Enlargement Of The Vestibular Aqueduct Research Articles

The role of SLC26A4 in bony labyrinth development and otoconial mineralization in mouse models.

Inner ear malformations are predominantly attributed to developmental arrest during the embryonic stage of membranous labyrinth development. Due to the inherent difficulty in clinically assessing the status of the membranous labyrinth, these malformations are diagnosed with radiographic imaging, based on the morphological characteristics of the bony labyrinth. While extensive research has elucidated the intricacies of membranous labyrinth development in mouse models, comprehensive investigations into the developmental trajectory of the bony labyrinth, especially about its calcification process, have been notably lacking. One of the most prominent types of inner ear malformations is known as incomplete partition (IP), characterized by nearly normal external cochlear appearance but pronounced irregularities in the morphology of the modiolus and inter-scalar septa. IP type II (IP-II), also known as Mondini dysplasia, is generally accompanied by an enlargement of the vestibular aqueduct and is primarily attributed to mutations in the SLC26A4 gene. In the case of IP-II, the modiolus and inter-scalar septa of the cochlear apex are underdeveloped or missing, resulting in the manifestation of a cystic structure on radiographic imaging. In this overview, we not only explore the normal development of the bony labyrinth in mice but also present our observations on otolith mineralization. Furthermore, we investigated the specifics of bony labyrinth and otolith mineralization in Slc26a4-deficient mice, which served as an animal model for IP-II. We ensured that these findings promise to provide valuable insights for the establishment of therapeutic interventions, optimal timing, targeted sites, and preventive measures when considering the management of this condition.

CHD7 variants associated with hearing loss and enlargement of the vestibular aqueduct

Enlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inner ear malformation identified in patients with sensorineural hearing loss. EVA is associated with pathogenic variants in SLC26A4. However, in European–Caucasian populations, about 50% of patients with EVA carry no pathogenic alleles of SLC26A4. We tested for the presence of variants in CHD7, a gene known to be associated with CHARGE syndrome, Kallmann syndrome, and hypogonadotropic hypogonadism, in a cohort of 34 families with EVA subjects without pathogenic alleles of SLC26A4. In two families, NM_017780.4: c.3553A > G [p.(Met1185Val)] and c.5390G > C [p.(Gly1797Ala)] were detected as monoallelic CHD7 variants in patients with EVA. At least one subject from each family had additional signs or potential signs of CHARGE syndrome but did not meet diagnostic criteria for CHARGE. In silico modeling of these two missense substitutions predicted detrimental effects upon CHD7 protein structure. Consistent with a role of CHD7 in this tissue, Chd7 transcript and protein were detected in all epithelial cells of the endolymphatic duct and sac of the developing mouse inner ear. These results suggest that some CHD7 variants can cause nonsyndromic hearing loss and EVA. CHD7 should be included in DNA sequence analyses to detect pathogenic variants in EVA patients. Chd7 expression and mutant phenotype data in mice suggest that CHD7 contributes to the formation or function of the endolymphatic sac and duct.

Correction 2: A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct.

Correction 2: A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct.

Quantitative analysis and correlative evaluation of video-oculography, micro-computed tomography, and histopathology in Pendrin-null mice

Patients with SLC26A4 mutations exhibit highly variable hearing loss and vestibular dysfunction. Although Slc26a4 mutant mice similarly exhibit vestibular deficits, including circling behavior, head tilting, and torticollis, the underlying pathogenesis of the vestibular symptoms remains unclear, hindering its effective management for patients with SLC26A4 mutations. In this study, we evaluated the equilibrium function using the inspection equipment, which can record eye movements against rotational, gravitational, and thermal stimulations. Moreover, we correlated the degree of functional impairment with the morphological alterations observed in Slc26a4Δ/Δ mice. The rotational stimulus and ice water caloric tests revealed considerable impairment of the semicircular canal, while the tilted gravitational stimulus test showed a severe functional decline of the otolithic system in Slc26a4Δ/Δ mice. Generally, the degree of impairment was more severe in circling Slc26a4Δ/Δ mice than in non-circling Slc26a4Δ/Δ mice. In non-circling Slc26a4Δ/Δ mice, the semicircular canal function was normal. Micro-computed tomography results showed enlargement of the vestibular aqueduct and bony semicircular canals but no correlative relationship between the severity of the caloric response and the size of bony labyrinths. Giant otoconia and a significant decrease in total otolith volume in the saccule and utricle were observed in Slc26a4Δ/Δ mice. However, the giant otoconia were not overly dislocated in the bony otolithic system and ectopic otoconia were absent in the semicircular canal. The number and morphology of the utricular hair cells in Slc26a4Δ/Δ mice were not significantly reduced compared to those in Slc26a4Δ/+ mice. Collectively, we can conclude that vestibular impairments are mainly associated with otoconia formation and morphology rather than hair cell degeneration. In addition, severe disturbances of semicircular canals cause circling behavior in Slc26a4Δ/Δ mice. Our comprehensive morphological and functional assessments apply to mouse models of other genetic diseases with vestibular impairment.

