Bilateral Enlarged Vestibular Aqueduct Research Articles

Evidence of vestibular dysfunction in children with enlarged vestibular aqueduct

ObjectiveTo investigate the occurrence and characteristics of balance and vestibular deficits in pediatric patients with enlarged vestibular aqueduct (EVA). Materials and methodsRetrospective review of 53 children with EVA who underwent a comprehensive vestibular evaluation in our pediatric balance and vestibular program. Laboratory testing included videonystagmography (VNG), rotary chair, video head impulse testing (vHIT), vestibular evoked myogenic potential (VEMP), subjective visual vertical (SVV) and Sensory Organization Test (SOT) in posturography. ResultsThe mean age of these children, 31 girls and 22 boys, was 7.1 years (SD = 4.8). Among these 53 children, 16 had unilateral EVA (7 on the left side and 9 on the right side) and 37 had bilateral EVA, in which genetic testing confirmed 5 cases of Pendred syndrome. Abnormal testing results were found in 58% (11/19) on SOT, 67% (32/48) on rotary chair, 55% (48/88 of ears) on VEMP, 30% (8/27) on vHIT, 39% (7/18) on SVV, and 8% (4/53) on VNG. ConclusionsVestibular dysfunction may be a common finding in children with EVA. Clinicians who provide medical care for children with EVA need to be familiar with signs of potential balance and vestibular impairments. Although performing vestibular evaluation on young children with EVA can be difficult, objective testing is important in order to identify any potential vestibular deficit in these pediatric patients so that proper vestibular rehabilitation and balance retraining can be provided.

Analysis of genotypes on 850 newborns with SLC26A4 single-allele mutation and the phenotypes of those with second variant

Objective: To clarify the phenotypes of the newborns with SLC26A4 single-allele mutation in deafness genetic screening and second variant; to analyze the SLC26A4 genotype and hearing phenotype. Methods: 850 newborns born in Beijing from April 2015 to December 2019 were included and there were 468 males and 382 females. They received genetic deafness screening for 9 or 15 variants, with the result of SLC26A4 single-allele mutation. Firstly, three step deafness gene sequencing was adopted in this work, i.e., the first step was "SLC26A4 gene whole exons and splice sites" sequencing; the second step was "SLC26A4 gene promoter, FOXI1 gene and KCNJ10 gene whole exons" sequencing; and the third step was detection for "SLC26A4 gene copy number variation". Secondly, we collected the results of newborn hearing screening for all patients with the second mutation found in the three step test, and conducted audiological examinations, such as acoustic immittance, auditory brainstem response and auditory steady state response. Thirdly, for novel/VUS mutations, we searched the international deafness gene database or software, such as DVD, ClinVar and Mutation Taster, to predict the pathogenicity of mutations according to the ACMG guideline. Lastly, we analyzed the relationship between genotype and phenotype of newborns with SLC26A4 single allele mutation. Results: Among 850 cases, the median age of diagnosis was 4 months. In the first step, 850 cases were sequenced. A total of 32 cases (3.76%, 32/850) of a second variants were detected, including 18 cases (2.12%, 18/850) with identified pathogenic variants; 832 cases were sequenced and 8 cases of KCNJ10 gene missense variants were detected among the second step. No missense mutations in the FOXI1 gene and abnormal SLC26A4 gene promoter were detected; the third step sequencing results were all negative. Genotypes and hearing phenotypes included 18 cases combined with the second clear pathogenic variant, 16 cases (16/18) referred newborn hearing screening and 2 cases (2/18) passed in both ears; degree of hearing loss consisted of 18 profound ears (18/36), 13 severe ears (13/36) and 5 moderate ears (5/36); audiogram patterns comprised 17 high frequency drop ears (17/36), 14 flat ears (14/36), 3 undistinguished ears (3/36), and 2 U shaped ears (2/36); 11 cases underwent imaging examination, all of which were bilateral enlarged vestibular aqueduct. As for 22 cases of other genotypes, all passed neonatal hearing screening and the hearing diagnosis was normal, including 9 cases with VUS or possibly novel benign variants, 8 cases with KCNJ10 double gene heterozygous variants, and 5 cases with double heterozygous variants. Conclusions: The probability of individuals with SLC26A4 single-allele variant who merge with a second pathogenic variant is 2.12%, all of which are SNV, which can provide scientific basis for the genetic diagnosis and genetic counseling of SLC26A4 variants. Those who have merged with second pathogenic variant are all diagnosed with sensorineural hearing loss. Patients with KCNJ10 gene mutations do not manifest hearing loss during the infancy, suggesting the need for further follow-up.

