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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>TXNL4A-Related Craniofacial Disorders - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="TXNL4A-Related Craniofacial Disorders">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2022/05/12">
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<meta name="citation_author" content="Hermann-Josef Lüdecke">
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<meta name="citation_author" content="Dagmar Wieczorek">
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<meta name="citation_keywords" content="Burn-McKeown Syndrome (BMKS)">
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<meta name="citation_keywords" content="TXNL4A-Related Choanal Atresia with Minor Anomalies">
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<meta name="citation_keywords" content="TXNL4A-Related Isolated Choanal Atresia">
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<meta name="citation_keywords" content="Thioredoxin-like protein 4A">
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<meta name="citation_keywords" content="TXNL4A">
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<meta name="citation_keywords" content="TXNL4A-Related Craniofacial Disorders">
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<meta name="DC.Title" content="TXNL4A-Related Craniofacial Disorders">
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<meta name="DC.Contributor" content="Hermann-Josef Lüdecke">
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<meta name="DC.Contributor" content="Dagmar Wieczorek">
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<meta name="description" content="TXNL4A-related craniofacial disorders comprise a range of phenotypes that includes: isolated choanal atresia; choanal atresia with minor anomalies; and Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears). Hearing loss is common and cardiac defects and short stature have been reported. Intellectual disability is rare.">
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class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK373577_"><span class="title" itemprop="name"><i>TXNL4A</i>-Related Craniofacial Disorders</span></h1><p class="contribs">Lüdecke HJ, Wieczorek D.</p><p class="fm-aai"><a href="#_NBK373577_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 13 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="burn-mckeown.Summary" itemprop="description"><h2 id="_burn-mckeown_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>TXNL4A</i>-related craniofacial disorders comprise a range of phenotypes that includes: isolated choanal atresia; choanal atresia with minor anomalies; and Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears). Hearing loss is common and cardiac defects and short stature have been reported. Intellectual disability is rare.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of a <i>TXNL4A</i>-related craniofacial disorder is established in a proband with suggestive findings and biallelic pathogenic variants in <i>TXNL4A</i> identified by molecular genetic testing. All probands described to date have had at least one copy of one of the two partially overlapping 34-bp deletions in the <i>TXNL4A</i> promoter.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia. Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring. Treatment of hearing loss is individualized and may involve hearing aids. Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team. Cardiac defects are managed in a routine manner.</p><p><i>Surveillance:</i> Monitoring by an ophthalmologist, audiologist, and craniofacial team is recommended.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>TXNL4A</i>-related craniofacial disorders are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance inheriting neither of the familial <i>TXNL4A</i> pathogenic variants. Once the <i>TXNL4A</i> pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.</p></div></div><div id="burn-mckeown.GeneReview_Scope"><h2 id="_burn-mckeown_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figburnmckeownTd"><a href="/books/NBK373577/table/burn-mckeown.Td/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobburnmckeownTd"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="burn-mckeown.Td"><a href="/books/NBK373577/table/burn-mckeown.Td/?report=objectonly" target="object" rid-ob="figobburnmckeownTd">Table</a></h4><p class="float-caption no_bottom_margin">Burn-McKeown Syndrome (BMKS) Choanal atresia with minor anomalies</p></div></div></div><div id="burn-mckeown.Diagnosis"><h2 id="_burn-mckeown_Diagnosis_">Diagnosis</h2><div id="burn-mckeown.Suggestive_Findings"><h3>Suggestive Findings</h3><p>A <i>TXNL4A</i>-related craniofacial disorder <b>should be suspected</b> in individuals with the following clinical findings and family history.</p><p><b>Clinical findings.</b> Bilateral choanal atresia/stenosis WITH OR WITHOUT:</p><ul><li class="half_rhythm"><div>Distinctive facies (<a class="figpopup" href="/books/NBK373577/figure/burn-mckeown.F1/?report=objectonly" target="object" rid-figpopup="figburnmckeownF1" rid-ob="figobburnmckeownF1">Figure 1</a>):</div><ul><li class="half_rhythm"><div>Short palpebral fissures (i.e., distance between inner canthus and outer canthus)</div></li><li class="half_rhythm"><div>Lower eyelid defects including coloboma and thick eyelashes</div></li><li class="half_rhythm"><div>Prominent nasal bridge and widely spaced eyes, leading to a typical facial profile</div></li><li class="half_rhythm"><div>Short philtrum, thin vermilion of the upper lip, thick vermilion of the lower lip, and reduced opening of the mouth</div></li></ul></li><li class="half_rhythm"><div>Normal intellect</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figburnmckeownF1" co-legend-rid="figlgndburnmckeownF1"><a href="/books/NBK373577/figure/burn-mckeown.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figburnmckeownF1" rid-ob="figobburnmckeownF1"><img class="small-thumb" src="/books/NBK373577/bin/burn-mckeown-Image001.gif" src-large="/books/NBK373577/bin/burn-mckeown-Image001.jpg" alt="Figure 1. . Craniofacial phenotype in individuals with a TXNL4A-related craniofacial disorder." /></a><div class="icnblk_cntnt" id="figlgndburnmckeownF1"><h4 id="burn-mckeown.F1"><a href="/books/NBK373577/figure/burn-mckeown.F1/?report=objectonly" target="object" rid-ob="figobburnmckeownF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Craniofacial phenotype in individuals with a <i>TXNL4A</i>-related craniofacial disorder. Note short palpebral fissures (i.e., the distance between inner and outer canthi), prominent nasal bridge, large and (to some extent) protruding ears, and short philtrum. <a href="/books/NBK373577/figure/burn-mckeown.F1/?report=objectonly" target="object" rid-ob="figobburnmckeownF1">(more...)</a></p></div></div><p><b>Family history</b> is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.</p></div><div id="burn-mckeown.