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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>SLC26A4-Related Sensorineural Hearing Loss - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="SLC26A4-Related Sensorineural Hearing Loss">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2025/01/09">
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<meta name="citation_author" content="Richard JH Smith">
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<meta name="citation_author" content="Hela Azaiez">
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<meta name="citation_author" content="Amanda M Odell">
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<meta name="citation_pmid" content="20301640">
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<meta name="citation_keywords" content="PDS/NSEVA">
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<meta name="citation_keywords" content="PDS/DFNB4">
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<meta name="citation_keywords" content="Nonsyndromic SLC26A4-Related Sensorineural Hearing Loss">
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<meta name="citation_keywords" content="DFNB4">
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<meta name="citation_keywords" content="NSEVA">
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<meta name="citation_keywords" content="DFNB4/NSEVA">
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<meta name="citation_keywords" content="Pendred Syndrome (PDS)">
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<meta name="citation_keywords" content="Pendrin">
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<meta name="citation_keywords" content="SLC26A4">
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<meta name="citation_keywords" content="SLC26A4-Related Sensorineural Hearing Loss">
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<meta name="DC.Title" content="SLC26A4-Related Sensorineural Hearing Loss">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Richard JH Smith">
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<meta name="DC.Contributor" content="Hela Azaiez">
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<meta name="DC.Contributor" content="Amanda M Odell">
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<meta name="DC.Date" content="2025/01/09">
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<meta name="description" content="SLC26A4-related sensorineural hearing loss (SLC26A4-SNHL), characterized by inner ear malformations also associated with vestibular dysfunction, comprises two phenotypes: (1) nonsyndromic SLC26A4-SNHL (also referred to as DFNB4 or nonsyndromic enlargement of the vestibular aqueduct [NSEVA]) and (2) Pendred syndrome (PDS) that includes thyroid involvement (typically identified more frequently in countries without universal salt iodization programs). The time of onset and type of presentation of the SNHL vary (such that some newborns pass their newborn hearing screening); however, by age three years most children have bilateral and severe-to-profound hearing loss. Manifestations of vestibular dysfunction (such as head-tilting, vomiting, and/or delayed ambulation or clumsiness in a child who previously walked well) can precede or accompany the fluctuations in hearing typical of this disorder. Thyroid enlargement (goiter) occurs gradually and is typically evident in the second decade, especially if iodine is not routinely included in the diet.">
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<meta name="og:description" content="SLC26A4-related sensorineural hearing loss (SLC26A4-SNHL), characterized by inner ear malformations also associated with vestibular dysfunction, comprises two phenotypes: (1) nonsyndromic SLC26A4-SNHL (also referred to as DFNB4 or nonsyndromic enlargement of the vestibular aqueduct [NSEVA]) and (2) Pendred syndrome (PDS) that includes thyroid involvement (typically identified more frequently in countries without universal salt iodization programs). The time of onset and type of presentation of the SNHL vary (such that some newborns pass their newborn hearing screening); however, by age three years most children have bilateral and severe-to-profound hearing loss. Manifestations of vestibular dysfunction (such as head-tilting, vomiting, and/or delayed ambulation or clumsiness in a child who previously walked well) can precede or accompany the fluctuations in hearing typical of this disorder. Thyroid enlargement (goiter) occurs gradually and is typically evident in the second decade, especially if iodine is not routinely included in the diet.">
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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="_NBK1467_"><span class="title" itemprop="name"><i>SLC26A4</i>-Related Sensorineural Hearing Loss</span></h1><p class="contribs">Smith RJH, Azaiez H, Odell AM.</p><p class="fm-aai"><a href="#_NBK1467_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 27 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="pendred.Summary" itemprop="description"><h2 id="_pendred_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>SLC26A4</i>-related sensorineural hearing loss (<i>SLC26A4</i>-SNHL), characterized by inner ear malformations also associated with vestibular dysfunction, comprises two phenotypes: (1) nonsyndromic <i>SLC26A4</i>-SNHL (also referred to as DFNB4 or nonsyndromic enlargement of the vestibular aqueduct [NSEVA]) and (2) Pendred syndrome (PDS) that includes thyroid involvement (typically identified more frequently in countries without universal salt iodization programs). The time of onset and type of presentation of the SNHL vary (such that some newborns pass their newborn hearing screening); however, by age three years most children have bilateral and severe-to-profound hearing loss. Manifestations of vestibular dysfunction (such as head-tilting, vomiting, and/or delayed ambulation or clumsiness in a child who previously walked well) can precede or accompany the fluctuations in hearing typical of this disorder. Thyroid enlargement (goiter) occurs gradually and is typically evident in the second decade, especially if iodine is not routinely included in the diet.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>SLC26A4</i>-SNHL is established in a proband with suggestive findings and biallelic pathogenic variants in <i>SLC26A4</i> identified by molecular genetic testing<i>.</i></p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Supportive treatment includes multidisciplinary care by specialists in hearing habilitation, as early auditory intervention is critical to the development of speech and language. Habilitation options tailored to the degree and frequency of hearing loss can include hearing aids when hearing loss is mild to severe and consideration of cochlear implantation (CI) when hearing aids have had limited benefit. When considering CI, it is essential that the treating otolaryngologist be aware of the possible perioperative complications (most commonly perilymph gusher/oozing) and postoperative complications (most commonly transient vertigo) in individuals with <i>SLC26A4</i>-SNHL. Educational and early intervention programs designed for individuals with hearing loss are recommended. Medical treatment of thyroid enlargement and/or abnormal thyroid function requires consultation with an endocrinologist.</p><p><i>Surveillance:</i> Audiometric testing every three to six months until age three years and annually thereafter; baseline ultrasound to assess thyroid size at age ten years, followed by repeat ultrasound every five to ten years based on findings on palpation of thyroid size.</p><p><i>Agents/circumstances to avoid:</i> Follow standard recommendations for individuals with hearing loss. Despite anecdotal reports that head injuries resulting in increased intracranial pressure in individuals with enlarged vestibular aqueduct can occasionally trigger a decline in hearing, evidence is insufficient to support that avoidance of these activities decreases the overall risk of progression of hearing loss. While health care providers should alert families to this possible association, it is recommended that families be encouraged to make their own decisions on participation in contact sports.</p><p><i>Evaluation of at-risk sibs:</i> It is appropriate to determine the genetic status of at-risk sibs of a proband with <i>SLC26A4</i>-SNHL (i.e., a proband with known biallelic <i>SLC26A4</i> pathogenic variants) shortly after birth so that appropriate and early support and management can be provided to the child and family.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>SLC26A4</i>-SNHL is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an <i>SLC26A4</i> pathogenic variant, each sib of the proband has at conception a 25% chance of having <i>SLC26A4</i>-SNHL, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the pathogenic variants. Once biallelic <i>SLC26A4</i> pathogenic variants have been identified in the proband, heterozygote testing for relatives of an individual with <i>SLC26A4</i>-SNHL and prenatal/preimplantation genetic testing are possible.