The Genetic Background of Hearing Loss in Patients with EVA and Cochlear Malformation.

The most frequently observed congenital inner ear malformation is enlarged vestibular aqueduct (EVA). It is often accompanied with incomplete partition type 2 (IP2) of the cochlea and a dilated vestibule, which together constitute Mondini malformation. Pathogenic SLC26A4 variants are considered the major cause of inner ear malformation but the genetics still needs clarification. The aim of this study was to identify the cause of EVA in patients with hearing loss (HL). Genomic DNA was isolated from HL patients with radiologically confirmed bilateral EVA (n = 23) and analyzed by next generation sequencing using a custom HL gene panel encompassing 237 HL-related genes or a clinical exome. The presence and segregation of selected variants and the CEVA haplotype (in the 5' region of SLC26A4) was verified by Sanger sequencing. Minigene assay was used to evaluate the impact of novel synonymous variant on splicing. Genetic testing identified the cause of EVA in 17/23 individuals (74%). Two pathogenic variants in the SLC26A4 gene were identified as the cause of EVA in 8 of them (35%), and a CEVA haplotype was regarded as the cause of EVA in 6 of 7 patients (86%) who carried only one SLC26A4 genetic variant. In two individuals with a phenotype matching branchio-oto-renal (BOR) spectrum disorder, cochlear hypoplasia resulted from EYA1 pathogenic variants. In one patient, a novel variant in CHD7 was detected. Our study shows that SLC26A4, together with the CEVA haplotype, accounts for more than half of EVA cases. Syndromic forms of HL should also be considered in patients with EVA. We conclude that to better understand inner ear development and the pathogenesis of its malformations, there is a need to look for pathogenic variants in noncoding regions of known HL genes or to link them with novel candidate HL genes.

Hearing loss patterns in enlarged vestibular aqueduct syndrome: Do fluctuations have clinical significance?

ObjectivesTo reveal hearing loss patterns in patients with enlarged vestibular aqueduct (EVA) syndrome according to demographic and clinical characteristics. MethodsA retrospective, longitudinal study design was utilized to identify patients with EVA. Ears of patients were categorized into one of four cohorts: progressive fluctuating, progressive non-fluctuating, stable fluctuating, and stable non-fluctuating patterns. Pairwise and group comparisons were performed with non-parametric tests to assess vestibular aqueduct (VA) morphology, clinical, and demographic variables between hearing loss pattern cohorts. Rates of hearing loss in the subgroups were determined utilizing a mixed linear effects model. Results44 patients (25 female, 19 male, median diagnosis age: 8.06 years) met inclusion criteria. 16 individuals demonstrated unilateral EVA and 29 had bilateral EVA, resulting in 74 total ears with EVA. Amongst the four cohorts, differences in operculum widths amongst groups were statistically significant (p = 0.049) while VA midpoint widths were not (p = 0.522). Progressive hearing loss ears without fluctuations demonstrated a 3.20 dB per year (p < 0.001) progression while progressive hearing loss ears with fluctuations reported a rate of 3.52 dB loss per year (p < 0.001). ConclusionHearing fluctuations occur similarly in EVA patients with stable and progressive hearing loss. With the exception of increased rates of hearing loss progression for fluctuating progressive hearing loss patients, vestibular aqueduct morphology, demographic, and clinical characteristics commonly reported are likely not strong predictors for whether patients will or will not experience fluctuating patterns of hearing loss.