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of a <i>TXNL4A</i>-related craniofacial disorder <b>is established</b> in a proband with suggestive findings and biallelic pathogenic variants in <i>TXNL4A</i> identified by molecular genetic testing (see <a href="/books/NBK373577/table/burn-mckeown.T.molecular_genetic_testing/?report=objectonly" target="object" rid-ob="figobburnmckeownTmoleculargenetictesting">Table 1</a>).</p><p>All probands described to date have had at least one copy of a 34-bp deletion in the promoter of <i>TXNL4A</i>. Two partially overlapping 34-bp deletions have been described:</p><ul><li class="half_rhythm"><div>Type 1: chr18:g. 77,748,581_77,748,614del [<a href="https://www.ncbi.nlm.nih.gov/grc/human" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GRCh37/hg19</a>]</div></li><li class="half_rhythm"><div>Type 2: chr18:g.77,748,604_77,748,637del [<a href="https://www.ncbi.nlm.nih.gov/grc/human" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GRCh37/hg19</a>]</div></li></ul><p>The majority of reported probands have a type 1 promoter deletion on one allele and a loss-of-function pathogenic variant on the other.</p><p>Note: Identification of biallelic <i>TXNL4A</i> variants of uncertain significance (or identification of one known <i>TXNL4A</i> pathogenic variant and one <i>TXNL4A</i> variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.</p><p>Molecular genetic testing approaches can include <b>targeted assay to detect promoter deletions</b>, <b>single-gene testing</b>, <b>chromosomal microarray analysis (CMA)</b>, use of a <b>multigene panel</b>, and <b>more comprehensive</b>
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<b>genomic testing</b>.</p><div id="burn-mckeown.Recommended_Testing"><h4>Recommended Testing</h4><p><b>Tier 1 testing.</b> Targeted assay to detect the type 1 and type 2 promoter deletions (e.g., PCR and sequence analysis of the <i>TXNL4A</i> promoter, allele-specific PCR, or other targeted assay) is performed first.</p><p>Note: If a deletion that includes <i>TXNL4A</i> was previously detected by CMA, detection of one copy of the type 1 or type 2 promoter deletion establishes the diagnosis of a <i>TXNL4A</i>-related craniofacial disorder.</p><p><b>Tier 2 testing.</b> If Tier 1 testing detects one copy of a type 1 or type 2 promoter deletion, additional studies to detect a second variant can include:</p><ul><li class="half_rhythm"><div><b>Sequence analysis</b> of <i>TXNL4A</i> to test for loss-of-function variants;</div></li><li class="half_rhythm"><div><b>Chromosomal microarray analysis (CMA</b>) to identify larger deletions in 18q23, which cannot be detected by either sequence analysis or gene-targeted deletion/duplication analysis;</div></li><li class="half_rhythm"><div><b>Gene-targeted deletion/duplication analysis</b> of <i>TXNL4A</i> to test for whole-exon deletions or duplications.</div></li></ul></div><div id="burn-mckeown.Other_Testing_to_Consider"><h4>Other Testing to Consider</h4><p><b>A multigene panel</b> that includes promoter deletion assays of <i>TXNL4A</i> and testing of other genes of interest (see <a href="#burn-mckeown.Differential_Diagnosis">Differential Diagnosis</a>) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</p><p><b>Comprehensive genomic testing</b> does not require the clinician to determine which gene is most likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible and is the genomic testing method recommended for individuals with a suspected <i>TNXL4A</i>-related craniofacial disorder as it can detect pathogenic variants in both coding and noncoding regions associated with <i>TNXL4A</i>.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figburnmckeownTmoleculargenetictesting"><a href="/books/NBK373577/table/burn-mckeown.T.molecular_genetic_testing/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobburnmckeownTmoleculargenetictesting"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="burn-mckeown.T.molecular_genetic_testing"><a href="/books/NBK373577/table/burn-mckeown.T.molecular_genetic_testing/?report=objectonly" target="object" rid-ob="figobburnmckeownTmoleculargenetictesting">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>TXNL4A</i>-Related Craniofacial Disorders </p></div></div></div></div></div><div id="burn-mckeown.Clinical_Characteristics"><h2 id="_burn-mckeown_Clinical_Characteristics_">Clinical Characteristics</h2><div id="burn-mckeown.Clinical_Description"><h3>Clinical Description</h3><p><i>TXNL4A</i>-related craniofacial disorders range from isolated choanal atresia to choanal atresia with minor anomalies to Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears). Hearing loss is common and cardiac defects and short stature have been reported. Intellectual disability is rare [<a class="bibr" href="#burn-mckeown.REF.wieczorek.2014.698" rid="burn-mckeown.REF.wieczorek.2014.698">Wieczorek et al 2014</a>].</p><p>To date, 20 individuals with biallelic pathogenic variants in <i>TXNL4A</i> have been identified [<a class="bibr" href="#burn-mckeown.REF.wieczorek.2014.698" rid="burn-mckeown.REF.wieczorek.2014.698">Wieczorek et al 2014</a>, <a class="bibr" href="#burn-mckeown.REF.goos.2017.1126" rid="burn-mckeown.REF.goos.2017.1126">Goos et al 2017</a>, <a class="bibr" href="#burn-mckeown.REF.narayanan.2020.1313" rid="burn-mckeown.REF.narayanan.2020.1313">Narayanan et al 2020</a>, <a class="bibr" href="#burn-mckeown.REF.wood.2022.255" rid="burn-mckeown.REF.wood.2022.255">Wood et al 2022</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figburnmckeownTtxnl4arelatedcraniofacia"><a href="/books/NBK373577/table/burn-mckeown.T.txnl4arelated_craniofacia/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobburnmckeownTtxnl4arelatedcraniofacia"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="burn-mckeown.T.txnl4arelated_craniofacia"><a href="/books/NBK373577/table/burn-mckeown.T.txnl4arelated_craniofacia/?report=objectonly" target="object" rid-ob="figobburnmckeownTtxnl4arelatedcraniofacia">Table 2. </a></h4><p class="float-caption no_bottom_margin"><i>TXNL4A</i>-Related Craniofacial Disorders: Frequency of Select Features </p></div></div><p><b>Bilateral choanal stenosis/atresia</b> is potentially life threatening.</p><p><b>Defects of lower eyelids</b> can result in corneal exposure and, hence, drying.</p><p><b>Hearing loss.</b> Detailed clinical information regarding the severity and course of hearing loss has not been reported.</p><p><b>Cleft lip/palate.</b> Submucous cleft palate and uni-/bilateral cleft lip/palate have been described.</p><p><b>Cardiac defects</b> include persistent ductus arteriosus and patent foramen ovale.</p><p><b>Short stature</b> is proportionate and mild.</p><p><b>Intellectual disability.</b> One female had mild learning disabilities and another had severe intellectual disability [<a class="bibr" href="#burn-mckeown.REF.strangkarlsson.2017.193" rid="burn-mckeown.REF.strangkarlsson.2017.193">Strang-Karlsson et al 2017</a>].