</p></div></div><div id="pendred.GeneReview_Scope"><h2 id="_pendred_GeneReview_Scope_"><i>GeneReview</i> Scope</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpendredTc"><a href="/books/NBK1467/table/pendred.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobpendredTc"><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="pendred.Tc"><a href="/books/NBK1467/table/pendred.Tc/?report=objectonly" target="object" rid-ob="figobpendredTc">Table</a></h4><p class="float-caption no_bottom_margin">Nonsyndromic <i>SLC26A4-</i>related sensorineural hearing loss (also referred to as DFNB4, NSEVA, and DFNB4/NSEVA) Pendred syndrome (PDS)</p></div></div></div><div id="pendred.Diagnosis"><h2 id="_pendred_Diagnosis_">Diagnosis</h2><p>No consensus clinical diagnostic criteria for <i>SLC26A4</i>-related sensorineural hearing loss (<i>SLC26A4</i>-SNHL) have been published.</p><div id="pendred.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>SLC26A4</i>-SNHL <b>should be considered</b> in probands with the following clinical findings of sensorineural hearing loss, inner ear malformations, vestibular dysfunction, and thyroid abnormalities and family history [<a class="bibr" href="#pendred.REF.honda.2022.455" rid="pendred.REF.honda.2022.455">Honda & Griffith 2022</a>].</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>
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<b>Sensorineural hearing loss (SNHL)</b>
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</div><ul><li class="half_rhythm"><div>Onset varies (congenital, prelingual, postlingual).</div></li><li class="half_rhythm"><div>Newborn hearing screening can be normal.</div></li><li class="half_rhythm"><div>Average hearing thresholds are 80 dB (severe hearing loss) by age three years [<a class="bibr" href="#pendred.REF.mey.2019.e178" rid="pendred.REF.mey.2019.e178">Mey et al 2019</a>].</div></li><li class="half_rhythm"><div>Fluctuating or progressive SNHL can occur.</div></li><li class="half_rhythm"><div>An air-bone gap (indicative of a conductive hearing loss) with normal tympanometry can be seen in low frequencies and reflects the "third window" effect of an enlarged vestibular aqueduct (EVA), which absorbs some of the sound transmission in the labyrinth, shunting it from the cochlea [<a class="bibr" href="#pendred.REF.merchant.2007.532" rid="pendred.REF.merchant.2007.532">Merchant et al 2007</a>].</div></li></ul></li><li class="half_rhythm"><div><b>Inner ear malformations</b> detected by CT or MRI</div><ul><li class="half_rhythm"><div class="half_rhythm"><b>Bilateral enlargement of the vestibular aqueduct *</b>
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<b>(EVA).</b> The vestibular aqueduct, the bony canal that surrounds the endolymphatic duct and part of the endolymphatic sac, is abnormally dilated in all individuals. EVA is defined as a midpoint diameter of the endolymphatic duct ≥1.0 mm or diameter of the operculum ≥2.0 mm [<a class="bibr" href="#pendred.REF.boston.2007.972" rid="pendred.REF.boston.2007.972">Boston et al 2007</a>, <a class="bibr" href="#pendred.REF.vijayasekaran.2007.1133" rid="pendred.REF.vijayasekaran.2007.1133">Vijayasekaran et al 2007</a>, <a class="bibr" href="#pendred.REF.chattaraj.2013.907" rid="pendred.REF.chattaraj.2013.907">Chattaraj et al 2013</a>] (see <a class="figpopup" href="/books/NBK1467/figure/pendred.F1/?report=objectonly" target="object" rid-figpopup="figpendredF1" rid-ob="figobpendredF1">Figure 1</a>).</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Incomplete cochlear partition type II * (IP-II),</b> observed in 22%-74% of individuals, is an undersegmentation anomaly of the cochlea with specific imaging and histologic findings. Deficient partitioning of the upper turns of the cochlea (the cochlea usually has 2½ turns) results in a cochlea with 1½ turns and a cystic apex or "scala communis" [<a class="bibr" href="#pendred.REF.darco.2024.1397" rid="pendred.REF.darco.2024.1397">D'Arco et al 2024</a>].</div><div class="half_rhythm">* The triad of an incomplete cochlea, an enlarged vestibule, and an enlarged vestibular aqueduct may be referred to as the Mondini triad (or Mondini malformation). Of note, the term "Mondini dysplasia" is often used more broadly to describe a range of congenital inner ear malformations (including various degrees of cochlear and vestibular anomalies) and is not synonymous with "Mondini triad."</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Cochlear modiolar hypoplasia or deficiency,</b> which is also common, can be detected by CT or MRI.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Note:</b> A radiologic diagnosis of EVA with or without cochlear hypoplasia is not specific to <i>SLC26A4</i>-SNHL (see <a href="#pendred.Differential_Diagnosis">Differential Diagnosis</a> for other causes of these temporal bone malformations).</div></li></ul></li><li class="half_rhythm"><div><b>Vestibular dysfunction</b> (4%-47% of individuals)</div><ul><li class="half_rhythm"><div>Vestibular dysfunction should be suspected in young children with normal motor development who then regress and have episodic rotatory vertigo, clumsiness, head-tilting, and/or vomiting.</div></li><li class="half_rhythm"><div>Objective evidence of vestibular dysfunction includes abnormal caloric responses (about 30% of individuals), abnormal rotational chair testing (about 25% of individuals), and abnormal cervical vestibular evoked myogenic potentials (cVEMPs) (about 20% of individuals) [<a class="bibr" href="#pendred.REF.zalewski.2015.257" rid="pendred.REF.zalewski.2015.257">Zalewski et al 2015</a>].</div></li><li class="half_rhythm"><div><b>Note:</b> There is no correlation between the severity of hearing loss and clinical signs and symptoms of vestibular dysfunction or objective evidence of vestibular dysfunction.</div></li></ul></li><li class="half_rhythm"><div>
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<b>Thyroid findings of Pendred syndrome</b>
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</div><ul><li class="half_rhythm"><div class="half_rhythm">Thyroid involvement results from deficiency of iodide organification * that can lead to hypothyroidism with or without a goiter. Diagnosis of thyroid involvement relies on imaging studies rather than serologic testing; however, serologic testing is important in the evaluation and management of thyroid disease [<a class="bibr" href="#pendred.REF.madeo.2009.670" rid="pendred.REF.madeo.2009.670">Madeo et al 2009</a>, <a class="bibr" href="#pendred.REF.honda.2022.455" rid="pendred.REF.honda.2022.455">Honda & Griffith 2022</a>] (see <a href="#pendred.Management">Management</a>).</div><div class="half_rhythm">* (1) Deficiency of iodide organification may be referred to more broadly as "thyroid dyshormonogenesis," a term including several genetic conditions involving thyroid hormone synthesis or iodide transport/utilization. (2) The perchlorate discharge test, the most sensitive clinical diagnostic method to detect deficiency of iodide organification, is currently rarely used [<a class="bibr" href="#pendred.REF.madeo.2009.670" rid="pendred.REF.madeo.2009.670">Madeo et al 2009</a>, <a class="bibr" href="#pendred.REF.honda.2022.455" rid="pendred.REF.honda.2022.455">Honda & Griffith 2022</a>]. Click <a href="/books/NBK1467/bin/pendred-perchlorate_test.pdf">here</a> (pdf) for details of the perchlorate discharge test.</div></li><li class="half_rhythm"><div class="half_rhythm">Euthyroid goiter is incompletely penetrant [<a class="bibr" href="#pendred.REF.honda.2022.455" rid="pendred.REF.honda.2022.455">Honda & Griffith 2022</a>]. Goiter generally becomes apparent after age ten years if iodine is not routinely included in the diet; it is rarely observed in countries with universal salt iodization programs.</div></li><li class="half_rhythm"><div class="half_rhythm">In the absence of dietary iodine, the odds of developing goiter increase by a factor of 1.1 for each one-year increase in age. Thus, five- and ten-year differences in age translate to a 1.6- and 2.6-fold increase in odds of developing goiter [<a class="bibr" href="#pendred.REF.madeo.2009.670" rid="pendred.REF.madeo.2009.670">Madeo et al 2009</a>].</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Note:</b> Consensus clinical diagnostic criteria for Pendred syndrome (used in the past before the availability of molecular genetic testing) included the presence of sensorineural hearing loss, enlarged vestibular aqueduct (EVA) with or without cochlear and vestibular malformations, and an iodide organification defect that may or may not lead to goiter.</div></li></ul></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpendredF1" co-legend-rid="figlgndpendredF1"><a href="/books/NBK1467/figure/pendred.