takata, A., Ogata, K., Matsumoto, N.
<strong>A case of atypical Kabuki syndrome arising from a novel missense variant in HNRNPK. (Letter)</strong>
Clin. Genet. 92: 554-555, 2017.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28771707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28771707</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28771707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/cge.13023" target="_blank">Full Text</a>]
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<a id="Okamoto1997" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Okamoto, N., Matsumoto, F., Shimada, K., Satomura, K.
<strong>New MCA/MR syndrome with generalized hypotonia, congenital hydronephrosis, and characteristic face.</strong>
Am. J. Med. Genet. 68: 347-349, 1997.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9024570/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9024570</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9024570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="11" class="mim-anchor"></a>
<a id="Okamoto2019" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Okamoto, N.
<strong>Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation.</strong>
Am. J. Med. Genet. 179A: 822-826, 2019.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30793470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30793470</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30793470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.61079" target="_blank">Full Text</a>]
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<a id="Taylor2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Taylor, J., Aftimos, S.
<strong>A newborn with likely Okamoto syndrome.</strong>
Clin. Dysmorph. 19: 103-106, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20179579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20179579</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20179579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/MCD.0b013e328337bb8d" target="_blank">Full Text</a>]
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<a id="Wallerstein2013" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wallerstein, R., Rhoads, F.
<strong>Natural history of a child with Okamoto syndrome.</strong>
Clin. Dysmorph. 22: 127-128, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23591295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23591295</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23591295" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1097/MCD.0b013e32836127d0" target="_blank">Full Text</a>]
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<a id="Wallerstein2005" class="mim-anchor"></a>
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<p class="mim-text-font">
Wallerstein, R., Shih, L., Fong, M.-H., Zheng, S., Poon, E.
<strong>A new case of Okamoto syndrome.</strong>
Clin. Dysmorph. 14: 85-87, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15770130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15770130</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15770130" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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Hilary J. Vernon - updated : 07/20/2023
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Ada Hamosh - updated : 06/05/2023<br>Hilary J. Vernon - updated : 11/18/2022<br>Sonja A. Rasmussen - updated : 04/08/2019<br>Sonja A. Rasmussen - updated : 03/26/2019
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Creation Date:
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Cassandra L. Kniffin : 9/29/2015
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alopez : 01/11/2024
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carol : 07/20/2023<br>carol : 06/06/2023<br>carol : 06/05/2023<br>carol : 11/21/2022<br>carol : 11/18/2022<br>carol : 04/08/2019<br>carol : 03/27/2019<br>carol : 03/26/2019<br>carol : 10/05/2015<br>ckniffin : 10/5/2015
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<strong>#</strong> 616580
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AU-KLINE SYNDROME; AUKS
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<em>Alternative titles; symbols</em>
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AU-KLINE-OKAMOTO SYNDROME<br />
OKAMOTO SYNDROME<br />
HYDRONEPHROSIS, CONGENITAL, WITH CLEFT PALATE, CHARACTERISTIC FACIES, HYPOTONIA, AND MENTAL RETARDATION
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<strong>ORPHA:</strong> 352665, 453499, 453504; &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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9q21.32
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Au-Kline syndrome