The impact of cochlear implantation on speech and language outcomes in children with asymmetric sensorineural hearing loss

IntroductionCochlear implantation (CI) is considered in children with asymmetric sensorineural hearing loss (ASHL), or severe to profound sensorineural hearing loss in one ear, and better hearing contralaterally. The benefits of a CI in these children are not well established. This study investigated the impact of unilateral CI on speech and language outcomes in pediatric patients with ASHL. MethodsThe retrospective chart review identified pediatric patients who underwent cochlear implantation for ASHL at a tertiary single center institution between 2014 and 2017. Children who underwent cochlear implantation in the poorer ear and maintained a hearing aid in the better ear were included, while children with cognitive impairment or prior cochlear nerve deficiency and auditory neuropathy were excluded. Speech and language measures were evaluated prior to implantation and at regular six-month intervals postoperatively. Ear specific Audiometry was evaluated at every visit and varied developmentally appropriate speech recognition tasks, including questionnaires, closed-set, and open-set measures, accounted for advancing childhood milestones. Specific measures of speech articulation, expressive and receptive language, and vocabulary were assessed including: Goldman Fristoe Test of Articulation (GFTA-3), Clinical Evaluation of Language Fundamentals (CELF-P2 or CELF-5), Receptive One-Word Picture Vocabulary Test (ROWPVT) and Expressive One Word Picture Vocabulary Test (EOWPVT). The mean difference and standard deviation of speech and language outcomes at preoperative and postoperative evaluations were calculated. The change in outcomes were further assessed over each post-operative time point. ResultsTwenty-six children with asymmetric sensorineural hearing loss were included in the analysis, with 11 (42%) having bilateral enlarged vestibular aqueducts (EVA). At time of CI, unaided mean Pure Tone Average (PTA-4) for the better ear was 62Db HL, and worse ear was 92Db HL. There was an improvement in speech recognition in the implanted ear as expected. All preoperative speech and language evaluations were conducted within 7 months of cochlear implantation. Twenty-three patients had at least 1 postoperative re-evaluation. Fourteen children had preoperative and postoperative assessments with the same tool, with 13 patients (93%) showing improvement in at least 1 domain. For patients with repeated assessment within 12 months of surgery, we observed an average improvement in standard scores of: GFTA-3 (+11.2), CELF-P2 Core Language (+10.3), CELF-5 Core Language (+7.0), ROWPVT (+2.8) and EOWPVT (+4.5). Individual results are described. ConclusionImprovement in speech and language measures can be demonstrated in children undergoing unilateral cochlear implantation for asymmetric sensorineural hearing losses. These children, who are not typical CI candidates, can benefit from a CI in the poorer ear.

Clinical and genetic analysis of children with hearing loss and bilateral enlarged vestibular aqueducts