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figpendredF1" rid-ob="figobpendredF1"><img class="small-thumb" src="/books/NBK1467/bin/pendred-Image001.gif" src-large="/books/NBK1467/bin/pendred-Image001.jpg" alt="Figure 1. . Computed tomography in a proband with Pendred syndrome shows absence of the upper turn of the cochlea and deficiency of the modiolus (white arrow)." /></a><div class="icnblk_cntnt" id="figlgndpendredF1"><h4 id="pendred.F1"><a href="/books/NBK1467/figure/pendred.F1/?report=objectonly" target="object" rid-ob="figobpendredF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Computed tomography in a proband with Pendred syndrome shows absence of the upper turn of the cochlea and deficiency of the modiolus (white arrow). EVA is also present (black arrow). Inset shows a normal right cochlea and no enlargement of the vestibular <a href="/books/NBK1467/figure/pendred.F1/?report=objectonly" target="object" rid-ob="figobpendredF1">(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="pendred.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>SLC26A4</i>-SNHL <b>is established</b> in a proband with <a href="#pendred.Suggestive_Findings">suggestive findings</a> and biallelic pathogenic (or likely pathogenic) variants in <i>SLC26A4</i> identified by molecular genetic testing (see <a href="/books/NBK1467/table/pendred.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobpendredTmoleculargenetictestingused">Table 1</a>).</p><p>Note: The diagnosis of <i>SLC26A4</i>-SNHL cannot be made when only a single <i>SLC26A4</i> pathogenic variant is identified (for more details see <a href="#pendred.Molecular_Genetics">Molecular Genetics</a>, <b>Other molecular mechanisms under investigation</b>.</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bibr" href="#pendred.REF.richards.2015.405" rid="pendred.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of biallelic <i>SLC26A4</i> variants of uncertain significance (or of one known <i>SLC26A4</i> pathogenic variant and one <i>SLC26A4</i> variant of uncertain significance) does not establish or rule out the diagnosis. (3) If only a single <i>SLC26A4</i> pathogenic variant is identified, the possibility of intragenic deletions or duplications should be considered [RJH Smith, personal observation].</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not.</p><p>Note: Single-gene testing (sequence analysis of <i>SLC26A4</i>, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>A</b>
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<b>multigene hearing loss panel</b>
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<b>that includes</b>
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<i>SLC26A4</i> and other genes of interest that cause sensorineural hearing loss (see <a href="#pendred.Differential_Diagnosis">Differential Diagnosis</a>) while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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.</div><div class="half_rhythm">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>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Comprehensive genomic testing</b> does not require the clinician to determine which gene(s) is likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible. To date, more than 600 pathogenic variants have been reported in <i>SLC26A4</i> [<a class="bibr" href="#pendred.REF.azaiez.2018.484" rid="pendred.REF.azaiez.2018.484">Azaiez et al 2018</a>], most of which are single-nucleotide variants (e.g., missense, nonsense) or small deletion/duplications that impact the coding regions and the intronic regions closely flanking the exons (i.e., splice sites) and thus are likely to be identified on exome sequencing.</div><div class="half_rhythm">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>.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpendredTmoleculargenetictestingused"><a href="/books/NBK1467/table/pendred.T.molecular_genetic_testing_used/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobpendredTmoleculargenetictestingused"><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="pendred.T.molecular_genetic_testing_used"><a href="/books/NBK1467/table/pendred.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobpendredTmoleculargenetictestingused">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>SLC26A4</i>-Related Sensorineural Hearing Loss </p></div></div></div></div><div id="pendred.Clinical_Characteristics"><h2 id="_pendred_Clinical_Characteristics_">Clinical Characteristics</h2><div id="pendred.Clinical_Description"><h3>Clinical Description</h3><p><i>SLC26A4</i>-related sensorineural hearing loss (<i>SLC26A4</i>-SNHL), characterized by inner ear malformations associated with vestibular dysfunction, comprises two phenotypes: (1) nonsyndromic <i>SLC26A4</i>-SNHL (also referred to as DFNB4 or nonsyndromic enlargement of the vestibular aqueduct [NSEVA]) and (2) Pendred syndrome (PDS) that includes thyroid involvement (typically identified more frequently in countries without universal salt iodization programs).</p><p>The considerable intrafamilial variability (i.e., variability in clinical presentation of a particular disorder among affected individuals within the same immediate or extended family) in temporal bone anomalies, hearing loss, and thyroid disease makes the distinction between nonsyndromic <i>SLC26A4</i>-SNHL and PDS during childhood difficult [<a class="bibr" href="#pendred.REF.reardon.1999.595" rid="pendred.REF.reardon.1999.595">Reardon et al 1999</a>, <a class="bibr" href="#pendred.REF.tsukamoto.2003.916" rid="pendred.REF.tsukamoto.2003.916">Tsukamoto et al 2003</a>, <a class="bibr" href="#pendred.REF.napiontek.2004.5347" rid="pendred.REF.napiontek.2004.5347">Napiontek et al 2004</a>, <a class="bibr" href="#pendred.REF.goldfeld.2005.537" rid="pendred.REF.goldfeld.2005.537">Goldfeld et al 2005</a>, <a class="bibr" href="#pendred.REF.madeo.2009.670" rid="pendred.REF.madeo.2009.670">Madeo et al 2009</a>, <a class="bibr" href="#pendred.REF.mey.2019.e178" rid="pendred.REF.mey.2019.e178">Mey et al 2019</a>].</p><p>Hundreds of individuals have been identified with biallelic <i>SLC26A4</i> pathogenic variants. The following description of the phenotypic features associated with <i>SLC26A4</i>-SNHL is based on data from more than 300 affected persons [<a class="bibr" href="#pendred.REF.azaiez.2007.451" rid="pendred.REF.azaiez.2007.451">Azaiez et al 2007</a>, <a class="bibr" href="#pendred.REF.aimoni.2017.254" rid="pendred.REF.aimoni.2017.254">Aimoni et al 2017</a>, <a class="bibr" href="#pendred.REF.mey.2019.e178" rid="pendred.REF.mey.2019.e178">Mey et al 2019</a>, <a class="bibr" href="#pendred.REF.forli.2021.2305" rid="pendred.REF.forli.2021.2305">Forli et al 2021</a>, <a class="bibr" href="#pendred.REF.smits.2022.465" rid="pendred.REF.smits.2022.465">Smits et al 2022</a>, <a class="bibr" href="#pendred.REF.darco.2024.1397" rid="pendred.REF.darco.2024.1397">D'Arco et al 2024</a>].</p><div id="pendred.SLC26A4SNHL"><h4><i>SLC26A4</i>-SNHL</h4><p><b>Sensorineural hearing loss (SNHL)</b> over time is bilateral and severe to profound in nearly all persons; however, time of onset and presentation may vary. Many children with <i>SLC26A4</i>-SNHL pass their newborn hearing screening test but develop hearing loss in early childhood that fluctuates (i.e., improved hearing between episodes of hearing loss). The progression of hearing loss can be very rapid, and by age three years hearing thresholds in children drop such that the pure tone average typically becomes ~80 dB [<a class="bibr" href="#pendred.REF.mey.2019.e178" rid="pendred.REF.mey.2019.e178">Mey et al 2019</a>].</p><p>Although there are reports describing progressive hearing loss in association with head injury, infection, or balance disturbances and tinnitus [<a class="bibr" href="#pendred.REF.luxon.2003.82" rid="pendred.REF.luxon.2003.82">Luxon et al 2003</a>], head trauma should not be considered a major risk factor for overall progression of hearing loss [<a class="bibr" href="#pendred.REF.brodsky.2018.2219" rid="pendred.REF.brodsky.2018.2219">Brodsky & Choi 2018</a>].</p><p><b>Vestibular dysfunction.</b> The signs and symptoms of vestibular dysfunction (whether unilateral or bilateral) can precede or accompany fluctuations in hearing and can present as head-tilting, vomiting, and/or delayed ambulation or clumsiness in a child who previously walked well [<a class="bibr" href="#pendred.REF.sugiura.2005a.241" rid="pendred.REF.sugiura.2005a.241">Sugiura et al 2005a</a>, <a class="bibr" href="#pendred.REF.sugiura.2005b.737" rid="pendred.REF.sugiura.2005b.737">Sugiura et al 2005b</a>, <a class="bibr" href="#pendred.REF.honda.2022.455" rid="pendred.REF.honda.2022.455">Honda & Griffith 2022</a>].</p></div><div id="pendred.Pendred_Syndrome_PDS_Thyroid_Inv"><h4>Pendred Syndrome (PDS) Thyroid Involvement</h4><p>Thyroid enlargement (goiter) occurs gradually and is typically not evident until the second decade, especially if iodine is not routinely included in the diet (in contrast to countries that have salt iodization programs). Thyroid size can be identified by ultrasonography; whereas thyroid function tests are not helpful in diagnosing goiter, they are important in <a href="#pendred.Management">Management</a>.</p></div></div><div id="pendred.