Novel POU3F4 variants identified in patients with inner ear malformations exhibit aberrant cellular distribution and lack of SLC6A20 transcriptional upregulation.

Hearing loss (HL) is the most common sensory defect and affects 450 million people worldwide in a disabling form. Pathogenic sequence alterations in the POU3F4 gene, which encodes a transcription factor, are causative of the most common type of X-linked deafness (X-linked deafness type 3, DFN3, DFNX2). POU3F4-related deafness is characterized by a typical inner ear malformation, namely an incomplete partition of the cochlea type 3 (IP3), with or without an enlargement of the vestibular aqueduct (EVA). The pathomechanism underlying POU3F4-related deafness and the corresponding transcriptional targets are largely uncharacterized. Two male patients belonging to a Caucasian cohort with HL and EVA who presented with an IP3 were submitted to genetic analysis. Two novel sequence variants in POU3F4 were identified by Sanger sequencing. In cell-based assays, the corresponding protein variants (p.S74Afs*8 and p.C327*) showed an aberrant expression and subcellular distribution and lack of transcriptional activity. These two protein variants failed to upregulate the transcript levels of the amino acid transporter gene SLC6A20, which was identified as a novel transcriptional target of POU3F4 by RNA sequencing and RT-qPCR. Accordingly, POU3F4 silencing by siRNA resulted in downregulation of SLC6A20 in mouse embryonic fibroblasts. Moreover, we showed for the first time that SLC6A20 is expressed in the mouse cochlea, and co-localized with POU3F4 in the spiral ligament. The findings presented here point to a novel role of amino acid transporters in the inner ear and pave the way for mechanistic studies of POU3F4-related HL.

Dissection of the Endolymphatic Sac from Mice.

The study of mutant mouse models of human hearing and balance disorders has unraveled many structural and functional changes which may contribute to the human phenotypes. Although important progress has been done in the understanding of the development and function of the neurosensory epithelia of the cochlea and vestibula, limited knowledge is available regarding the development, cellular composition, molecular pathways and functional characteristics of the endolymphatic sac. This is, in large part, due to the difficulty of visualizing and microdissecting this tissue, which is an epithelium comprised of only one cell layer. The study presented here describes an approach to access and microdissect the endolymphatic sac from the wild-type mouse inner ear at different ages. The result of a similar dissection is shown in a pendrin-deficient mouse model of enlargement of the vestibular aqueduct. A transgenic mouse with a fluorescent endolymphatic sac is presented. This reporter mouse can be used to readily visualize the endolymphatic sac with limited dissection and determine its size. It can also be used as an educational tool to teach how to dissect the endolymphatic sac. These dissection procedures should facilitate further characterization of this understudied part of the inner ear.

Analysis of the correlation between radiological and audiological features of patients with enlarged vestibular aqueduct