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616580
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Autosomal dominant
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3
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HNRNPK
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600712
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that Au-Kline syndrome (AUKS) is caused by heterozygous mutation in the HNRNPK gene (600712) on chromosome 9q21.</p>
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<strong>Description</strong>
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<p>Au-Kline syndrome (AUKS) is an autosomal dominant disorder characterized by hypotonia, global developmental delay, characteristic facies (long palpebral fissures, shallow orbits, ptosis, a broad nasal bridge, hypoplastic alae nasi, downturned corners of the mouth and a long face), congenital heart defects, genitourinary abnormalities, skeletal abnormalities, and variable other congenital malformations (summary by Choufani et al., 2022). </p>
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<strong>Clinical Features</strong>
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<p>Okamoto et al. (1997) described what they considered to be a new MCA/MR syndrome in a 2-year-old Japanese girl and an unrelated 15-month-old Japanese boy. Manifestations included congenital hydronephrosis, severe mental retardation, growth failure, generalized floppiness, and cleft palate. The facies showed midface hypoplasia, hypertrichosis, long eyelashes, prominent eyes, epicanthus, low-set ears, long ear lobe, flat nasal bridge, short upturned nose, long philtrum, and webbed neck. The girl had mild aortic stenosis and regurgitation; ventricular septal defect, atrial septal defect, and patent ductus arteriosus (see 607411) had closed. The boy had endocardial cushion defect. In both patients, the karyotype was normal, the parents were nonconsanguineous and healthy, and sibs were normal. </p><p>Wallerstein et al. (2005) reported a 6-month-old Chinese American boy with congenital hydronephrosis, cleft palate, severe hypotonia, congenital heart defect, developmental delay, and characteristic facial features with an open-mouthed appearance and full lower lip. The authors considered this to be the third reported case of Okamoto syndrome. The infant also had idiopathic splenomegaly and nonspecific MRI changes in the brain, which had not been reported in the first 2 cases. Wallerstein and Rhoads (2013) provided a follow-up of this patient. At age 8 years, he had significant developmental disabilities, with a motor level of approximately 6 to 8 months and a language age of about 24 months. Conteh et al. (2017) noted that the patient was diagnosed with a tethered spinal cord at age 8 years 7 months. At age 11 years and 3 months, he presented with back and leg pain with severe gait difficulty, lower extremity paresthesia, numbness, and weakness, with worsening bladder dysfunction. Following filum terminale sectioning with neuromonitoring for release of his cord, his symptoms improved and he was able to ambulate independently. </p><p>Markouri et al. (2008) reported a 2-year-old Greek female with Okamoto syndrome, born to healthy, nonconsanguineous parents. The child had multiple congenital anomalies including cleft palate, stenosis of the ureteropelvic junction with hydronephrosis, and cardiac anomalies, along with generalized hypotonia, severe developmental delay, and growth failure. The distinctive facial appearance included microcephaly, midface hypoplasia, prominent eyes, epicanthal folds, long eyelashes, synophrys, low-set ears with long earlobe, flat nasal bridge with short upturned nose, open mouth appearance, full lower lip, and downturned mouth. Unlike previously reported patients, she had severe anal stenosis. </p><p>Taylor and Aftimos (2010) reported what they believed to be the fifth reported case of Okamoto syndrome. The female offspring of nonconsanguineous parents of mixed ethnic background had multiple congenital anomalies and characteristic facial features. Echocardiogram showed severe aortic stenosis with mildly hypoplastic left ventricle, mild mitral valve hypoplasia, and 2 small atrial septal defects. She was profoundly hypotonic and made little spontaneous movement. In the facies, she had mild supraorbital ridging and hypertrichosis of the forehead, temple, and cheeks, prominent eyes with large palpebral fissures and hypertelorism, depressed nasal bridge and infraorbital grooves, short upturned nose, tented upper lip, cleft palate, large and low-set ears, and redundancy of skin of the