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No genotype-phenotype correlations have been identified in individuals with biallelic <i>SLC26A4</i> pathogenic variants.</p></div><div id="pendred.Nomenclature"><h3>Nomenclature</h3><p>Nonsyndromic <i>SLC26A4</i>-SNHL is also referred to as <b>DFNB4</b> (autosomal recessive nonsyndromic deafness 4), nonsyndromic enlargement of the vestibular aqueduct (<b>NSEVA</b>), and <b>DFNB4/NSEVA</b>.</p><p>Pendred syndrome is also referred to as "autosomal recessive sensorineural hearing loss, enlarged vestibular aqueduct, and goiter."</p><p>EVA is also referred to as <b>dilation of the vestibular aqueduct (DVA).</b></p><p><b>Large vestibular aqueduct syndrome (LVAS)</b> or <b>enlarged vestibular aqueduct syndrome (EVAS)</b> refers to EVA-related hearing loss and includes EVA-related hearing loss of unknown cause, nonsyndromic <i>SLC26A4</i>-SNHL, and Pendred syndrome [<a class="bibr" href="#pendred.REF.honda.2022.455" rid="pendred.REF.honda.2022.455">Honda & Griffith 2022</a>].</p></div><div id="pendred.Prevalence"><h3>Prevalence</h3><p>EVA is the most common radiologic malformation of the inner ear associated with SNHL [<a class="bibr" href="#pendred.REF.valvassori.1978.723" rid="pendred.REF.valvassori.1978.723">Valvassori & Clemis 1978</a>]; when nonsyndromic <i>SLC26A4</i>-SNHL and PDS are considered part of the same disease spectrum, biallelic <i>SLC26A4</i> pathogenic variants are the third most frequent cause of hearing loss (see <a class="figpopup" href="/books/NBK1467/figure/pendred.F2/?report=objectonly" target="object" rid-figpopup="figpendredF2" rid-ob="figobpendredF2">Figure 2</a>). See also <a href="/books/n/gene/deafness-overview/?report=reader">Genetic Hearing Loss Overview</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figpendredF2" co-legend-rid="figlgndpendredF2"><a href="/books/NBK1467/figure/pendred.F2/?report=objectonly" target="object" title="Figure 2. " class="img_link icnblk_img figpopup" rid-figpopup="figpendredF2" rid-ob="figobpendredF2"><img class="small-thumb" src="/books/NBK1467/bin/pendred-Image002.gif" src-large="/books/NBK1467/bin/pendred-Image002.jpg" alt="Figure 2. . In an unbiased screen of 2,434 persons who underwent comprehensive genetic testing for hearing loss, Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) caused by biallelic SLC26A4 pathogenic variants was the third most common diagnosis of 79 different genetic diagnoses, comprising 6% of the total [Sloan-Heggen et al 2016; Smith et al, unpublished data]." /></a><div class="icnblk_cntnt" id="figlgndpendredF2"><h4 id="pendred.F2"><a href="/books/NBK1467/figure/pendred.F2/?report=objectonly" target="object" rid-ob="figobpendredF2">Figure 2. </a></h4><p class="float-caption no_bottom_margin">In an unbiased screen of 2,434 persons who underwent comprehensive genetic testing for hearing loss, Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) caused by biallelic <i>SLC26A4</i> pathogenic variants was the third most common <a href="/books/NBK1467/figure/pendred.F2/?report=objectonly" target="object" rid-ob="figobpendredF2">(more...)</a></p></div></div><p>For studies of the <i>SLC26A4</i> mutational spectrum and ethnicity-specific differences in the prevalence of pathogenic variants, see <a class="bibr" href="#pendred.REF.tsukada.2015.61s" rid="pendred.REF.tsukada.2015.61s">Tsukada et al [2015]</a>.</p></div></div><div id="pendred.Genetically_Related_Allelic_Diso"><h2 id="_pendred_Genetically_Related_Allelic_Diso_">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>SLC26A4</i>.</p></div><div id="pendred.Differential_Diagnosis"><h2 id="_pendred_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Congenital (or prelingual) genetic hearing loss</b> affects approximately one in 1,000 newborns; 30% of these infants have additional anomalies, making the diagnosis of a syndromic form of hearing loss possible (see <a href="/books/n/gene/deafness-overview/?report=reader">Genetic Hearing Loss Overview</a>).</p><p>
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<b>Temporal bone malformations</b>
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</p><ul><li class="half_rhythm"><div>Although enlarged vestibular aqueduct (EVA) with or without cochlear hypoplasia are seen in virtually all individuals with <i>SLC26A4</i>-related sensorineural hearing loss (<i>SLC26A4</i>-SNHL), neither EVA nor cochlear hypoplasia is specific to <i>SLC26A4</i>-SNHL. Other causes of these types of temporal bone malformations include acquired conditions such as congenital cytomegalovirus (cCMV) infection and genetic disorders (see <a href="/books/NBK1467/table/pendred.T.genetic_disorders_with_tempora/?report=objectonly" target="object" rid-ob="figobpendredTgeneticdisorderswithtempora">Table 2</a>).</div></li><li class="half_rhythm"><div><i>SLC26A4</i> molecular genetic testing is not indicated for individuals with temporal bone anomalies that do not match the typical <i>SLC26A4</i>-SNHL-associated findings. Anomalies not associated with <i>SLC26A4</i>-SNHL include cochlear aplasia, Michel aplasia, common cavity malformation, and isolated semicircular canal dysplasia.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpendredTgeneticdisorderswithtempora"><a href="/books/NBK1467/table/pendred.T.genetic_disorders_with_tempora/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobpendredTgeneticdisorderswithtempora"><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="pendred.T.genetic_disorders_with_tempora"><a href="/books/NBK1467/table/pendred.T.genetic_disorders_with_tempora/?report=objectonly" target="object" rid-ob="figobpendredTgeneticdisorderswithtempora">Table 2. </a></h4><p class="float-caption no_bottom_margin">Genetic Disorders with Temporal Bone Malformations in the Differential Diagnosis of <i>SLC26A4</i>-Related Sensorineural Hearing Loss </p></div></div></div><div id="pendred.Management"><h2 id="_pendred_Management_">Management</h2><p>No clinical practice guidelines for <i>SLC26A4</i>-related sensorineural hearing loss (<i>SLC26A4</i>-SNHL) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.</p><div id="pendred.Evaluations_Following_Initial_Di"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>SLC26A4</i>-SNHL, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><ul><li class="half_rhythm"><div>Assessment of auditory acuity (auditory brain stem response testing, pure tone audiometry)</div></li><li class="half_rhythm"><div>Assessment of vestibular function during early childhood (should be considered)</div></li><li class="half_rhythm"><div>Thyroid ultrasonography and thyroid function tests (T<sub>3</sub> [triiodothyronine], T<sub>4</sub> [thyroxine], and TSH [thyroid-stimulating hormone]) during early childhood with endocrinologist consultation as needed</div></li><li class="half_rhythm"><div>Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of <i>SLC26A4</i>-SNHL to facilitate medical and personal decision making</div></li><li class="half_rhythm"><div>Assessment of need for family support and resources including community or online <a href="#pendred.Resources">resources</a> and social work involvement for parental support</div></li></ul><p>See also <a href="/books/n/gene/deafness-overview/?report=reader">Genetic Hearing Loss Overview</a>.</p></div><div id="pendred.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>There is no cure for <i>SLC26A4</i>-SNHL.</p><p>For general information on management of hearing loss in children and adults, see Genetic Hearing Loss Overview, <a href="/books/n/gene/deafness-overview/?report=reader#deafness-overview.Management">Management</a>.</p><p><b>Hearing habilitation.</b> Early auditory intervention is critical to the development of speech and language. Habilitation options are tailored to the degree and frequency of hearing loss.</p><ul><li class="half_rhythm"><div>Hearing aids may be used in persons with mild-to-severe hearing loss.</div></li><li class="half_rhythm"><div>Cochlear implantation (CI), which provides good hearing habilitation in individuals with <i>SLC26A4</i>-SNHL, should be considered if hearing aids have provided only limited benefit. As hearing loss fluctuates and gradually progresses, children with <i>SLC26A4</i>-SNHL receive implants later than children with other types of nonsyndromic hearing loss [<a class="bibr" href="#pendred.REF.mey.2020.46" rid="pendred.REF.mey.2020.46">Mey et al 2020</a>]. Indeed, a systematic review found the average age at CI was 60 months for children with <i>SLC26A4</i>-SNHL as compared to 12 months or younger for children with other types of severe-to-profound nonsyndromic hearing loss [<a class="bibr" href="#pendred.REF.hansen.2023.440" rid="pendred.REF.hansen.2023.440">Hansen et al 2023</a>].</div></li><li class="half_rhythm"><div>CI in individuals with <i>SLC26A4</i>-SNHL is associated with a higher risk of perioperative complications (most commonly perilymph gusher/oozing) and postoperative complications (most commonly transient vertigo). Therefore, preoperative vestibular testing should be considered to (1) inform the otolaryngologist regarding the abnormal vestibular anatomy and (2) anticipate possible vestibular dysfunction following CI [<a class="bibr" href="#pendred.REF.hansen.2023.440" rid="pendred.REF.hansen.2023.440">Hansen et al 2023</a>].</div></li></ul><p><b>Educational and early intervention programs</b> designed for individuals with hearing loss are recommended (see Genetic Hearing Loss Overview, <a href="/books/n/gene/deafness-overview/?report=reader#deafness-overview.Management">Management</a>).</p><p><b>Medical treatment</b> of thyroid enlargement and/or abnormal thyroid function requires consultation with an endocrinologist.</p></div><div id="pendred.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.</p><p>