</p></div><div id="burn-mckeown.GenotypePhenotype_Correlati"><h3>Genotype-Phenotype Correlations</h3><p>No genotype-phenotype correlations have been identified.</p></div><div id="burn-mckeown.Nomenclature"><h3>Nomenclature</h3><p>Initially described as a distinct entity in a highly consanguineous Alaskan family by <a class="bibr" href="#burn-mckeown.REF.hing.2006.804" rid="burn-mckeown.REF.hing.2006.804">Hing et al [2006]</a>, oculootofacial dysplasia (OOFD) was reclassified as Burn-McKeown syndrome (BMKS) when <a class="bibr" href="#burn-mckeown.REF.wieczorek.2014.698" rid="burn-mckeown.REF.wieczorek.2014.698">Wieczorek et al [2014]</a> identified homozygous type 2 <i>TXNL4A</i> promoter deletions in affected members of this family.</p></div><div id="burn-mckeown.Prevalence"><h3>Prevalence</h3><p>The prevalence of <i>TXNL4A</i>-related craniofacial disorders has not been established. To date 20 individuals with a <i>TXNL4A</i>-related craniofacial disorder have been reported.</p></div></div><div id="burn-mckeown.Genetically_Related_Allelic"><h2 id="_burn-mckeown_Genetically_Related_Allelic_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>TXNL4A</i>.</p></div><div id="burn-mckeown.Differential_Diagnosis"><h2 id="_burn-mckeown_Differential_Diagnosis_">Differential Diagnosis</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figburnmckeownTgeneticdisorderswithch"><a href="/books/NBK373577/table/burn-mckeown.T.genetic_disorders_with_ch/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobburnmckeownTgeneticdisorderswithch"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="burn-mckeown.T.genetic_disorders_with_ch"><a href="/books/NBK373577/table/burn-mckeown.T.genetic_disorders_with_ch/?report=objectonly" target="object" rid-ob="figobburnmckeownTgeneticdisorderswithch">Table 3. </a></h4><p class="float-caption no_bottom_margin">Genetic Disorders with Choanal Atresia/Stenosis in the Differential Diagnosis of <i>TXNL4A</i>-Related Craniofacial Disorders </p></div></div></div><div id="burn-mckeown.Management"><h2 id="_burn-mckeown_Management_">Management</h2><div id="burn-mckeown.Evaluations_Following_Initi"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with a <i>TXNL4A</i>-related craniofacial disorder, the evaluations summarized in <a href="/books/NBK373577/table/burn-mckeown.T.recommended_evaluations_f/?report=objectonly" target="object" rid-ob="figobburnmckeownTrecommendedevaluationsf">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figburnmckeownTrecommendedevaluationsf"><a href="/books/NBK373577/table/burn-mckeown.T.recommended_evaluations_f/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobburnmckeownTrecommendedevaluationsf"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="burn-mckeown.T.recommended_evaluations_f"><a href="/books/NBK373577/table/burn-mckeown.T.recommended_evaluations_f/?report=objectonly" target="object" rid-ob="figobburnmckeownTrecommendedevaluationsf">Table 4. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with a <i>TXNL4A</i>-Related Craniofacial Disorder </p></div></div></div><div id="burn-mckeown.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figburnmckeownTtreatmentofmanifestatio"><a href="/books/NBK373577/table/burn-mckeown.T.treatment_of_manifestatio/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobburnmckeownTtreatmentofmanifestatio"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="burn-mckeown.T.treatment_of_manifestatio"><a href="/books/NBK373577/table/burn-mckeown.T.treatment_of_manifestatio/?report=objectonly" target="object" rid-ob="figobburnmckeownTtreatmentofmanifestatio">Table 5. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with a <i>TXNL4A</i>-Related Craniofacial Disorder </p></div></div></div><div id="burn-mckeown.Surveillance"><h3>Surveillance</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figburnmckeownTrecommendedsurveillance"><a href="/books/NBK373577/table/burn-mckeown.T.recommended_surveillance/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobburnmckeownTrecommendedsurveillance"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="burn-mckeown.T.recommended_surveillance"><a href="/books/NBK373577/table/burn-mckeown.T.recommended_surveillance/?report=objectonly" target="object" rid-ob="figobburnmckeownTrecommendedsurveillance">Table 6. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with a <i>TXNL4A</i>-Related Craniofacial Disorder </p></div></div></div><div id="burn-mckeown.Evaluation_of_Relatives_at"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#burn-mckeown.Related_Genetic_Counseling">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="burn-mckeown.Therapies_Under_Investigati"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="burn-mckeown.Genetic_Counseling"><h2 id="_burn-mckeown_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="burn-mckeown.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>TXNL4A</i>-related craniofacial disorders are inherited in an autosomal recessive manner.</p></div><div id="burn-mckeown.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>The parents of an affected child are presumed to be heterozygous for a <i>TXNL4A</i> pathogenic variant.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a <i>TXNL4A</i> pathogenic variant and to allow reliable recurrence risk assessment.</div></li><li class="half_rhythm"><div>If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a <i>de novo</i> event in the proband or as a postzygotic <i>de novo</i> event in a mosaic parent [<a class="bibr" href="#burn-mckeown.REF.j_nsson.2017.519" rid="burn-mckeown.REF.j_nsson.2017.519">Jónsson et al 2017</a>]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:</div><ul><li class="half_rhythm"><div>A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.</div></li></ul></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>If both parents are known to be heterozygous for a <i>TXNL4A</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial <i>TXNL4A</i> pathogenic variants.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p><b>Offspring of a proband.</b> The offspring of an individual with a <i>TXNL4A</i>-related craniofacial disorder are obligate heterozygotes (carriers) for a pathogenic variant in <i>TXNL4A</i>.</p><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being a carrier of a <i>TXNL4A</i> pathogenic variant.</p></div><div id="burn-mckeown.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>TXNL4A</i> pathogenic variants in the family.</p></div><div id="burn-mckeown.Related_Genetic_Counseling"><h3>Related Genetic Counseling Issues</h3><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.</div></li></ul></div><div id="burn-mckeown.Prenatal_Testing_and_Preimp"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>TXNL4A</i> pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="burn-mckeown.Resources"><h2 id="_burn-mckeown_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>BabyHearing.org</b>
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</div><div>