posterior neck. A brain MRI showed thinning of the corpus callosum and presence of germinolytic cysts within the lateral ventricles. She also had intestinal malrotation and uterine didelphyis, features not reported previously. She died at age 12 days after the withdrawal of supportive medical care. </p><p>Au et al. (2015) reported 2 unrelated boys, aged 17 and 11 years, with a complex syndromic neurodevelopmental disorder and a mutation in the HNRNPK gene. The patients had delayed psychomotor development with moderate intellectual disability and speech impairment. One had attention deficit-hyperactivity disorder. Both had somewhat variable dysmorphic features apparent since birth, including dolichocephaly, ridged metopic suture, long face, long palpebral fissures, ptosis, broad or sparse lateral eyebrows, underdeveloped ear helices, wide nasal ridge with dip at the nasal tip, open downturned mouth, high palate, prominent midline tongue groove, missing molars, and excess nuchal skin. Both patients had cryptorchidism and skeletal anomalies, including hip dysplasia, scoliosis, and extra lumbar vertebrae; 1 had multiple vertebral segmentation defects. One patient had planovalgus feet and crowded toes, whereas the other had postaxial polydactyly and overlapping toes. Cardiac defects included 2 small ventricular septal defects in 1 patient, and bicuspid aortic valve and aortic root dilation in the other. Additional features included hypotonia, hyporeflexia, and high pain tolerance. </p><p>Lange et al. (2016) described a boy with a mutation in the HNRNPK gene and a complex phenotype that expanded the phenotype of AUKS. Nuchal thickening was noted at 12 weeks' gestation, but karyotype was normal. Postnatally, the child had an atrioventricular septal defect, cleft palate, renal pelvic dilatation, bilateral talipes, partial agenesis of the corpus callosum, hypotonia, and significant developmental delay. Dysmorphic features included a prominent metopic ridge, medial flare of the eyebrows, long palpebral fissures with lateral eversion of the lower eyelids, hypoplastic alae nasi, low-set prominent ears, and thick wrinkled skin in the back of the neck. He also had hypoplastic toenails, deep palmar and plantar creases, and a midline groove on his tongue. He had a shallow acetabulum and mild scoliosis. He had sagittal craniosynostosis on skull CT scan and agenesis of the corpus callosum with nodular heterotopia in the frontal horns on brain MRI. His weight and head circumference were within normal limits, but his height was above the 90th centile. </p><p>Miyake et al. (2017) described a 4-year-old Japanese boy with AUKS who had severe developmental delay, broad and laterally sparse eyebrows, long palpebral fissures, ectropion of the lateral lower eyelids, and prominent digit pads. He also had right ureteropelvic junction stenosis, left ureteral stenosis, and bilateral hydronephrosis. Brain imaging at 2 years 8 months was normal. Miyake et al. (2017) noted that previously reported patients with AUKS had ridged metopic sutures, long faces, long palpebral fissures, prominent ears, full cheeks, open mouths, high palates, genitourinary anomalies, various hand/foot abnormalities, hypotonia, high pain tolerance, and intellectual disabilities. Some patients with AUKS also had lateral sparse eyebrows, low-set ears, downturned mouths, prominent midline grooves of the tongue, cardiac anomalies, hip dysplasia, scoliosis, and thick/wrinkled skin on the neck. Multiple ear pits and creases of the earlobes were seen in their patient, and earlobe creases were described in a patient with AUKS by Au et al. (2015). Miyake et al. (2017) noted that although AUKS has many features in common with Kabuki syndrome (see 147920), the AUKS features of ridged metopic sutures, long faces, full cheeks, open mouths, prominent midline grooves of the tongue, and high pain tolerance are rarely seen in Kabuki syndrome and could be helpful in differential diagnosis. </p><p>Au et al. (2018) reported 6 new patients with AUKS and reviewed the clinical features of the previously reported 6 patients. Prenatal presentation was notable; 5 patients had increased nuchal translucency and 5 patients had hydronephrosis. Shared facial features included long palpebral fissures, shallow orbits, ptosis, broad nasal bridge, hypoplastic alae nasi, and a downturned mouth. Missing teeth were seen in 2 patients and malocclusion in at least 3. Craniosynostosis affecting the sagittal suture and/or metopic ridging was seen in one-third of patients, with involvement of the lambdoid suture in only 1 patient. A long face and mildly coarse facial features were also seen. Variable