ObjectivesTo evaluate the clinical and genetic features of children with hearing loss associated with one of the most common malformations of the inner ear: bilateral enlargement of vestibular aqueducts (EVA). MethodsClinical and genetic features were investigated in 28 children with hearing loss diagnosed with bilateral EVA by computed tomography from January 2008 to September 2019. ResultsFourteen subjects had undergone newborn hearing screening (NHS). Nine subjects (64.3%) were referred in both ears, 4 subjects (28.6%) were referred in one ear, and one subject (7.1%) passed in both ears. Nineteen of 26 subjects (73.1%) who were followed for more than 3 years had hearing fluctuations, while 17 (65.4%) had hearing loss progression. Eleven of 28 subjects (39.2%) had vertigo attacks. Pathogenic variants were identified in two alleles of the SLC26A4 gene in 24 of 27 subjects (88.9%) by sequencing of all exons and flanking introns, leading to genetic diagnosis of Pendred syndrome/DFNB4. Our results indicate that genetic screening for specific SLC26A4 variants using a commercial clinical laboratory test in Japan would have achieved genetic diagnoses in 13 of the 27 subjects (54.2%). Although there was no statistically significance in the frequency of hearing fluctuation or progression depending on the presence or absence of the gene variant, mean hearing level was severe in subjects with two pathogenic variants in SLC26A4 gene. The most common variant detected in our subjects was p.His723Arg (13 alleles, 27.1%), followed by c. 919-2A > G (four alleles, 8.3%). Two novel variants were detected in this study: c.1544+1G > T and c.1614+5G > A. ConclusionsOur data suggest that some subjects may present with bilateral EVA that cannot be detected by NHS. We estimated that genetic diagnosis for SLC264 gene would not have been made in almost half subjects with the commercial genetic screening approach used in the present study in Japan. Although there were some limitations in this study, the subjects with pathogenic variants in two alleles of the SLC26A4 gene could have more severe hearing loss.

Exploring the missing heritability in subjects with hearing loss, enlarged vestibular aqueducts, and a single or no pathogenic SLC26A4 variant

Pathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype–phenotype correlation, a significant part of cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4. To explore the missing heritability, we first determined the presence of the previously described EVA-associated haplotype (Caucasian EVA (CEVA)), characterized by 12 single nucleotide variants located upstream of SLC26A4. We found this haplotype and a delimited V1-CEVA haplotype to be significantly enriched in our M1 patient cohort (10/16 cases). The CEVA haplotype was also present in two M0 cases (2/12). Short- and long-read whole genome sequencing and optical genome mapping could not prioritize any of the variants present within the CEVA haplotype as the likely pathogenic defect. Short-read whole-genome sequencing of the six M1 cases without this haplotype and the two M0/CEVA cases only revealed previously overlooked or misinterpreted splice-altering SLC26A4 variants in two cases, who are now genetically explained. No deep-intronic or structural variants were identified in any of the M1 subjects. With this study, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases. For pinpointing the pathogenic effect of the CEVA haplotype, additional analyses are required addressing defect(s) at the RNA, protein, or epigenetic level.

Cochlear implantation in patients with Pendred syndrome

ObjectiveTo examine the outcomes of cochlear implantation in children with Pendred Syndrome. Material and methodsA retrospective case series of nine pediatric patients with Pendred syndrome undergoing cochlear implantation at a tertiary academic medical center from 2003 to 2017. ResultsAll patients were diagnosed with bilateral mild-to-profound to severe-to-profound sensorineural hearing loss and used hearing aids prior to implantation. Preoperative imaging results revealed that all patients exhibited bilateral enlarged vestibular aqueducts and 8 of 9 had cochlear dysplasia equivalent to Incomplete Partition II. Despite inner ear malformations, all electrodes were successfully implanted with minimal complications and favorable post-operative audiological outcomes. ConclusionsCochlear implantation is an effective and successful treatment for severe-to-profound hearing loss in children with Pendred syndrome and for whom traditional amplification aids provide limited benefit. With early intervention, cochlear implantation allows speech and cognitive development in Pendred children comparable to that of normal hearing individuals, allowing patients to learn in a mainstream educational setting.

Pediatric sudden sensorineural hearing loss: Experience in a pediatric ENT emergency care center