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<i>This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.</i>
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</div><div>
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<a href="https://www.babyhearing.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">babyhearing.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Face Equality International</b>
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</div><div>United Kingdom</div><div>
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<a href="https://faceequalityinternational.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">faceequalityinternational.org</a>
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</div></li></ul>
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</div><div id="burn-mckeown.Molecular_Genetics"><h2 id="_burn-mckeown_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figburnmckeownmolgenTA"><a href="/books/NBK373577/table/burn-mckeown.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobburnmckeownmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="burn-mckeown.molgen.TA"><a href="/books/NBK373577/table/burn-mckeown.molgen.TA/?report=objectonly" target="object" rid-ob="figobburnmckeownmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">TXNL4A-Related Craniofacial Disorders: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figburnmckeownmolgenTB"><a href="/books/NBK373577/table/burn-mckeown.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobburnmckeownmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="burn-mckeown.molgen.TB"><a href="/books/NBK373577/table/burn-mckeown.molgen.TB/?report=objectonly" target="object" rid-ob="figobburnmckeownmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for TXNL4A-Related Craniofacial Disorders (View All in OMIM) </p></div></div><div id="burn-mckeown.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>TXNL4A</i> encodes a highly conserved component of the U5 spliceosomal complex that is essential for U4/U6·U5 tri-snRNP assembly and cell cycle progression. While complete loss of <i>TXNL4A</i> is hypothesized to be lethal, reduced <i>TXNL4A</i> function results in a <i>TXNL4A</i>-related craniofacial disorder.</p><p>Two 34-bp deletions (type 1 and type 2) in the promoter region of <i>TXNL4A</i> have been described. The type 1 and type 2 promoter deletions partially overlap and occur at a fairly high frequency in the general population. Among 3,343 healthy individuals, 45 were heterozygous and one was homozygous for the type 1 promoter deletion; one individual was heterozygous for the type 2 promoter deletion [<a class="bibr" href="#burn-mckeown.REF.wieczorek.2014.698" rid="burn-mckeown.REF.wieczorek.2014.698">Wieczorek et al 2014</a>].</p><p>Probands identified to date are compound heterozygous for the type 1 promoter deletion and a loss-of-function allele, or homozygous for the type 2 promoter deletion, or more rarely, homozygous for the type 1 promoter deletion [<a class="bibr" href="#burn-mckeown.REF.goos.2017.1126" rid="burn-mckeown.REF.goos.2017.1126">Goos et al 2017</a>].</p><p><b>Mechanism of disease causation.</b> The type 1 and type 2 promoter deletions result in reduced promoter activity and reduced <i>TXNL4A</i> expression [<a class="bibr" href="#burn-mckeown.REF.wieczorek.2014.698" rid="burn-mckeown.REF.wieczorek.2014.698">Wieczorek et al 2014</a>]. They must therefore be considered hypomorphic alleles. Of note, the type 2 promoter deletion results in significantly lower transcription than the type 1 promoter deletion.</p><p>In yeast, homozygous null variants of the orthologous gene <i>DIB1</i> are lethal [<a class="bibr" href="#burn-mckeown.REF.liu.2006.1418" rid="burn-mckeown.REF.liu.2006.1418">Liu et al 2006</a>]. Thus, homozygous loss-of-function <i>TXNL4A</i> variants in humans may be lethal as well. This is compatible with findings in individuals with a <i>TXNL4A</i>-related craniofacial disorder described to date.</p><p><b><i>TXNL4A</i>-specific laboratory technical considerations.</b> The ability of a clinical molecular genetic laboratory to detect one or two deletions in the promoter region of <i>TXNL4A</i> is important for diagnosis of <i>TXNL4A</i>-related craniofacial disorders. Confirmation of clinical diagnosis is possible in every molecular laboratory that offers Sanger sequencing, multiplex ligation-dependent probe amplification, and chromosomal microarray analysis. Genome sequencing also allows detection of the promoter deletions, larger deletions, and loss-of-function pathogenic variants.</p></div></div><div id="burn-mckeown.Chapter_Notes"><h2 id="_burn-mckeown_Chapter_Notes_">Chapter Notes</h2><div id="burn-mckeown.Author_Notes"><h3>Author Notes</h3><p>Dagmar Wieczorek has longstanding expertise in syndromic entities, especially those with intellectual disability (ID) and craniofacial malformations. She was principal investigator in the German Mental Retardation Network, funded by NGFNplus, and in the CRANIRARE, FACE, and Chromatin-Net consortia, all funded by the BMBF. She has published many papers on gene identification in individuals with ID and with craniofacial anomalies (e.g., Treacher Collins syndrome, Burn-McKeown syndrome, and acrofacial dysostosis, Cincinnati type), as well as papers on the clinical spectrum of new entities with special emphasis on the facial phenotype.</p><p>Dagmar Wieczorek<br />Institut für Humangenetik<br />Universitätsklinikum Düsseldorf<br />Universitätsstr. 1<br />40225 Düsseldorf, Germany<br />Email: dagmar.wieczorek@hhu.de</p></div><div id="burn-mckeown.Acknowledgments"><h3>Acknowledgments</h3><p>The authors wish to gratefully acknowledge the contribution of the patients and their families.</p></div><div id="burn-mckeown.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>12 May 2022 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>14 July 2016 (bp) Review posted live</div></li><li class="half_rhythm"><div>19 January 2016 (dw) Original submission</div></li></ul></div></div><div id="burn-mckeown.References"><h2 id="_burn-mckeown_References_">References</h2><div id="burn-mckeown.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="burn-mckeown.REF.goos.2017.1126">Goos JAC, Swagemakers SMA, Twigg SRF, van Dooren MF, Hoogeboom AJM, Beetz C, Günther S, Magielsen FJ, Ockeloen CW. A Ramos-Arroyo M, Pfundt R, Yntema HG, van der Spek PJ, Stanier P, Wieczorek D, Wilkie AOM, van den Ouweland AMW, Mathijssen IMJ, Hurst JA. Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia. <span><span class="ref-journal">Eur J Hum Genet. </span>2017;<span class="ref-vol">25</span>:1126–33.</span> [<a href="/pmc/articles/PMC5602009/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5602009</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28905882" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28905882</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="burn-mckeown.REF.hing.2006.804">Hing AV, Leblond C, Sze RW, Starr JR, Monks S, Parisi MA. A novel oculo-oto-facial dysplasia in a Native Alaskan community with autosomal recessive inheritance. <span><span class="ref-journal">Am J Med Genet A. </span>2006;<span class="ref-vol">140</span>:804–12.