ear anomalies were present in many patients, and both sensorineural and conductive hearing loss were reported. Vision abnormalities were variable, with optic nerve abnormalities seen in at least 3 patients. Congenital heart defects were reported in 10 of 12 patients, with ventricular septal defects being the most common. Genitourinary anomalies were also common. Gastrointestinal malformations were rarely described, but motility issues (e.g., constipation) was common. All patients had global developmental delay, and older patients had moderate to severe intellectual disability. High pain tolerance was reported in at least 4 patients. Brain MRI findings were variable, with hypoplasia or agenesis of the corpus callosum being the most common. Skeletal findings, in particular vertebral anomalies, were common. </p><p>Choufani et al. (2022) reported clinical features in a cohort of 32 patients with Au-Kline syndrome, including 6 previously reported patients. All 32 patients had global developmental delay/intellectual disability and hypotonia. Other neurologic features included CNS malformations in 50%, abnormal myelination in 10%, hypo- or areflexia in 39%, and high pain tolerance in 37%. Fifty percent of patients had metopic ridging and 23% had craniosynostosis. Sixty-two percent of patients had a congenital heart defect and 10% of patients had aortic dilation. Oral features included cleft palate in 26% of patients and a high-arched palate in 19%. Musculoskeletal involvement included scoliosis (39%), vertebral segmentation defects (10%), joint hypermobility (59%), and muscle weakness (45%). Five of 22 patients had hearing loss, 13/17 males had cryptorchidism, and 16/31 had hydronephrosis. </p><p>Okamoto (2019) reported a 4-year-old boy, born to nonconsanguineous Japanese parents, with the initial diagnosis of Okamoto syndrome. His features were similar to those of patients with AUKS and he was found to have a mutation in the HNRNPK gene. Okamoto (2019) noted that none of the patients previously reported with Okamoto syndrome had a molecular diagnosis, including the original patients of Okamoto et al. (1997). Okamoto (2019) concluded that Okamoto syndrome and Au-Kline syndrome are the same disorder with the characteristic features of impaired intellectual development, distinctive facial dysmorphism, skeletal/connective tissue abnormalities, cardiac anomalies, and genitourinary anomalies. A hypotonic face and open mouth are consistent features. </p><p>Maystadt et al. (2020) reported a patient who presented at birth with hypotonia, posterior cleft palate, and dysmorphic features including coarse facies, dolichocephaly, low-set ears, and macroglossia. She also had a ventricular septal defect and hydronephrosis. Brain MRI showed periventricular leukomalacia and mild ventricular dilation. At 10 years of age she had severe developmental delay and joint hyperlaxity. </p>
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<strong>Inheritance</strong>
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<p>The heterozygous mutations in the HNRNPK gene that were identified in patients with AUKS by Au et al. (2015), Lange et al. (2016), and others occurred de novo. </p>
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<strong>Diagnosis</strong>
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<p>Choufani et al. (2022) developed clinical diagnostic criteria for Au-Kline syndrome which required 3 major criteria for diagnosis: (1) global developmental delay or intellectual disability; (2) congenital hypotonia; and (3) 5 of 6 facial features (long facies, shallow orbits, increased length of palpebral fissures, broad nasal ridge and/or thick alae nasi with narrow nares, upper lip with exaggerated cupid's bow, and a tongue that is large or bifid and/or with a deep midline groove). Choufani et al. (2022) also defined a unique DNA methylation episignature consisting of 429 differentially methylated sites in a patient's blood compared to controls. This methylation signature was highly sensitive and specific for a diagnosis of AUKS. </p>
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<strong>Molecular Genetics</strong>