Objective: The radiological and audiological results of patients with hearing loss associated with enlarged vestibular aqueduct (EVA) were analyzed statistically to explore the association between them. Methods: In this retrospective study, we screened 64 patients (128 ears) with EVA diagnosed in the Department of Otorhinolaryngology, Shengjing Hospital of China Medical University from January 2012 to June 2016, who met the inclusion criteria and the exclusion criteria at the same time, including 37 males (74 ears) and 27 females (54 ears), aged from 6 months to 17 years, all of whom showed varying degrees of sensorineural hearing loss (SNHL). The imaging observations included the midpoint measurement (MP) and the operculum measurement(OP) of the temporal bone HRCT, the long signal area cross-sectional area (ES(L)), the short signal area cross-sectional area (ES(S)), as well as the largest total signal area cross-sectional area (ES(T)) of the endolymphatic sac(ES) of the cochlear MRI. The audiological observations included collecting detailed medical history and subjective and/or objective audiological examinations to determine the character and degree of hearing loss. According to the progress and changes of hearing loss, they were divided into hearing stability group (86 ears) and fluctuation/progression group (42 ears). SPSS22.0 statistical software was used to carry out statistical analysis of the imaging measurement results. Results: The sizes of MP and OP were smaller in the stable group than those in the fluctuating/progressive group, and the difference was statistically significant (P<0.05). For ES(L), ES(S) or ES(T), there was no significant difference between the stable group and the fluctuating/progressive group (P>0.05). For the 13 patients with asymmetric hearing loss, the sizes of MP, OP, ES(L), ES(S) or ES(T) were not significantly different between the mild side and the serious side (P>0.05). For the ears whose ES(L)/ES(S) was>2 or the ES(S)/ES(L) was>2, the proportion was not significantly different between the stable group and the fluctuating/progressive group (P>0.05). Conclusions: For patients with EVA,the smaller the enlarged vestibular aqueduct is,the more likely it is congenital severe sensorineural hearing loss. Patients with significantly enlarged vestibular aqueduct often exhibit volatility/progressive hearing loss. The degree of enlargement of the endolymphatic vessels and endolymphatic sac is not related to the degree of hearing loss. For EVA patients with asymmetric hearing loss, the mild or serious side of hearing loss is random, which is not affected by the degree of enlargement of the vestibular aqueduct and endolymphatic sac. The degree of hearing loss in patients with EVA is not related to the ratio of ES(L)/ES(S).

SLC26A4-linked CEVA haplotype correlates with phenotype in patients with enlargement of the vestibular aqueduct

BackgroundRecessive mutations of coding regions and splice sites of the SLC26A4 gene cause hearing loss with enlargement of the vestibular aqueduct (EVA). Some patients also have a thyroid iodination defect that can lead to multinodular goiter as part of Pendred syndrome. A haplotype of variants upstream of SLC26A4, called CEVA, acts as a pathogenic recessive allele in trans to mutations affecting the coding regions or splice sites of SLC26A4. Our first hypothesis is that CEVA, acting as a pathogenic recessive allele, is correlated with a less severe phenotype than mutations affecting the coding regions and splice sites of SLC26A4. Our second hypothesis is that CEVA acts as a modifier of the phenotype in patients with EVA caused by mutations affecting the coding regions or splice sites of both alleles of SLC26A4 or EVA caused by other factors.MethodsThis was a prospective cohort study of 114 individuals and 202 ears with EVA. To test our first hypothesis, we compared the thyroid and auditory phenotypes of subjects with mutations affecting coding regions of both alleles of SLC26A4 with those of subjects carrying CEVA in trans to mutations affecting the coding regions. To test our second hypothesis, we compared the phenotypes associated with the presence versus absence of CEVA among subjects with no coding region mutations, as well as among subjects with mutations affecting coding regions of both alleles.ResultsSubjects carrying CEVA in trans to a mutation of SLC26A4 have a normal thyroid phenotype and less severe hearing loss in comparison to individuals with mutations affecting coding regions of both alleles of SLC26A4. In subjects with no mutant alleles of SLC26A4, hearing loss was more severe in subjects who carry the CEVA haplotype in comparison to non-carriers. There was no correlation of CEVA with the phenotype of subjects with mutations affecting coding regions of both alleles.ConclusionsCEVA, acting as a likely pathogenic recessive allele, is associated with a less severe phenotype than alleles with a mutation affecting the coding regions or splice sites of SLC26A4. CEVA may act as a genetic modifier in patients with EVA caused by other factors.

Sex-specific enlarged vestibular aqueduct morphology and audiometry.