ObjectivesSudden sensorineural hearing loss (SSNHL) is relatively rare and its physiopathology remains unclear, particularly in children. Our goal was to evaluate clinical characteristics, etiologies, management, treatment outcomes and prognostic factors in the pediatric population. MethodsWe performed a retrospective chart review of all children registered for SSNHL between August 2004 and September 2017 in a tertiary care pediatric hospital. We analysed data regarding clinical symptoms, audiological characteristics, diagnostic investigations and treatment outcomes. ResultsThirty-five patients were included. Mean age was 12 years (range 4–18 years). Male:female ratio was 15:20. Hearing loss was left-sided for 18 patients, right-sided for 12 patients and bilateral for 5 patients. Degree of hearing loss varied from mild to profound across frequencies in the 40 ears studied. Thirty-four patients had associated otologic symptoms: the most frequent was tinnitus (28 ears), followed by vertigo (23 ears), otalgia (5 ears) and sensation of blocked ear (5 ears). Twenty-nine patients received systemic steroids and 3 intra-tympanic steroids. In the treated group, 69% had improvement on the audiograms (14% total, 55% partial). Vestibular tests were performed in 16 patients and were abnormal in 10 patients. Radiological examination included computed tomography scan (n = 16) and/or magnetic resonance imaging (n = 33). They revealed 2 bilateral enlarged vestibular aqueducts, 1 labyrinthitis, 1 intra-cochlear haemorrhage. ConclusionSSNHL can affect speech and language development in children. There are differences among the pediatric population, including inner ear malformation and immune disease. Specific work up is proposed. Appropriate diagnosis and therapeutic management are discussed.

Novel Ocular and Inner Ear Anomalies in a Patient with Myhre Syndrome

Myhre syndrome is a rare autosomal dominant multisystemic disorder. Typical features of this disorder include distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, brachydactyly, and skeletal anomalies. Gain-of-function mutations in the SMAD4 gene are responsible for this syndrome. Herein, we present a 9.6-year-old Turkish girl with molecularly confirmed Myhre syndrome who had novel findings including bilateral Axenfield Rieger anomaly with secondary glaucoma and bilateral enlarged vestibular aqueducts.

ATP6V1B1 recurrent mutations in Algerian deaf patients associated with renal tubular acidosis

Hereditary distal renal tubular acidosis (dRTA) is a rare disorder characterized by metabolic acidosis due to impaired renal acid excretion. To date, three genes (ATP6V1B1, ATP6V0A4 and SLC4A1) have been reported to be responsible for this genetic disorder. Notably, mutations of ATP6V1B1 gene, which encode B1-subunit of H + -ATPase pump cause distal renal tubular acidosis often, associated with sensorineural hearing loss (SNHL). Furthermore, enlarged vestibular aqueduct (EVA) was also described in some patients with ATP6V1B1 mutations. Four Algerian unrelated patients presented with dRTA and SNHL were recruited. The ATP6V1B1 gene was preferentially analyzed in all these patients by Sanger sequencing.We identified two previously reported variants in ATP6V1B1 gene: a frameshift mutation (c.1155dupC: p.(Ile386Hisfs*56) in exon 12 and a splicing mutation in intron 2 (c.175-1G > C: p?). Both mutations were homozygous in affected members. Interestingly, one patient with p.(Ile386Hisfs*56) mutation presented profound SNHL and bilateral enlarged vestibular aqueduct (EVA).Our study indicates the importance contribution of ATP6V1B1 gene mutations to the pathogenesis of the dRTA in the Algerian population and will contribute to introducing principles to predict the characteristics of the dRTA in patients. Thus, screening for this gene could allow rapid patient management and provide adequate genetic counseling.