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<p>In 2 unrelated boys with Au-Kline syndrome, Au et al. (2015) identified 2 different de novo heterozygous putative loss-of-function mutations in the HNRNPK gene (600712.0001 and 600712.0002). The mutations were found by exome sequencing. Functional studies of the variants were not performed. </p><p>Using trio-based whole-exome sequencing, Lange et al. (2016) identified a de novo heterozygous 2-bp insertion (c.931_932insTT; 600712.0003) in exon 11 of the HNRNPK gene in a boy with a phenotype consistent with AUKS. The variant was confirmed by Sanger sequencing. </p><p>By exome sequencing, Miyake et al. (2017) identified a de novo heterozygous missense mutation in the HNRNPK gene (L155P; 600712.0005) in a Japanese boy with AUKS. The variant was confirmed by Sanger sequencing and was not present in the ExAC, Exome Variant Server, or Human Genetic Variation databases or in an in-house database of 575 exomes. </p><p>Using whole-exome sequencing, Au et al. (2018) identified 5 patients with AUKS with de novo heterozygous loss-of-function variants in HNRNPK, including nonsense, frameshift, and canonical splice variants. In addition, they reported a girl (patient 10) with a de novo 264-kb microdeletion encompassing 9q21.32, which disrupts HNRNPK as well as 3 additional genes and a microRNA with no known human disease association. The common phenotype between the patients with HNRNPK truncating variants and the microdeletion supported haploinsufficiency of the HNRNPK gene as the pathogenic mechanism of AUKS. </p><p>Choufani et al. (2022) reported heterozygous mutations in the HNRNPK gene in a cohort of 32 patients with AUKS, 6 of whom had previously been reported. In the cohort, 13 patients had missense mutations (including E85K (600712.0006), reported in 5 unrelated patients), 8 patients had nonsense mutations, 3 patients had splicing mutations, 2 patients had frameshift mutations, 4 patients had intronic mutations, 1 patient had an in-frame indel, and 1 patient had a large (264 kb) deletion that involved the HNRNPK gene. About 85% of the mutations were clustered in the K homology RNA-binding domain. </p><p>In a 4-year-old Japanese boy, born of nonconsanguineous parents, with AUKS, Okamoto (2019) identified a de novo heterozygous splice site mutation in the HNRNPK gene (600713.0007). The mutation was found by Sanger sequencing of the HNRNPK gene. The patient had originally been diagnosed with Okamoto syndrome. </p><p>In a 10-year-old girl, born of nonconsanguineous parents, with AUKS, Maystadt et al. (2020) identified a de novo heterozygous splice site mutation in the HNRNPK gene (600713.0008). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. </p><p>In an 11-year-old girl with AUKS, who was initially thought to have Kabuki syndrome, Dentici et al. (2018) identified a de novo heterozygous frameshift mutation in the HNRNPK gene (600713.0009). mRNA analysis in patient leukocytes demonstrated lack of expression of the HNRNPK allele with the mutation, indicating that the mutation led to nonsense-mediated decay. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Based on a molecular, clinical, and DNA methylation analysis in a cohort of 32 patients with AUKS, Choufani et al. (2022) found that individuals with missense mutations in the HNRNPK gene were more likely to have an intermediate AUKS DNA methylation episignature and a lower AUKS clinical severity score. </p>
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<strong>REFERENCES</strong>
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<ol>
<li>
<p class="mim-text-font">
Au, P. Y. B., Goedhart, C., Ferguson, M., Breckpot, J., Devriendt, K., Wierenga, K., Fanning, E., Grange, D. K., Graham, G. E., Galarreta, C., Jones, M. C., Kini, U., Stewart, H., Parboosingh, J. S., Kline, A. D., Innes, A. M., Care for Rare Canada Consortium.
<strong>Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature.</strong>
Europ. J. Hum. Genet. 26: 1272-1281, 2018.
[PubMed: 29904177]
[Full Text: https://doi.org/10.1038/s41431-018-0187-2]
</p>
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<li>
<p class="mim-text-font">
Au, P. Y. B., You, J., Caluseriu, O., Schwartzentruber, J., Majewski, J., Bernier, F. P., Ferguson, M., Care for Rare Canada Consortium, Valle, D., Parboosingh, J. S., Sobreira, N., Innes, A. M., Kline, A. D.
<strong>GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.</strong>
Hum. Mutat. 36: 1009-1014, 2015.
[PubMed: 26173930]
[Full Text: https://doi.org/10.1002/humu.22837]
</p>
</li>
<li>
<p class="mim-text-font">
Choufani, S., McNiven, V., Cytrynbaum, C., Jangjoo, M., Adam, M. P., Bjornsson, H. T., Harris, J., Dyment, D. A., Graham, G. E., Nezarati, M. M., Aul, R. B., Castiglioni, C., and 50 others.
<strong>An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.</strong>
Am. J. Hum. Genet. 109: 1867-1884, 2022.
[PubMed: 36130591]
[Full Text: https://doi.org/10.1016/j.ajhg.2022.08.014]
</p>
</li>
<li>
<p class="mim-text-font">
Conteh, F. S., Tyagi, R., Brooks, S. S.
<strong>A new finding of a tethered cord in a patient with Okamoto syndrome.</strong>
Clin. Dysmorph. 26: 110-113, 2017.