Enlargement of the vestibular aqueduct (EVA) is one of the most common congenital malformations in pediatric patients presenting with sensorineural or mixed hearing loss. The relationship between vestibular aqueduct (VA) morphology and hearing loss across sex is not well characterized. This study assesses VA morphology and frequency-specific hearing thresholds with sex as the primary predictor of interest. A retrospective, longitudinal, and repeated-measures study was used. 47 patients at an academic tertiary care center with hearing loss and a record of CT scan of the internal auditory canal were candidates, and included upon meeting EVA criteria after confirmatory measurements of vestibular aqueduct midpoint and operculum widths. Audiometric measures included pure-tone average and frequency-specific thresholds. Of the 47 patients (23 female and 24 male), 79 total ears were affected by EVA; the median age at diagnosis was 6.60 years. After comparing morphological measurements between sexes, ears from female patients were observed to have a greater average operculum width (3.25 vs. 2.70 mm for males, p = 0.006) and a greater average VA midpoint width (2.80 vs. 1.90 mm for males, p = 0.004). After adjusting for morphology, male patients' ears had pure-tone average thresholds 17.6 dB greater than female patients' ears (95% CI, 3.8 to 31.3 dB). Though females seem to have greater enlargement of the vestibular aqueduct, this difference does not extend to hearing loss. Therefore, our results indicate that criteria for EVA diagnoses may benefit from re-evaluation. Further exploration into morphological and audiometric discrepancies across sex may help inform both clinician and patient expectations.

When is a Vestibular Aqueduct Enlarged?

A ten-year-old boy with bilateral moderate sensorineural hearing loss underwent computerized tomographic (CT) imaging (GE Brightspeed, Wisconsin, USA) of the temporal bone as part of the work-up to determine the etiology of his condition. The formal radiologic interpretation of the scan stated that the vestibular aqueducts were not enlarged. However, independent review of the axial CT images appeared to indicate the presence of enlarged vestibular aqueducts. (Figure 1) This can be contrasted with a scan from another patient with no evidence of sensorineural hearing loss. (Figure 2)&#x0D; What can explain the discrepancy between the two?&#x0D; &#x0D; If simple visual inspection of the vestibular aqueduct (VA) can lead to conflicting interpretations, then what radiographic parameters can be used to resolve the issue? Is there a more objective means of determining the presence of a clinically significant vestibular aqueduct enlargement?&#x0D; &#x0D; In 1978, Valvasorri and Clemis1 first described an association between congenital sensorineural hearing loss and an abnormality in vestibular aqueduct anatomy which they labelled as the “large vestibular aqueduct syndrome.” In this landmark study that utilized hypocycloidal polytomographic temporal bone studies, they proposed that a vestibular aqueduct is enlarged when its midpoint diameter is greater than 1.5 mm. Although this parameter is generally considered to be the defining characteristic of the condition, one must realize that this measurement was based on less accurate imaging technology and measurement tools. Contemporary studies utilize high-resolution CT imaging with digital workstation measurement software to evaluate vestibular aqueduct anatomy. Currently, the two most commonly used radiographic parameters are the VA midpoint (MP) width and the VA opercular (OP) width. (Figure 3)&#x0D; More recently, Boston et al.2 in 2007 published normative values for these parameters based on a study population of 73 children without known sensorineural hearing loss. They considered a vestibular aqueduct enlarged when one or both of the measured widths were above the 95th percentile of the normal study group measurements. On this basis, a VA midpoint width of &gt;0.9 mm and/or a VA opercular width of &gt;1.9 mm was the criteria established to define an enlarged vestibular aqueduct.&#x0D; &#x0D; The patient’s measured vestibular aqueduct midpoint width on the right was 2.1 mm, while the vestibular aqueduct opercular width was 2.9 mm. (Figure 4) These measurements, when evaluated against either the original Valvassori criteria or the newer criteria of Boston et al., confirm what was visually apparent– the presence of a clinically significant enlargement of the vestibular aqueduct as the etiology of the patient’s sensorineural hearing loss.&#x0D;

A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

BackgroundEnlargement of the vestibular aqueduct (EVA) is the most common radiological abnormality in children with sensorineural hearing loss. Mutations in coding regions and splice sites of the SLC26A4 gene are...

Clinical data analysis of genotypes and phenotypes of deafness gene mutations in newborns: A retrospective study.