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<b>Hearing loss</b>
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</p><ul><li class="half_rhythm"><div>The primary focus should be routinely scheduled audiometric follow up that includes assessment of suitability for CI to avoid unnecessary and counterproductive delay if/when the hearing loss progresses and hearing aids are no longer adequate [<a class="bibr" href="#pendred.REF.hansen.2023.440" rid="pendred.REF.hansen.2023.440">Hansen et al 2023</a>].</div></li><li class="half_rhythm"><div>Repeat audiometric testing every three to six months until age three years and annually thereafter.</div></li></ul><p>
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<b>Thyroid function</b>
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</p><ul><li class="half_rhythm"><div>Baseline ultrasonography should be performed to assess thyroid size after age ten years and repeated every five to ten years based on findings on palpation of thyroid size. (The odds of developing a goiter are 1.1 for each one-year increase in age. Thus, after age 20 years, the increase in odds of developing goiter is 6.7-fold [<a class="bibr" href="#pendred.REF.madeo.2009.670" rid="pendred.REF.madeo.2009.670">Madeo et al 2009</a>]).</div></li><li class="half_rhythm"><div>While tests of thyroid function are usually normal in individuals with <i>SLC26A4</i>-SNHL irrespective of thyroid size, this testing is important in the evaluation and management of signs and symptoms of hypo- and hyperthyroidism and should be considered when the medical history and/or physical examination suggest thyroid dysfunction [<a class="bibr" href="#pendred.REF.madeo.2009.670" rid="pendred.REF.madeo.2009.670">Madeo et al 2009</a>].</div></li></ul></div><div id="pendred.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>See Genetic Hearing Loss Overview, <a href="/books/n/gene/deafness-overview/?report=reader#deafness-overview.AgentsCircumstances_to">Agents/Circumstances to Avoid</a>.</p><p>There are anecdotal reports that increased intracranial pressure in individuals with enlarged vestibular aqueduct (EVA) can occasionally trigger a decline in hearing, leading some providers to recommend avoiding activities like weightlifting and contact sports [<a class="bibr" href="#pendred.REF.forli.2021.2305" rid="pendred.REF.forli.2021.2305">Forli et al 2021</a>]. However, evidence is insufficient to support the claim that avoiding these activities will decrease the risk of overall hearing loss progression [<a class="bibr" href="#pendred.REF.brodsky.2018.2219" rid="pendred.REF.brodsky.2018.2219">Brodsky & Choi 2018</a>]. While health care providers should alert families to the possible association between EVA and hearing loss following head injuries, families should be encouraged to make their own decisions on participation in contact sports, taking into account that head trauma may not significantly affect the overall risk of hearing loss progression [<a class="bibr" href="#pendred.REF.brodsky.2018.2219" rid="pendred.REF.brodsky.2018.2219">Brodsky & Choi 2018</a>].</p></div><div id="pendred.Evaluation_of_Sibs_at_Risk"><h3>Evaluation of Sibs at Risk</h3><p>It is appropriate to determine the genetic status of at-risk sibs of a proband with <i>SLC26A4</i>-SNHL (i.e., a proband with known biallelic <i>SLC26A4</i> pathogenic variants) shortly after birth so that appropriate and early support and management can be provided to the child and family. Sibs found to have biallelic <i>SLC26A4</i> pathogenic variants should be evaluated for hearing loss, vestibular dysfunction, and abnormal thyroid function (see <a href="#pendred.Evaluations_Following_Initial_Di">Evaluations Following Initial Diagnosis</a>).</p><p>Note: As individuals with nonsyndromic enlarged vestibular aqueduct can have normal hearing at birth only to develop progressive hearing loss during early childhood, a normal newborn hearing screening does not rule out the possibility that an at-risk sib has <i>SLC26A4</i>-SNHL.</p><p>See <a href="#pendred.Related_Genetic_Counseling_Issue">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="pendred.Therapies_Under_Investigation"><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="pendred.Genetic_Counseling"><h2 id="_pendred_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="pendred.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>SLC26A4</i>-related sensorineural hearing loss (<i>SLC26A4</i>-SNHL) is inherited in an autosomal recessive manner.</p><p>Note: Although digenic inheritance of hearing loss with enlarged vestibular aqueduct has been described involving pathogenic variants in <i>SLC26A4</i> in <i>trans</i> with pathogenic variants in <i>EPHA2</i> [<a class="bibr" href="#pendred.REF.li.2020.1343" rid="pendred.REF.li.2020.1343">Li et al 2020</a>], <i>FOXI1</i> [<a class="bibr" href="#pendred.REF.yang.2007.1055" rid="pendred.REF.yang.2007.1055">Yang et al 2007</a>], or <i>KCNJ10</i> [<a class="bibr" href="#pendred.REF.yang.2009.651" rid="pendred.REF.yang.2009.651">Yang et al 2009</a>], more recent studies have not supported this pattern of inheritance [<a class="bibr" href="#pendred.REF.smits.2022.465" rid="pendred.REF.smits.2022.465">Smits et al 2022</a>].</p></div><div id="pendred.Risk_to_Family_Members_Proband_w"><h3>Risk to Family Members (Proband with Biallelic <i>SLC26A4</i> Pathogenic Variants)</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 a child with biallelic <i>SLC26A4</i> pathogenic variants are presumed to be heterozygous for an <i>SLC26A4</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 an <i>SLC26A4</i> pathogenic variant and to allow reliable recurrence assessment.</div></li><li class="half_rhythm"><div>If an <i>SLC26A4</i> 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="#pendred.REF.j_nsson.2017.519" rid="pendred.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 do not develop <i>SLC26A4</i>-SNHL.</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 an <i>SLC26A4</i> pathogenic variant, each sib of the proband has at conception a 25% chance of having <i>SLC26A4</i>-SNHL, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the <i>SLC26A4</i> pathogenic variants.</div></li><li class="half_rhythm"><div>Considerable intrafamilial variability in hearing loss, temporal bone anomalies, and thyroid dysfunction may be observed among sibs with <i>SLC26A4</i>-SNHL [<a class="bibr" href="#pendred.REF.honda.2022.455" rid="pendred.REF.honda.2022.455">Honda & Griffith 2022</a>].</div></li><li class="half_rhythm"><div>Heterozygotes do not develop <i>SLC26A4</i>-SNHL.</div></li></ul><p><b>Offspring of a proband.</b> The offspring of an individual with biallelic <i>SLC26A4</i> pathogenic variants are obligate heterozygotes for an <i>SLC26A4</i> pathogenic variant.</p><p><b>Other family members.</b> Each sib of the proband's parents has a 50% probability of being heterozygous for an <i>SLC26A4</i> pathogenic variant.</p><p><b>Heterozygote detection.</b> Heterozygote testing for relatives of an individual with <i>SLC26A4</i>-SNHL requires prior identification of the <i>SLC26A4</i> pathogenic variants.</p></div><div id="pendred.Related_Genetic_Counseling_Issue"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#pendred.Evaluation_of_Sibs_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p><b>Sibs of an individual with SNHL and one identified <i>SLC26A4</i> pathogenic variant.</b> If only one <i>SLC26A4</i> pathogenic variant has been identified in a person with SNHL, evaluation of sibs should be individualized and may include computed tomography to assess inner ear anatomy and audiometry. Molecular genetic testing may be of questionable value, and consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse may facilitate decision making. See <a href="#pendred.Molecular_Genetics">Molecular Genetics</a>, <b>Other molecular mechanisms under investigation</b>.</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for clarification of genetic status 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 to young adults with <i>SLC26A4</i>-SNHL or who may be heterozygous for an <i>SLC26A4</i> pathogenic variant.</div></li></ul></div><div id="pendred.Prenatal_Testing_and_Preimplanta"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once biallelic <i>SLC26A4</i> pathogenic variants have been identified in the proband, prenatal and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="pendred.Resources"><h2 id="_pendred_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>MedlinePlus</b>