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16523509" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16523509</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="burn-mckeown.REF.j_nsson.2017.519">Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. <span><span class="ref-journal">Nature. </span>2017;<span class="ref-vol">549</span>:519–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28959963" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28959963</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="burn-mckeown.REF.liu.2006.1418">Liu S, Rauhut R, Vornlocher H-P, Lührmann R. The network of protein-protein interactions within the human U4/U6·U5 tri-snRNP. <span><span class="ref-journal">RNA. </span>2006;<span class="ref-vol">12</span>:1418–30.</span> [<a href="/pmc/articles/PMC1484429/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1484429</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16723661" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16723661</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="burn-mckeown.REF.narayanan.2020.1313">Narayanan DL, Purushothama G, Bhavani GS, Shukla A. Burn-McKeown syndrome with biallelic promoter type 2 deletion in TXNL4A in two siblings. <span><span class="ref-journal">Am J Med Genet A. </span>2020;<span class="ref-vol">182</span>:1313–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/32187816" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32187816</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="burn-mckeown.REF.strangkarlsson.2017.193">Strang-Karlsson S, Urquhart J, Newman WG, Douzgou S. Severe intellectual disability in a patient with Burn-McKeown syndrome. <span><span class="ref-journal">Clin Dysmorphol. </span>2017;<span class="ref-vol">26</span>:193–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28225383" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28225383</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="burn-mckeown.REF.wieczorek.2014.698">Wieczorek D, Newman WG, Wieland T, Berulava T, Kaffe M, Falkenstein D, Beetz C, Graf E, Schwarzmayr T, Douzgou S, Clayton-Smith J, Daly SB, Williams SG, Bhaskar SS, Urquhart JE, Anderson B, O'Sullivan J, Boute O, Gundlach J, Czeschik JC, van Essen AJ, Hazan F, Park S, Hing A, Kuechler A, Lohmann DR, Ludwig KU, Mangold E, Steenpaß L, Zeschnigk M, Lemke JR, Lourenco CM, Hehr U, Prott EC, Waldenberger M, Böhmer AC, Horsthemke B, O'Keefe RT, Meitinger T, Burn J, Lüdecke HJ, Strom TM. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome. <span><span class="ref-journal">Am J Hum Genet. </span>2014;<span class="ref-vol">95</span>:698–707.</span> [<a href="/pmc/articles/PMC4259969/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4259969</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25434003" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25434003</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="burn-mckeown.REF.wood.2022.255">Wood KA, Ellingford JM, Thomas HB, Douzgou S, Beaman GM, Hobson E, Prescott K, O'Keefe RT, Newman WG, et al. Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome. <span><span class="ref-journal">Clin Genet. </span>2022;<span class="ref-vol">101</span>:255–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/34713892" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34713892</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK373577_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Hermann-Josef Lüdecke</span>, PhD<div class="affiliation small">Institut für Humangenetik
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Universitätsklinikum Düsseldorf
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Heinrich-Heine-Universität
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Düsseldorf, Germany<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ed.frodlesseud-inu@ekcedeul.fesoj-nnamreh" class="oemail">ed.frodlesseud-inu@ekcedeul.fesoj-nnamreh</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Dagmar Wieczorek</span>, MD<div class="affiliation small">Institut für Humangenetik
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Universitätsklinikum Düsseldorf
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Heinrich-Heine-Universität
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Düsseldorf, Germany<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ed.frodlesseud-inu@kerozceiw.ramgad" class="oemail">ed.frodlesseud-inu@kerozceiw.ramgad</a><span style="unicode-bidi: bidi-override; direction: ltr;">; </span><a href="mailto:dev@null" data-email="ed.uhh@kerozceiw.ramgad" class="oemail">ed.uhh@kerozceiw.ramgad</a><div></div></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">July 14, 2016</span>; Last Update: <span itemprop="dateModified">May 12, 2022</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Lüdecke HJ, Wieczorek D. TXNL4A-Related Craniofacial Disorders. 2016 Jul 14 [Updated 2022 May 12]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/tubb4a-leuk/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/tangier/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobburnmckeownTd"><div id="burn-mckeown.Td" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK373577/table/burn-mckeown.Td/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__burn-mckeown.Td_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_burn-mckeown.Td_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>TXNL4A</i>-Related Craniofacial Disorders: Included Phenotypes <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_burn-mckeown.Td_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Burn-McKeown Syndrome (BMKS)</div></li><li class="half_rhythm"><div>Choanal atresia with minor anomalies</div></li><li class="half_rhythm"><div>Isolated choanal atresia</div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">For synonyms and outdated names, see <a href="#burn-mckeown.Nomenclature">Nomenclature</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="burn-mckeown.TF.d.1"><p class="no_margin">For other genetic causes of these phenotypes, see <a href="#burn-mckeown.Differential_Diagnosis">Differential Diagnosis</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobburnmckeownTmoleculargenetictesting"><div id="burn-mckeown.T.molecular_genetic_testing" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>TXNL4A</i>-Related Craniofacial Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK373577/table/burn-mckeown.T.molecular_genetic_testing/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__burn-mckeown.T.molecular_genetic_testing_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TXNL4A</i>