We retrospectively analyzed newborns with deafness gene mutations and summarized the relationship between genotype and phenotype to provide a basis for genetic counseling. We studied 582 subjects positive for deafness gene mutations that were treated in the otology outpatient department of Beijing Tongren Hospital, Capital Medical University, between April 2012 and April 2016. The subjects were divided into 3 categories: a diagnosed group (group A), which was further subdivided into subgroups A1 (homozygous and compound heterozygous GJB2 mutations) and A2 (homozygous and compound heterozygous SLC26A4 mutations); a drug-induced deafness group (group B, mitochondrial (Mt) gene mutations); and a mutation carrier group (group C), which was further subdivided into the subgroups C1 (GJB2 heterozygous mutations), C2 (SLC26A4 heterozygous mutations), C3 (GJB3 heterozygous mutations), and C4 (double gene mutations). Partial sequences positive for GJB2 or SLC26A4 were sequenced and analyzed for mutations. Subjects underwent otoscopic examination and comprehensive audiological evaluation, and temporal bone computerized tomography and/or inner ear magnetic resonance imaging were performed. GJB2 235delC was the most common mutation locus. The highest proportion of deafness detected during universal newborn hearing screening was for drug-induced deafness, whereas the lowest was for the diagnosed group. GJB2 gene mutations mainly resulted in flat-type, profound-to-severe sensorineural hearing loss (SNHL). SLC26A4 gene mutation was mainly associated with high-frequency drop-type and profound-severe SNHL and was closely related to enlargement of the vestibular aqueduct.

Frequency and specific characteristics of the incomplete partition type III anomaly in children.

To determine the frequency of the incomplete partition type III anomaly and the genetic and clinical features associated with POU3F4 mutations in children with hearing loss. Retrospective case series from 2000 to 2014 at the National Hospital Organization Tokyo Medical Center and collaborating hospitals. A total of 1,004 patients (from 938 families) who had hearing loss by 10 years of age and had undergone computed tomography scanning of their temporal bones were enrolled in this genetic, clinical, and radiological study. The incomplete partition type III anomaly was identified in six patients (0.6%), each of whom had an enlargement of the vestibular aqueduct at the end close to the vestibule. The six patients also had POU3F4 variants, and a genetic analysis revealed frameshift deletions in three patients, a missense variant in two patients of the same family, and a large deletion in one patient. Three of the six patients with POU3F4 variants were sporadic cases, and in one patient the genetic mutation occurred de novo. It was indicated that POU3F4 mutations can be predicted by incomplete partition type III anomaly by radiological examination of the inner ear. All six of the patients showed mixed hearing loss, but none showed fluctuations in hearing, which may be related to the lack of vestibular aqueduct enlargement at the operculum. 4 Laryngoscope, 127:1663-1669, 2017.

Human SLC26A4/Pendrin STAS domain is a nucleotide-binding protein: Refolding and characterization for structural studies

Mutations in the human SLC26A4/Pendrin polypeptide (hPDS) cause Pendred Syndrome /DFNB4, syndromic deafness with enlargement of the vestibular aqueduct and low-penetrance goiter. Here we present data on cloning, protein overexpression and purification, refolding, and biophysical characterization of the recombinant hPDS STAS domain lacking its intrinsic variable sequence (STAS-ΔIVS). We report a reproducible protein refolding protocol enabling milligram scale expression and purification of uniformly 15N- and 13C/15N-enriched hPDS STAS-ΔIVS domain suitable for structural characterization by solution NMR. Circular dichroism, one-dimensional 1H, two-dimensional 1H–15N HSQC, and 1H–13C HSQC NMR spectra confirmed the well-folded state of purified hPDS STAS-ΔIVS in solution. Heteronuclear NMR chemical shift perturbation of select STAS-ΔIVS residues by GDP was observed at fast-to-intermediate NMR time scales. Intrinsic tryptophan fluorescence quench experiments demonstrated GDP binding to hPDS STAS-ΔIVS with Kd of 178μM. These results are useful for structure/function characterization of hPDS STAS, the cytoplasmic subdomain of the congenital deafness protein, pendrin, as well as for studies of other mammalian STAS domains.

A nationwide study on enlargement of the vestibular aqueduct in Japan.