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</div><div>
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<a href="https://medlineplus.gov/genetics/condition/pendred-syndrome/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Pendred syndrome</a>
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</div></li><li class="half_rhythm"><div>
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<b>American Society for Deaf Children</b>
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</div><div><b>Phone:</b> 800-942-2732 (ASDC)</div><div><b>Email:</b> info@deafchildren.org</div><div>
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<a href="https://deafchildren.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">deafchildren.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Association of the Deaf</b>
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</div><div><b>Phone:</b> 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)</div><div><b>Fax:</b> 301-587-1791</div><div><b>Email:</b> nad.info@nad.org</div><div>
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<a href="https://www.nad.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">nad.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Newborn Screening in Your State</b>
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</div><div>Health Resources & Services Administration</div><div>
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<a href="https://newbornscreening.hrsa.gov/your-state" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">newbornscreening.hrsa.gov/your-state</a>
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</div></li></ul>
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</div><div id="pendred.Molecular_Genetics"><h2 id="_pendred_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="figpendredmolgenTA"><a href="/books/NBK1467/table/pendred.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobpendredmolgenTA"><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="pendred.molgen.TA"><a href="/books/NBK1467/table/pendred.molgen.TA/?report=objectonly" target="object" rid-ob="figobpendredmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">SLC26A4-Related Sensorineural Hearing Loss: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpendredmolgenTB"><a href="/books/NBK1467/table/pendred.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobpendredmolgenTB"><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="pendred.molgen.TB"><a href="/books/NBK1467/table/pendred.molgen.TB/?report=objectonly" target="object" rid-ob="figobpendredmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for SLC26A4-Related Sensorineural Hearing Loss (View All in OMIM) </p></div></div><div id="pendred.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>SLC26A4</i> encodes the protein pendrin, which functions as a nonspecific exchanger of anions (e.g., chloride and iodide) and bases (e.g., HCO<sub>3</sub><sup>−</sup> and OH<sup>−</sup>) across the apical plasma membranes of epithelial cells. Pendrin is expressed in a limited number of tissues, including the inner ear, thyroid, kidney, and lungs (where it is expressed in the epithelial cells of the respiratory tract). In the inner ear, absence or reduced function of pendrin leads to acidification of endolymphatic fluid and antenatal formation of enlarged vestibular aqueduct and, by unknown means, degeneration of the sensory cells in the cochlea [<a class="bibr" href="#pendred.REF.griffith.2011.11" rid="pendred.REF.griffith.2011.11">Griffith & Wangemann 2011</a>, <a class="bibr" href="#pendred.REF.wangemann.2011.527" rid="pendred.REF.wangemann.2011.527">Wangemann 2011</a>]. The thyroid phenotype in <i>SLC26A4</i>-related sensorineural hearing loss (<i>SLC26A4</i>-SNHL) results from reduced iodide efflux into the thyroid follicle and impaired iodide organification [<a class="bibr" href="#pendred.REF.honda.2022.455" rid="pendred.REF.honda.2022.455">Honda & Griffith 2022</a>].</p><p><b>Mechanism of disease causation.</b> Loss of function</p><p><b>Other molecular mechanisms under investigation.</b> In individuals with a phenotype consistent with <i>SLC26A4</i>-SNHL and a single identified <i>SLC26A4</i> pathogenic variant (i.e., individuals with a postulated "missing variant"), noncoding variants affecting the level of expression of <i>SLC26A4</i> could be involved.</p><p>In individuals of Chinese, Korean, and Japanese ancestry with enlarged vestibular aqueduct (EVA), 67%-90% have biallelic <i>SLC26A4</i> pathogenic variants (called the M2 genotype), and 8%-21% have a single <i>SLC26A4</i> pathogenic variant (called the M1 genotype) [<a class="bibr" href="#pendred.REF.choi.2009.856" rid="pendred.REF.choi.2009.856">Choi et al 2009</a>, <a class="bibr" href="#pendred.REF.miyagawa.2014.262" rid="pendred.REF.miyagawa.2014.262">Miyagawa et al 2014</a>, <a class="bibr" href="#pendred.REF.honda.2022.455" rid="pendred.REF.honda.2022.455">Honda & Griffith 2022</a>].</p><p>In individuals of northern European ancestry with EVA, about 25% have biallelic <i>SLC26A4</i> pathogenic variants (M2 genotype), ~25% have a single <i>SLC26A4</i> pathogenic variant (M1 genotype), and the remaining 50% do not have any identifiable <i>SLC26A4</i> pathogenic variants (called the M0 genotype). These percentages suggest the existence of an undetected/unrecognized <i>SLC26A4</i> pathogenic variant in a noncoding region in individuals in this ethnic group with EVA and an M1 genotype. Although to date no such <i>SLC26A4</i> pathogenic variants have been identified, a shared haplotype (referred to as the "Caucasian" EVA [CEVA] haplotype) has been identified in many individuals with the M1 genotype. The CEVA haplotype is a polymorphism comprised of 12 single-nucleotide variants spanning a 0.89-Mb region extending from upstream of <i>PRKAR2B</i> to intron 3 of <i>SLC26A4</i> [<a class="bibr" href="#pendred.REF.chattaraj.2017.665" rid="pendred.REF.chattaraj.2017.665">Chattaraj et al 2017</a>, <a class="bibr" href="#pendred.REF.smits.2022.465" rid="pendred.REF.smits.2022.465">Smits et al 2022</a>] that is present in 3% of the non-Finnish European population.</p><p>Although the CEVA haplotype is frequently reported in <i>trans</i> in affected persons with one <i>SLC26A4</i> pathogenic variant [<a class="bibr" href="#pendred.REF.chattaraj.2017.665" rid="pendred.REF.chattaraj.2017.665">Chattaraj et al 2017</a>], a detailed study using short- and long-read whole-genome sequencing and optical mapping could not identify any variant in the CEVA haplotype as pathogenic [<a class="bibr" href="#pendred.REF.smits.2022.465" rid="pendred.REF.smits.2022.465">Smits et al 2022</a>]. As the CEVA haplotype does not always segregate with the <i>SLC26A4</i>-SNHL phenotype and no functional evidence of its effect on gene expression has been identified, the CEVA haplotype is considered a variant of uncertain significance (VUS). Thus, a definitive diagnosis of <i>SLC26A4</i>-SNHL cannot be made even if a <i>SLC26A4</i> pathogenic variant is confirmed in <i>trans</i> with the CEVA haplotype.</p><p><b>Variants of uncertain significance.</b> The noncoding variant 2343+69C>A, reported by <a class="bibr" href="#pendred.REF.yuan.2012.e49984" rid="pendred.REF.yuan.2012.e49984">Yuan et al [2012]</a> in one individual, remains a VUS, as information on the phenotype or other variants in <i>trans</i> was not provided.</p><p>If molecular genetic testing reveals only one <i>SLC26A4</i> pathogenic (or likely pathogenic variant) in a symptomatic proband or if there is an <i>SLC26A4</i> variant of uncertain significance, perchlorate discharge testing may be considered. Although now rarely used, this test measures the amount of radioactive iodine released from the thyroid gland after administering perchlorate, which displaces iodine from the thyroid, thereby revealing a potential defect in iodine uptake and transport due to faulty pendrin function.</p></div></div><div id="pendred.Chapter_Notes"><h2 id="_pendred_Chapter_Notes_">Chapter Notes</h2><div id="pendred.Author_Notes"><h3>Author Notes</h3><p><b>Richard JH Smith, MD,</b> is a pediatric otolaryngologist, human geneticist, and complementologist at the University of Iowa. He directs the Molecular Otolaryngology and Renal Research Laboratories (MORL), which offers comprehensive genetic testing for hearing loss. He is interested in collaborating with clinicians treating families affected by genetic hearing loss in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. He is also actively involved in research in individuals with a phenotype suggestive of <i>SLC26A4</i>-SNHL in whom only one <i>SLC26A4</i> pathogenic variant has been identified. For questions about hearing loss and the diagnosis of <i>SLC26A4-</i>SNHL, email <a href="mailto:dev@null" data-email="ude.awoiu@lrom" class="oemail">ude.awoiu@lrom</a>. Lab website: <a href="https://morl.lab.uiowa.edu/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">morl.lab.uiowa.edu</a></p><p><b>Amanda M Odell, MS, LGC,</b> is a licensed and board-certified genetic counselor who specializes in hearing loss and deafness genetics at the University of Iowa. She works with the Molecular Otolaryngology and Renal Research Laboratories (MORL), which offers genetic testing for hearing loss. Amanda is actively involved in translational research studies for hearing loss, including genotype-phenotype studies, genetic counseling for persons with hearing loss, and implementation of genetic evaluation for hearing loss.