Hearing loss in unilateral and bilateral enlarged vestibular aqueduct syndrome

ObjectiveTo investigate any meaningful differences in hearing between patients with unilateral and bilateral enlarged vestibular aqueduct (EVA). EVA is a common radiological finding in children presenting with hearing loss. We hope to provide insight into the pathogenesis of EVA and provide further guidelines for unilateral EVA management. We hypothesized that hearing loss in unilateral EVA would be similar to that seen in bilateral EVA. MethodsA longitudinal retrospective study design was used. Three measures of hearing, pure tone average (PTA) word recognition score (WRS) and speech awareness threshold (SAT) and radiologic morphologies were tested for difference across unilateral versus bilateral ear EVA status. Linear mixed effects models were used to identify differences while accounting for time and multiple measurements per ear. ResultsUsing Cincinnati criteria, 89 ears fit inclusion criteria, 75 of which were from patients with bilateral EVA compared to 14 ears from patients with unilateral EVA. No significant differences across bilateral status were observed in audiological measurements. Models showed that speech recognition threshold (SRT) (p = 0.925), word recognition score (WRS)(p = 0.521) and pure tone average (PTA) of air and bone conduction from 250 to 4000 Hz (p = 0.281–0.933) were not statistically different with respect to bilateral status. Wilcoxon rank-sum tests showed no statistical difference in vestibular aqueduct width or operculum size (VA)(p = 0.234, p = 0.623). Each year after the first audiogram was associated with significantly greater SRT (p = 0.003) decreased WRS (0.014) and increased PTA (0.003.). Greater midpoint width was associated with significantly lower SRT (p = 0.004) WRS (<0.001) and PTA (<0.001.) ConclusionOur results indicate no statistically significant difference in hearing ability with respect to bilateral EVA status, suggesting that unilateral EVA patients require close follow-up. Our results also demonstrate the progressive nature of EVA and a relationship between VA midpoint width and hearing loss severity.

The SLC26A4 c.706C>G (p.Leu236Val) Variant is a Frequent Cause of Hearing Impairment in Filipino Cochlear Implantees.

Variants in SLC26A4 are an important cause of congenital hearing impairment in the Philippines. Cochlear implantation is a standard rehabilitation option for congenital hearing impairment worldwide, but places a huge cost burden in lower-income countries. The study of risk factors such as genetic variants that may help determine genetic etiology of hearing loss and also predict cochlear implant outcomes is therefore beneficial. DNA samples from 29 GJB2-negative Filipino cochlear implantees were Sanger-sequenced for the coding exons of SLC26A4. Exome sequencing was performed to confirm results. Four cochlear implantees with bilaterally enlarged vestibular aqueducts (EVA) were homozygous for the pathogenic SLC26A4 c.706C>G (p.Leu236Val) variant, which has a minor allele frequency of 0.0015 in Filipino controls. In patients with the SLC26A4 variant there was no association between cochlear implant outcome and age at implantation or duration of implant. There was also no association between the occurrence of the SLC26A4 variant and postsurgical audiometric thresholds and parents' evaluation of aural/oral performance of children (PEACH) scores. On the other hand, the SLC26A4 variant increased presurgical median audiometric thresholds (p = 0.01), particularly at 500 to 2000 Hz. The SLC26A4 c.706C>G (p.Leu236Val) variant is a frequent cause of congenital hearing impairment in Filipinos and is associated with bilateral EVA and increased presurgical audiometric thresholds, but does not adversely affect post-implant outcomes.

Hearing Preservation During Cochlear Implantation and Electroacoustic Stimulation in Patients With SLC26A4 Mutations

Patients with SCL26A4 mutations presenting with Mondini deformity and enlarged vestibular aqueduct (EVA) tend to have comparable residual hearing. Although cochlear implantation (CI) produces good results in this group, deterioration of residual hearing can be an adverse event after surgery due to accompanying cochlear malformation and perilymph leakage during cochleostomy. The purpose of this study was to investigate if CI in patients with SCL26A4 mutations via the round window (RW) approach could achieve preservation of residual hearing, and to evaluate their speech reception with electroacoustic stimulation (EAS). This is a retrospective chart review of eight patients with bilateral EVA, who were bi-allelic patients with SCL26A4 mutations. CI was performed in all patients by a single surgeon using the RW approach. Audiological results were compared before and after implantation. Additional hearing loss after CI was less than 10 dBHL in five out of eight patients. Average hearing deterioration after CI was 8.75 dB (range, 0-26). Six out of eight patients used EAS mode after CI. The acoustic stimulation frequency ranged from 271 to 438 Hz. Patients showed better speech recognition in quiet and in noise using EAS mode compared with electrical stimulation alone. Preservation of residual hearing could be achieved after CI in patients with the SLC26A4 mutation via the RW approach. For successful preservation of residual hearing, application of newly-developed soft electrode and meticulous surgical is necessary. Our study showed that patients with the SLC26A4 mutation can be good candidates for EAS surgery.