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</td><td headers="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Promoter deletion assays <sup>3</sup></td><td headers="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">17/17 <sup>4</sup></td></tr><tr><td headers="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>5</sup></td><td headers="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7/17 <sup>6</sup></td></tr><tr><td headers="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>7</sup></td><td headers="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4/17 <sup>8</sup></td></tr><tr><td headers="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">CMA <sup>9</sup></td><td headers="hd_h_burn-mckeown.T.molecular_genetic_testing_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4/17 <sup>8</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="burn-mckeown.TF.1.1"><p class="no_margin">See <a href="/books/NBK373577/?report=reader#burn-mckeown.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="burn-mckeown.TF.1.2"><p class="no_margin">See <a href="#burn-mckeown.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="burn-mckeown.TF.1.3"><p class="no_margin">The two reported 34-bp promoter deletions can be detected and distinguished by targeted assays (e.g., PCR and subsequent sequence analysis of PCR products).</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="burn-mckeown.TF.1.4"><p class="no_margin"><a class="bibr" href="#burn-mckeown.REF.wieczorek.2014.698" rid="burn-mckeown.REF.wieczorek.2014.698">Wieczorek et al [2014]</a>, <a class="bibr" href="#burn-mckeown.REF.goos.2017.1126" rid="burn-mckeown.REF.goos.2017.1126">Goos et al [2017]</a>, <a class="bibr" href="#burn-mckeown.REF.narayanan.2020.1313" rid="burn-mckeown.REF.narayanan.2020.1313">Narayanan et al [2020]</a>, <a class="bibr" href="#burn-mckeown.REF.wood.2022.255" rid="burn-mckeown.REF.wood.2022.255">Wood et al [2022]</a>. Of note, homozygous promoter deletions were reported in two families with isolated choanal atresia [<a class="bibr" href="#burn-mckeown.REF.goos.2017.1126" rid="burn-mckeown.REF.goos.2017.1126">Goos et al 2017</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="burn-mckeown.TF.1.5"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="burn-mckeown.TF.1.6"><p class="no_margin"><a class="bibr" href="#burn-mckeown.REF.wieczorek.2014.698" rid="burn-mckeown.REF.wieczorek.2014.698">Wieczorek et al [2014]</a>, <a class="bibr" href="#burn-mckeown.REF.goos.2017.1126" rid="burn-mckeown.REF.goos.2017.1126">Goos et al [2017]</a>, <a class="bibr" href="#burn-mckeown.REF.wood.2022.255" rid="burn-mckeown.REF.wood.2022.255">Wood et al [2022]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="burn-mckeown.TF.1.7"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions. To date, no partial or complete <i>TXNL4A</i> duplications have been identified.</p></div></dd></dl><dl class="bkr_refwrap"><dt>8. </dt><dd><div id="burn-mckeown.TF.1.8"><p class="no_margin">
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<a class="bibr" href="#burn-mckeown.REF.wieczorek.2014.698" rid="burn-mckeown.REF.wieczorek.2014.698">Wieczorek et al [2014]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>9. </dt><dd><div id="burn-mckeown.TF.1.9"><p class="no_margin">Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including <i>TXNL4A</i>) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 18q23 region. CMA designs in current clinical use target the 18q23 region.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobburnmckeownTtxnl4arelatedcraniofacia"><div id="burn-mckeown.T.txnl4arelated_craniofacia" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p><i>TXNL4A</i>-Related Craniofacial Disorders: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK373577/table/burn-mckeown.T.txnl4arelated_craniofacia/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__burn-mckeown.T.txnl4arelated_craniofacia_lrgtbl__"><table><thead><tr><th id="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"># of Persons w/Feature / # Assessed</th><th id="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bilateral choanal stenosis/atresia</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">20/20</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 persons have had isolated choanal atresia [<a class="bibr" href="#burn-mckeown.REF.goos.2017.1126" rid="burn-mckeown.REF.goos.2017.1126">Goos et al 2017</a>].</td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Short palpebral fissures</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">11/19</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Defects of lower eyelids</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12/20</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypertelorism</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12/17</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prominent nasal bridge</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">17/18</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Short philtrum</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">14/17</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Thin vermilion of the upper lip</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10/17</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Prominent ears</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">13/17</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Preauricular tags</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10/16</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing loss</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12/19</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Micrognathia</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12/19</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Submucous cleft palate or cleft lip/palate</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10/20</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiac defect</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5/16</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Short stature</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3/17</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Normal intellect</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">16/18</td><td headers="hd_h_burn-mckeown.T.txnl4arelated_craniofacia_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobburnmckeownTgeneticdisorderswithch"><div id="burn-mckeown.T.genetic_disorders_with_ch" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genetic Disorders with Choanal Atresia/Stenosis in the Differential Diagnosis of <i>TXNL4A</i>-Related Craniofacial Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK373577/table/burn-mckeown.T.genetic_disorders_with_ch/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__burn-mckeown.T.genetic_disorders_with_ch_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DiffDx Disorder</th><th id="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Key Features of DiffDx Disorder</th><th id="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment / Distinguishing Features</th></tr></thead><tbody><tr><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CHD7</i>