To document the clinical features and associated pure-tone audiometry data in patients with enlargement of the vestibular aqueduct (EVA), and to identify risk factors for fluctuating hearing loss (HL) and vertigo/dizziness in EVA patients. In this nationwide survey in Japan, a first survey sheet was mailed to 662 board-certified otolaryngology departments to identify the ones treating EVA patients. A second survey sheet, which contained solicited clinical information and the results of the hearing tests, was mailed to all facilities that reported treating EVA cases. We analyzed clinical information, including age at the time of the most recent evaluation, gender, EVA side, age at onset, initial symptoms, precipitating factors, and etiology from survey responses, and assessed 4-frequency (500, 1000, 2000, and 4000Hz) pure-tone average (PTA) from accompanying pure-tone audiometry data. A multivariate logistic regression analysis was utilized to identify the possible risk factors for fluctuating HL and vertigo/dizziness. In total, 513 hospitals (response rate, 77.5%) responded to the first survey, and 113 reported treating patients with EVA. Seventy-nine out of the 113 hospitals (response rate 69.9%) responded to the second survey, and the data of 380 EVA patients were registered and analyzed. Of the 380 patients, 221 (58.2%) were female, suggesting female preponderance. The patient age ranged from 0 to 73 years (mean, 16.7 years; median, 13 years; interquartile range, 6-24 years). EVA was bilateral in 91.1% of the patients (346/380). The most prevalent initial symptom was HL (341/380), followed by vertigo/dizziness/imbalance (34/380). Sudden HL occurred secondary to head trauma in 5.3% of the patients and upper respiratory infection in 5.0%. Pure-tone audiometry showed profound HL (PTA >91dB) in 316 (52.0%) of the 608 ears in the 304 patients tested, and asymmetric HL, defined as >10dB, in 147 (48.4%) of the 304 patients. The mean PTA was 83.7dB (median, 91.3dB; interquartile range, 71.3-103.8dB), and the severity in PTA did not correlate with age. Multivariate logistic regression identified age ≥10 years (compared to age of 0-9 years), bilateral HL (compared to unilateral HL/normal hearing), a history of head trauma, and Pendred syndrome (compared to the other EVA-associated disorders) as significant risk factors for fluctuating HL and/or vertigo/dizziness. The present nationwide survey of 380 EVA patients provided a more precise description of the clinical features, including risk factors for fluctuating HL and vertigo/dizziness.

Slc26a4 expression prevents fluctuation of hearing in a mouse model of large vestibular aqueduct syndrome

SLC26A4 mutations cause fluctuating and progressive hearing loss associated with enlargement of the vestibular aqueduct (EVA). SLC26A4 encodes a transmembrane anion exchanger called pendrin expressed in nonsensory epithelial cells of the lateral wall of cochlea, vestibular organs and endolymphatic sac. We previously described a transgenic mouse model of EVA with doxycycline (dox)-inducible expression of Slc26a4 in which administration of dox from conception to embryonic day 17.5 (DE17.5) resulted in hearing fluctuation between 1 and 3months of age. In the present study, we hypothesized that Slc26a4 is required to stabilize hearing in DE17.5 ears between 1 and 3months of age. We tested our hypothesis by evaluating the effect of postnatal re-induction of Slc26a4 expression on hearing. Readministration of dox to DE17.5 mice at postnatal day 6 (P6), but not at 1month of age, resulted in reduced click-evoked auditory brainstem response (ABR) thresholds, less fluctuation of hearing and a higher surface density of pendrin expression in spindle-shaped cells of the stria vascularis. Pendrin expression in spindle-shaped cells was inversely correlated with ABR thresholds. These findings suggest that stabilization of hearing by readministration of dox at P6 is mediated by pendrin expression in spindle-shaped cells. We conclude that early re-induction of Slc26a4 expression can prevent fluctuation of hearing in our Slc26a4-insufficient mouse model. Restoration of SLC26A4 expression and function could reduce or prevent fluctuation of hearing in EVA patients.

Mutation screening of the SLC26A4 gene in a cohort of 192 Chinese patients with congenital hypothyroidism.

Pendred syndrome (PS) is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by biallelic mutations in the SLC26A4 gene encoding for pendrin. Hypothyroidism in PS can be present from birth and therefore diagnosed by neonatal screening. The aim of this study was to examine the SLC26A4 mutation spectrum and prevalence among congenital hypothyroidism (CH) patients in the Guangxi Zhuang Autonomous Region of China and to establish how frequently PS causes hearing impairment in our patients with CH. Blood samples were collected from 192 CH patients in Guangxi Zhuang Autonomous Region, China, and genomic DNA was extracted from peripheral blood leukocytes. All exons of the SLC26A4 gene together with their exon-intron boundaries were screened by next-generation sequencing. Patients with SLC26A4 mutations underwent a complete audiological evaluation including otoscopic examination, audiometry and morphological evaluation of the inner ear. Next generation sequencing analysis of SLC26A4 in 192 CH patients revealed five different heterozygous variations in eight individuals (8/192, 4%). The prevalence of SLC26A4 mutations was 4% among studied Chinese CH. Three of the eight were diagnosed as enlargement of the vestibular aqueduct (EVA), no PS were found in our 192 CH patients. The mutations included one novel missense variant p.P469S, as well as four known missense variants, namely p.V233L, p.M147I, p.V609G and p.D661E. Of the eight patients identified with SLC26A4 variations in our study, seven patients showed normal size/location of thyroid gland, and one patients showed a decreased size one. The prevalence of SLC26A4 pathogenic variants was 4% among studied Chinese patients with CH. Our study expanded the SLC26A4 mutation spectrum, provided the best estimation of SLC26A4 mutation rate for Chinese CH patients and indicated the rarity of PS as a cause of CH.