Novel compound heterozygous mutations in SLC26A4 gene in a Chinese Han family with enlarged vestibular aqueduct

ObjectiveTo identify the disease-related SLC26A4 mutants in a Chinese Han pedigree associated with Enlarged vestibular aqueduct (EVA). MethodsEVA diagnosis was based on the family history, clinical examinations, systematically audiometric evaluations, high-resolution computed tomography (HRCT) of the temporal bone, and magnetic resonance imaging (MRI) of inner ear. Sanger sequencing and mutation analysis of the SLC26A4 gene were performed in all members of this family to identify the disease-related SLC26A4 mutants. Mutations in the SLC26A4 gene were compared with 200 ethnically matched control persons to exclude common polymorphism. ResultsAll members in this family were negative for systemic and thyroid diseases. There were three subjects (I-2, II-2 and II-3) with bilateral sensorineural deafness since childhood. Temporal bone HRCT scans and inner ear MRI showed bilateral enlarged vestibular aqueduct with Mondini malformation in II-2 and II-3. A novel SLC26A4 splice-site mutation c.1001 + 5G > C was identified in compound heterozygosity with the mutation c.919-2A > G in the proband and in II-2. This novel compound heterozygote of two splice site mutations was not found in 200 normal hearing Chinese Han controls. ConclusionsA novel splice site mutation of c.1001 + 5G > C was identified, and the novel compound heterozygote of two splice site mutations, c.1001 + 5G > C and c.919-2A > G, in the SLC26A4 gene has been linked to hearing impairment in EVA patients.

Vestibular Dysfunction in Patients with Enlarged Vestibular Aqueduct.

Enlarged vestibular aqueduct (EVA) is the most common inner ear malformation. While a strong correlative relationship between EVA and hearing loss is well established, its association with vestibular dysfunction is less well understood. In this study, we examine the effects of EVA on the vestibular system in patients with EVA. Prospective, cross-sectional study of a cohort ascertained between 1999 and 2013. National Institutes of Health Clinical Center, a federal biomedical research facility. In total, 106 patients with unilateral or bilateral EVA, defined as a midpoint diameter greater than 1.5 mm, were referred or self-referred to participate in a study of the clinical and molecular aspects of EVA. Clinical history was ascertained with respect to the presence or absence of various vestibular signs and symptoms and history of head trauma. Videonystagmography (VNG), cervical vestibular evoked myogenic potential (cVEMP), and rotational vestibular testing (RVT) were performed to assess the vestibular function. Of the patients with EVA, 45% had vestibular signs and symptoms, and 44% of tested patients had abnormal VNG test results. An increased number of vestibular signs and symptoms was correlated with the presence of bilateral EVA (P = .008) and a history of head injury (P < .001). Abnormal VNG results also correlated with a history of head injury (P = .018). Vestibular dysfunction is common in patients with EVA. However, not all patients with vestibular signs and symptoms have abnormal vestibular test results. Clinicians should be aware of the high prevalence of vestibular dysfunction in patients with EVA.

Government-funded universal newborn hearing screening and genetic analyses of deafness predisposing genes in Taiwan