</p><p><b>Hela Azaiez, MS, PhD,</b> is a human geneticist specializing in the molecular genetics and genomics of hearing loss at the Department of Otolaryngology at the University of Iowa. She is actively engaged in basic and translational research, with a focus on the genetic etiology of hearing loss. Her research aims to decode the molecular mechanisms of hearing and deafness, intending to translate this knowledge into improved clinical diagnostics and enhanced patient care. She also maintains a keen interest in collaborating with clinicians who treat families affected by genetic hearing loss, particularly when no causative variant has been identified through molecular genetic testing of known genes associated with hearing loss.</p></div><div id="pendred.Acknowledgments"><h3>Acknowledgments</h3><p>Supported in part by grants DC02842 and DC012049 from the NIDCD (RJHS).</p></div><div id="pendred.Author_History"><h3>Author History</h3><p>Fatemeh Alasti, PhD; University of Iowa (2011-2017)<br />Hela Azaiez, MS, PhD (2025-present)<br />Lorraine A Everett, MD; National Institutes of Health (1998-2001)<br />Eric D Green, MD, PhD; National Institutes of Health (1998-2001)<br />Yoichiro Iwasa, MD, PhD; University of Iowa (2020-2025)<br />Daryl A Scott, MD, PhD; University of Iowa (1998-2001)<br />Amanda M Odell, MS, LGC (2020-present)<br />Val C Sheffield, MD, PhD; University of Iowa School of Medicine (1998-2001)<br />Richard JH Smith, MD (1998-present)<br />Guy Van Camp, PhD; University of Antwerp (1998-2017)<br />Peter Van Hauwe; University of Antwerp (1998-2001)</p></div><div id="pendred.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>9 January 2025 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>19 October 2017 (bp) Comprehensive update posted live</div></li><li class="half_rhythm"><div>29 May 2014 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>22 December 2011 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>2 April 2009 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>31 August 2006 (me) Comprehensive update posted to live Web site</div></li><li class="half_rhythm"><div>28 June 2004 (me) Comprehensive update posted to live Web site</div></li><li class="half_rhythm"><div>1 May 2001 (me) Comprehensive update posted to live Web site</div></li><li class="half_rhythm"><div>28 September 1998 (pb) Review posted to live Web site</div></li><li class="half_rhythm"><div>4 April 1998 (rjhs) Original submission (with DFNA3) by RJH Smith, MD; LA Everett, MD; ED Green, MD, PhD; DA Scott, MD, PhD; VC Sheffield, MD, PhD; G Van Camp, PhD; P Van Hauwe</div></li></ul></div></div><div id="pendred.References"><h2 id="_pendred_References_">References</h2><div id="pendred.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="pendred.REF.aimoni.2017.254">Aimoni
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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Disclaimer</a>. No further modifications are allowed. For clarity, excerpts
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of GeneReviews chapters for use in lab reports and clinic notes are a permitted
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use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
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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>Smith RJH, Azaiez H, Odell AM. SLC26A4-Related Sensorineural Hearing Loss. 1998 Sep 28 [Updated 2025 Jan 9]. 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/edm/?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/slc39a8-cdg/?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="figobpendredTc"><div id="pendred.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1467/table/pendred.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pendred.Tc_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pendred.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>SLC26A4</i>-Related Sensorineural Hearing Loss: Included Phenotypes <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_pendred.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Nonsyndromic <i>SLC26A4-</i>related sensorineural hearing loss (also referred to as DFNB4, NSEVA, and DFNB4/NSEVA)</div></li><li class="half_rhythm"><div>Pendred syndrome (PDS)</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">NSEVA = nonsyndromic enlargement of the vestibular aqueduct</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="pendred.TF.c.1"><p class="no_margin">For additional synonyms and outdated names, see <a href="#pendred.Nomenclature">Nomenclature</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobpendredTmoleculargenetictestingused"><div id="pendred.T.molecular_genetic_testing_used" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>SLC26A4</i>-Related Sensorineural Hearing Loss</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1467/table/pendred.T.molecular_genetic_testing_used/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pendred.T.molecular_genetic_testing_used_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pendred.T.molecular_genetic_testing_used_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_pendred.T.molecular_genetic_testing_used_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_pendred.T.molecular_genetic_testing_used_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_pendred.T.molecular_genetic_testing_used_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SLC26A4</i>
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</td><td headers="hd_h_pendred.T.molecular_genetic_testing_used_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_pendred.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>99% <sup>4</sup></td></tr><tr><td headers="hd_h_pendred.T.molecular_genetic_testing_used_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_pendred.T.molecular_genetic_testing_used_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><1% <sup>6</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="pendred.TF.1.1"><p class="no_margin">See <a href="/books/NBK1467/?report=reader#pendred.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="pendred.TF.1.2"><p class="no_margin">See <a href="#pendred.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="pendred.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; 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>4. </dt><dd><div id="pendred.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#pendred.REF.stenson.2020.1197" rid="pendred.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="pendred.TF.1.5"><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 or duplications. Multigene panels and exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="pendred.TF.1.6"><p class="no_margin">Intragenic deletions/duplications are rare; two probands, one homozygous for a deletion encompassing exons 13-21 of <i>SLC26A4</i> and the second compound heterozygous for a deletion of exons 1-3 and a duplication of exons 9-21 of <i>SLC26A4,</i> have been identified [RJH Smith, personal observation].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobpendredTgeneticdisorderswithtempora"><div id="pendred.T.genetic_disorders_with_tempora" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Genetic Disorders with Temporal Bone Malformations in the Differential Diagnosis of <i>SLC26A4</i>-Related Sensorineural Hearing Loss</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1467/table/pendred.T.genetic_disorders_with_tempora/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pendred.T.genetic_disorders_with_tempora_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Features of Disorder</th></tr><tr><th headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_4" id="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/<br /><i>SLC26A4</i>-SNHL</th><th headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_4" id="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from <i>SLC26A4</i>-SNHL</th></tr></thead><tbody><tr><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ATP6V0A4</i>
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<br />
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<i>ATP6V1B1</i>
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<br />
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<i>FOXI1</i>
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</td><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distal renal tubular acidosis w/progressive SNHL (See <a href="/books/n/gene/hered-drta/?report=reader">Hereditary Distal Renal Tubular Acidosis</a>.)</td><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_4 hd_h_pendred.T.genetic_disorders_with_tempora_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>SNHL</div></li><li class="half_rhythm"><div>Malformations of inner ear incl EVA</div></li></ul>