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</td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CHARGE syndrome (See <a href="/books/n/gene/charge/?report=reader"><i>CHD7</i> Disorder</a>.)</td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intraocular coloboma, heart defects, choanal atresia, growth deficiency, DD, genital hypoplasia, & ear anomalies</td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">While some overlap exists between CHARGE syndrome & <i>TXNL4A</i>-related craniofacial disorders, esp choanal atresia, the CHARGE syndrome phenotype comprises clinical findings (intraocular coloboma, genital anomalies, & specific ear anomalies) not seen in <i>TXNL4A</i>-related craniofacial disorders. Note: The coloboma assoc w/<i>TXNL4A</i>-related craniofacial disorders involves the eyelid only & not intraocular structures.</td></tr><tr><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>EFTUD2</i>
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</td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/mf-dys-mic/?report=reader">Mandibulofacial dysostosis with microcephaly</a> (MFDM)</td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mandibulofacial dysostosis (e.g., upslanting palpebral fissures, micrognathia, & ear anomalies), prenatal (usually progressive) microcephaly, & moderate-to-severe ID</td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">While some overlap exists between MFDM & <i>TXNL4A</i>-related craniofacial disorders, severe microcephaly & moderate ID in MFDM & distinctive facial phenotypes help to clinically distinguish the 2 disorders.</td></tr><tr><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>POLR1B</i>
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<br />
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<i>POLR1C</i>
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<br />
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<i>POLR1D</i>
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<br />
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<i>TCOF1</i>
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</td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/tcs/?report=reader">Treacher Collins syndrome</a> (TCS)</td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD<br />AR <sup>1</sup></td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mandibulofacial dysostosis w/variable expressivity. Anomalies (usually restricted to craniofacial region) incl: downslanted palpebral fissures, hypoplasia of the zygomatic bones, lower-eyelid coloboma, microtia, & micrognathia.</td><td headers="hd_h_burn-mckeown.T.genetic_disorders_with_ch_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Downslanted palpebral fissures, hypoplasia of the zygomatic bones, & microtia have not been reported in <i>TXNL4A</i>-related craniofacial disorders. Cardiac defects & short stature are uncommon in TCS.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="burn-mckeown.TF.3.1"><p class="no_margin">Autosomal dominant TCS is caused by a heterozygous pathogenic variant in <i>TCOF1</i>, <i>POLR1D</i>, or <i>POLR1B</i>; autosomal recessive TCS is caused by biallelic pathogenic variants in <i>POLR1C</i> or <i>POLR1D</i>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobburnmckeownTrecommendedevaluationsf"><div id="burn-mckeown.T.recommended_evaluations_f" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with a <i>TXNL4A</i>-Related Craniofacial Disorder</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK373577/table/burn-mckeown.T.recommended_evaluations_f/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__burn-mckeown.T.recommended_evaluations_f_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Choanal</b>
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<br />
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<b>stenosis/atresia</b>
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</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Airway assessment for evidence of upper-airway obstruction</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Esp important in newborns</td></tr><tr><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Lower eyelid</b>
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<br />
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<b>defects</b>
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</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmology assessment for possible corneal issues</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hearing loss</b>
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</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiology assessment</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Submucous</b>
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<br />
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<b>cleft palate or</b>
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<br />
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<b>cleft lip/palate</b>
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</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cleft palate team assessment</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Structural</b>
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<br />
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<b>cardiac defects</b>
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</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiology assessment</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl echocardiography</td></tr><tr><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic</b>
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<br />
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<b>counseling</b>
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</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of a <i>TXNL4A</i>-related craniofacial disorder to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family support</b>
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<br />
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<b>& resources</b>
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</td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess need for:
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<ul><li class="half_rhythm"><div>Community or <a href="#burn-mckeown.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Social work involvement for parental support;</div></li><li class="half_rhythm"><div>Home nursing referral.</div></li></ul></td><td headers="hd_h_burn-mckeown.T.recommended_evaluations_f_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="burn-mckeown.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobburnmckeownTtreatmentofmanifestatio"><div id="burn-mckeown.T.treatment_of_manifestatio" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with a <i>TXNL4A</i>-Related Craniofacial Disorder</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK373577/table/burn-mckeown.T.treatment_of_manifestatio/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__burn-mckeown.T.treatment_of_manifestatio_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th></tr></thead><tbody><tr><td headers="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Choanal stenosis/atresia</b>