Atypical patterns of segregation of familial enlargement of the vestibular aqueduct.

Hearing loss and enlarged vestibular aqueduct (EVA) can be inherited as an autosomal recessive trait caused by mutant alleles of the SLC26A4 gene. In some other families, EVA does not segregate in a typical autosomal recessive pattern. The goal of this study was to characterize the SLC26A4 genotypes and phenotypes of extended families with atypical segregation of EVA. Prospective study of cohort of families ascertained between 1998 and 2014 at the National Institutes of Health Clinical Center. Study subjects were members of eight families segregating EVA in at least two members who were not related as siblings. Evaluations included pure-tone audiometry, temporal bone imaging, SLC26A4 nucleotide sequence analysis, SLC26A4-linked marker genotype and haplotype analysis, and pedigree analysis. One family had members with EVA caused by different etiologies, and two families had pseudodominant inheritance of recessive mutations of SLC26A4. In five families, the etiology remained unknown and could include inheritance of mutant alleles at another genetic locus, nongenetic influences, or a combination of these factors. Familial EVA can demonstrate a variety of atypical segregation patterns. Pseudodominant inheritance of SLC26A4 mutations or recessive alleles of other hearing loss genes may be more likely to occur in families in which deaf individuals have intermarried. The etiologic basis of atypical segregation of EVA without detectable SLC26A4 mutations remains unknown. Future studies of these families may reveal novel genes for EVA. NA Laryngoscope, 126:E240-E247, 2016.

Progressive irreversible hearing loss is caused by stria vascularis degeneration in an Slc26a4-insufficient mouse model of large vestibular aqueduct syndrome

Hearing loss of patients with enlargement of the vestibular aqueduct (EVA) can fluctuate or progress, with overall downward progression. The most common detectable cause of EVA is mutations of SLC26A4. We previously described a transgenic Slc26a4-insufficient mouse model of EVA in which Slc26a4 expression is controlled by doxycycline administration. Mice that received doxycycline from conception until embryonic day 17.5 (DE17.5; doxycycline discontinued at embryonic day 17.5) had fluctuating hearing loss between 1 and 6months of age with an overall downward progression after 6months of age. In this study, we characterized the cochlear functional and structural changes underlying irreversible hearing loss in DE17.5 mice at 12months of age. The endocochlear potential was decreased and inversely correlated with auditory brainstem response thresholds. The stria vascularis was thickened and edematous in ears with less severe hearing loss, and thinned and atrophic in ears with more severe hearing loss. There were pathologic changes in marginal cell morphology and gene expression that were not observed at 3months. We conclude that strial dysfunction and degeneration are the primary causes of irreversible progressive hearing loss in our Slc26a4-insufficient mouse model of EVA. This model of primary strial atrophy may be used to explore the mechanisms of progressive hearing loss due to strial dysfunction.

Syndromes de Pendred et surdités apparentées: une même entité?

Pendred syndrome is an autosomal recessive familial disorder, defined as a sensorineural deafness coinciding with a goiter related to an iodine organification defect. It constitutes 4 to 10 % of all causes of familial congenital hearing loss. It is now well established that this condition was caused by mutations in the SLC26A4 gene which codes for pendrin, a protein involved in the transport of anions (I-, Cl, HCO3-), particularly in apical iodine efflux in thyroid cells and chloride (Cl-|HCO3-) at the cochlear level. A current issue is to determine factors that distinguish Pendred syndrome from other varieties of isolated deafness also including enlargement of the vestibular aqueduct, but without evidence of thyroid expression. A prospective investigation of these 2 situations, conducted in Lille, leads us to redefine diagnostic criteria and assessment methods, and to discuss genetic or environmental factors contributing to the phenotypes.