[PubMed: 27552167]
[Full Text: https://doi.org/10.1097/MCD.0000000000000147]
</p>
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<li>
<p class="mim-text-font">
Dentici, M. L., Barresi, S., Niceta, M., Pantaleoni, F., Pizzi, S., Dallapiccola, B., Tartaglia, M., Digilio, M. C.
<strong>Clinical spectrum of Kabuki-like syndrome caused by HNRNPK haploinsufficiency.</strong>
Clin. Genet. 93: 401-407, 2018.
[PubMed: 28374925]
[Full Text: https://doi.org/10.1111/cge.13029]
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<li>
<p class="mim-text-font">
Lange, L., Pagnamenta, A. T., Lise, S., Clasper, S., Stewart, H., Akha, E. S., Quaghebeur, G., Knight, S. J. L., Keays, D. A., Taylor, J. C., Kini, U.
<strong>A de novo frameshift in HNRNPK causing a Kabuki-like syndrome with nodular heterotopia.</strong>
Clin. Genet. 90: 258-262, 2016.
[PubMed: 26954065]
[Full Text: https://doi.org/10.1111/cge.12773]
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<li>
<p class="mim-text-font">
Markouri, M., Karpathios, T., Dinopoulos, A., Attilakos, A., Fretzayas, A., Bakoula, C., Kitsiou-Tzeli, S.
<strong>Okamoto syndrome in a girl of Caucasian origin.</strong>
Dev. Med. Child Neurol. 50: 950-952, 2008.
[PubMed: 19046188]
[Full Text: https://doi.org/10.1111/j.1469-8749.2008.03147.x]
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<li>
<p class="mim-text-font">
Maystadt, I., Deprez, M., Moortgat, S., Benoit, V., Karadurmus, D.
<strong>A second case of Okamoto syndrome caused by HNRNPK mutation.</strong>
Am. J. Med. Genet. 182A: 1537-1539, 2020.
[PubMed: 32222014]
[Full Text: https://doi.org/10.1002/ajmg.a.61568]
</p>
</li>
<li>
<p class="mim-text-font">
Miyake, N., Inaba, M., Mizuno, S., Shiina, M., Imagawa, E., Miyatake, S., Nakashima, M., Mizuguchi, T., Takata, A., Ogata, K., Matsumoto, N.
<strong>A case of atypical Kabuki syndrome arising from a novel missense variant in HNRNPK. (Letter)</strong>
Clin. Genet. 92: 554-555, 2017.
[PubMed: 28771707]
[Full Text: https://doi.org/10.1111/cge.13023]
</p>
</li>
<li>
<p class="mim-text-font">
Okamoto, N., Matsumoto, F., Shimada, K., Satomura, K.
<strong>New MCA/MR syndrome with generalized hypotonia, congenital hydronephrosis, and characteristic face.</strong>
Am. J. Med. Genet. 68: 347-349, 1997.
[PubMed: 9024570]
</p>
</li>
<li>
<p class="mim-text-font">
Okamoto, N.
<strong>Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation.</strong>
Am. J. Med. Genet. 179A: 822-826, 2019.
[PubMed: 30793470]
[Full Text: https://doi.org/10.1002/ajmg.a.61079]
</p>
</li>
<li>
<p class="mim-text-font">
Taylor, J., Aftimos, S.
<strong>A newborn with likely Okamoto syndrome.</strong>
Clin. Dysmorph. 19: 103-106, 2010.
[PubMed: 20179579]
[Full Text: https://doi.org/10.1097/MCD.0b013e328337bb8d]
</p>
</li>
<li>
<p class="mim-text-font">
Wallerstein, R., Rhoads, F.
<strong>Natural history of a child with Okamoto syndrome.</strong>
Clin. Dysmorph. 22: 127-128, 2013.
[PubMed: 23591295]
[Full Text: https://doi.org/10.1097/MCD.0b013e32836127d0]
</p>
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Wallerstein, R., Shih, L., Fong, M.-H., Zheng, S., Poon, E.
<strong>A new case of Okamoto syndrome.</strong>
Clin. Dysmorph. 14: 85-87, 2005.
[PubMed: 15770130]
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