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</td><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_4 hd_h_pendred.T.genetic_disorders_with_tempora_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Metabolic acidosis assoc w/renal tubular acidosis, which may lead to softening & weakening of bones</td></tr><tr><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>EYA1</i>
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<br />
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<i>SIX1</i>
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<br />
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<i>SIX5</i>
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</td><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/bor/?report=reader">Branchiootorenal spectrum disorder</a>
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</td><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_4 hd_h_pendred.T.genetic_disorders_with_tempora_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>SNHL</div></li><li class="half_rhythm"><div>Malformations of inner ear incl EVA & cochlear hypoplasia</div></li></ul>
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</td><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_4 hd_h_pendred.T.genetic_disorders_with_tempora_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Abnormalities of semicircular canals</div></li><li class="half_rhythm"><div>Malformation of outer & middle ear</div></li><li class="half_rhythm"><div>Branchial fistulae & cysts</div></li><li class="half_rhythm"><div>Renal malformations</div></li></ul>
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</td></tr><tr><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_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_pendred.T.genetic_disorders_with_tempora_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/tcs/?report=reader">Treacher Collins syndrome</a>
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</td><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD<br />AR</td><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_4 hd_h_pendred.T.genetic_disorders_with_tempora_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hearing loss (conductive) in ~40%-50% of persons</div></li><li class="half_rhythm"><div>Occasionally, malformations of inner ear incl dysplasia of vestibule</div></li></ul>
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</td><td headers="hd_h_pendred.T.genetic_disorders_with_tempora_1_1_1_4 hd_h_pendred.T.genetic_disorders_with_tempora_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Abnormalities of semicircular canals</div></li><li class="half_rhythm"><div>Malformations of outer & middle ear</div></li><li class="half_rhythm"><div>Facial abnormalities incl maxillary hypoplasia & micrognathia</div></li><li class="half_rhythm"><div>Ocular abnormalities incl eyelid coloboma</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">AD = autosomal dominant; AR = autosomal recessive; EVA = enlarged vestibular aqueduct; MOI = mode of inheritance; SNHL = sensorineural hearing loss</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobpendredmolgenTA"><div id="pendred.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>SLC26A4-Related Sensorineural Hearing Loss: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1467/table/pendred.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pendred.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_pendred.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_pendred.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_pendred.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_pendred.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_pendred.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_pendred.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_pendred.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/5172" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>SLC26A4</i>
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</a>
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</td><td headers="hd_b_pendred.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=5172" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">7q22<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_b_pendred.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/O43511" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Pendrin</a>
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</td><td headers="hd_b_pendred.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://hereditaryhearingloss.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Hereditary Hearing Loss Homepage (SLC26A4)</a>
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<br />
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<a href="https://research.cchmc.org/LOVD2/home.php?select_db=SLC26A4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CCHMC - Human Genetics Mutation Database (SLC26A4)</a>
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<br />
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<a href="http://deafnessvariationdatabase.org/letter/s" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Deafness Variation Database (SLC26A4)</a>
|
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</td><td headers="hd_b_pendred.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=SLC26A4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC26A4</a>
|
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</td><td headers="hd_b_pendred.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=SLC26A4[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SLC26A4</a>
|
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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 id="pendred.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>.
|
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
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<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="figobpendredmolgenTB"><div id="pendred.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for SLC26A4-Related Sensorineural Hearing Loss (<a href="/omim/274600,600791,605646" 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/NBK1467/table/pendred.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pendred.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/274600" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">274600</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PENDRED SYNDROME; PDS</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/600791" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">600791</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DEAFNESS, AUTOSOMAL RECESSIVE 4, WITH ENLARGED VESTIBULAR AQUEDUCT; DFNB4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/605646" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">605646</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SOLUTE CARRIER FAMILY 26, MEMBER 4; SLC26A4</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobpendredF1"><div id="pendred.F1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK1467/bin/pendred-Image001.jpg" alt="Figure 1. . Computed tomography in a proband with Pendred syndrome shows absence of the upper turn of the cochlea and deficiency of the modiolus (white arrow)." /></div><h3><span class="label">Figure 1. </span></h3><div class="caption"><p>Computed tomography in a proband with Pendred syndrome shows absence of the upper turn of the cochlea and deficiency of the modiolus (white arrow). EVA is also present (black arrow). Inset shows a normal right cochlea and no enlargement of the vestibular aqueduct.</p></div></div></article><article data-type="fig" id="figobpendredF2"><div id="pendred.F2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK1467/bin/pendred-Image002.jpg" alt="Figure 2. . In an unbiased screen of 2,434 persons who underwent comprehensive genetic testing for hearing loss, Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) caused by biallelic SLC26A4 pathogenic variants was the third most common diagnosis of 79 different genetic diagnoses, comprising 6% of the total [Sloan-Heggen et al 2016; Smith et al, unpublished data]." /></div><h3><span class="label">Figure 2. </span></h3><div class="caption"><p>In an unbiased screen of 2,434 persons who underwent comprehensive genetic testing for hearing loss, Pendred syndrome / nonsyndromic enlarged vestibular aqueduct (PDS/NSEVA) caused by biallelic <i>SLC26A4</i> pathogenic variants was the third most common diagnosis of 79 different genetic diagnoses, comprising 6% of the total [<a class="bibr" href="#pendred.REF.sloanheggen.2016.441" rid="pendred.REF.sloanheggen.2016.441">Sloan-Heggen et al 2016</a>; Smith et al, unpublished data].</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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