|
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</td><td headers="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intubation &/or surgical correction</td></tr><tr><td headers="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Lower eyelid defects</b>
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</td><td headers="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Care directed by ophthalmologist to ↓ risk of corneal scarring</td></tr><tr><td headers="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hearing loss</b>
|
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</td><td headers="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing aids as needed</td></tr><tr><td headers="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Craniofacial manifestations</b>
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</td><td headers="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Individualized & managed by multidisciplinary team <sup>1</sup></td></tr><tr><td headers="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cardiac defects</b>
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</td><td headers="hd_h_burn-mckeown.T.treatment_of_manifestatio_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As directed by cardiologist</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="burn-mckeown.TF.5.1"><p class="no_margin">The team may include a oromaxillofacial surgeon, plastic surgeon, otolaryngologist, dentist/orthodontist, and speech-language therapist.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobburnmckeownTrecommendedsurveillance"><div id="burn-mckeown.T.recommended_surveillance" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with a <i>TXNL4A</i>-Related Craniofacial Disorder</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK373577/table/burn-mckeown.T.recommended_surveillance/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__burn-mckeown.T.recommended_surveillance_lrgtbl__"><table><thead><tr><th id="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Lower eyelid defects</b>
|
|
</td><td headers="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmology eval w/focus on cornea</td><td headers="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per ophthalmologist</td></tr><tr><td headers="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Hearing loss</b>
|
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</td><td headers="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing assessment</td><td headers="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Shortly after birth & then per audiologist</td></tr><tr><td headers="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Craniofacial manifestations</b>
|
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</td><td headers="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Regular visits to craniofacial team</td><td headers="hd_h_burn-mckeown.T.recommended_surveillance_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per craniofacial team</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobburnmckeownmolgenTA"><div id="burn-mckeown.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>TXNL4A-Related Craniofacial Disorders: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK373577/table/burn-mckeown.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__burn-mckeown.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_burn-mckeown.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_burn-mckeown.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_burn-mckeown.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_burn-mckeown.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_burn-mckeown.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_burn-mckeown.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="/gene/10907" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
|
<i>TXNL4A</i>
|
|
</a>
|
|
</td><td headers="hd_b_burn-mckeown.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=10907" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">18q23</a>
|
|
</td><td headers="hd_b_burn-mckeown.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.uniprot.org/uniprot/P83876" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Thioredoxin-like protein 4A</a>
|
|
</td><td headers="hd_b_burn-mckeown.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=TXNL4A" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TXNL4A</a>
|
|
</td><td headers="hd_b_burn-mckeown.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=TXNL4A[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">TXNL4A</a>
|
|
</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="burn-mckeown.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
|
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
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chromosome locus from
|
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
|
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
|
<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobburnmckeownmolgenTB"><div id="burn-mckeown.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for TXNL4A-Related Craniofacial Disorders (<a href="/omim/608572,611595" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK373577/table/burn-mckeown.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__burn-mckeown.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/608572" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">608572</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BURN-MCKEOWN SYNDROME; BMKS</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<a href="/omim/611595" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">611595</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">THIOREDOXIN-LIKE 4A; TXNL4A</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobburnmckeownF1"><div id="burn-mckeown.F1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK373577/bin/burn-mckeown-Image001.jpg" alt="Figure 1. . Craniofacial phenotype in individuals with a TXNL4A-related craniofacial disorder." /></div><h3><span class="label">Figure 1. </span></h3><div class="caption"><p>Craniofacial phenotype in individuals with a <i>TXNL4A</i>-related craniofacial disorder. Note short palpebral fissures (i.e., the distance between inner and outer canthi), prominent nasal bridge, large and (to some extent) protruding ears, and short philtrum.</p><p>From <a class="bibr" href="#burn-mckeown.REF.wieczorek.2014.698" rid="burn-mckeown.REF.wieczorek.2014.698">Wieczorek et al [2014]</a>; republished with permission from Elsevier, Inc</p></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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