ObjectiveTo investigate the association of eight connexin genes (GJB2, GJB4, GJA1P1, GJB6, GJB3, GJA1, GJB1, and GJC3) and the SLC26A4 gene with congenital hearing impairment among infants in a universal newborn hearing screening program. MethodFrom September 2009 to October 2013, the consecutive neonates born in all six branches of Taipei City Hospital were enrolled. Infants who failed the newborn hearing screening and were diagnosed with hearing impairment underwent the genetic analyses. Result15,404 neonates were born at Taipei City Hospital, and 15,345 neonates underwent newborn hearing screening. Among them, 32 infants were diagnosed with unilateral or bilateral hearing impairment. 26 of them underwent analyses of the connexin genes and the SLC26A4 gene. Of the connexin genes, two infants carried a GJB3 mutation (heterozygous c.580G>A and heterozygous c.520G>A, respectively). Only one infant carried a GJB2 mutation (homozygous c.235delC). One infant carried a GJA1P1 mutation (heterozygous c.929delC) and another carried a GJB4 mutation (heterozygous c.302G>A). Additionally, one infant carried a GJA1P1 novel variant (heterozygous c.1081C>T). Another infant carried a GJA1 novel variant (heterozygous c.1-33C>G). Of the SLC26A4 gene, one infant carried heterozygous c.919-2A>G mutation and a novel variant (heterozygous c.164+1G>C), and high-resolution computed tomography (HRCT) of the temporal bone revealed bilateral enlarged vestibular aqueducts. One infant carried heterozygous c.919-2A>G mutation and no inner ear anomalies were demonstrated by HRCT of the temporal bone. Another infant carried a novel variant (heterozygous c.818C>T). ConclusionThese results provide a genetic profile of the connexin genes and SLC26A4 gene among infants with hearing impairment detected by a universal newborn hearing screening program in Taiwan. Further studies and long-term follow up of this cohort are warranted to determine the pathogenicity of each variants and the long-term hearing consequence.

Vestibular Dysfunction in Patients with Enlarged Vestibular Aqueduct

Objectives: Enlarged vestibular aqueduct (EVA) is the most common inner ear malformation. While a strong correlative relationship between EVA and hearing loss exists, its association with vestibular dysfunction is less well established. In this study, we characterize the vestibular phenotype in patients with EVA. Methods: This was a prospective, cross-sectional study of 106 patients with unilateral (n = 26) or bilateral (n = 80) EVA, defined as a midpoint diameter greater than 1.5 mm, who were referred or self-referred to participate in a study of the clinical and molecular analysis of EVA at the National Institutes of Health. We obtained a clinical history focused on vestibular dysfunction, and specifically asked about age of independent walking, history of vertigo, head tilt with vomiting, and clumsiness. Based on tolerance and availability, participants underwent videonystagmography (VNG), cervical vestibular evoked myogenic potentials (cVEMP), and rotary vestibular chair testing (RVT) to objectively assess their vestibular function. Results: Forty-five percent of patients with EVA reported vestibular symptoms. A total of 44% (28 out of 66) of those completing VNG testing had abnormal results, as defined by abnormalities in caloric, ocular motor, and positional testing. An increased number of vestibular symptoms is correlated with the presence of bilateral (rather than unilateral) EVA ( P = .008) and a history of head injury ( P &lt; .001). Abnormal VNG results also correlated with a history of head injury ( P = .01). Conclusions: Vestibular dysfunction is common in patients with EVA. To our knowledge, this is one of the largest prospective EVA studies which specifically address the vestibular manifestations.

A case of bilateral enlarged vestibular aqueducts and unilateral hearing loss at birth

Screening of newborn hearing is nowadays widespread, and as many as 3.4% of all screened infants are found to have unilateral hearing loss. However, we, as clinicians and parents, usually dismiss the severity of unilateral hearing loss in pediatric patients. Recently, we experienced the case of unilateral hearing loss since birth in a 2-year-old girl who was finally found to have bilateral enlarged vestibular aqueducts when the disorder progressed to bilateral hearing loss. Proper evaluation of the cause of hearing loss, including imaging studies of the inner ear, and consecutive hearing evaluations should be mandatory in children with unilateral sensorineural hearing loss, due to the possibility of progression of hearing loss bilaterally.

Mutation spectrum and genotype–phenotype correlation of hearing loss patients caused by SLC26A4 mutations in the Japanese: a large cohort study

Mutations in SLC26A4 cause a broad phenotypic spectrum, from typical Pendred syndrome to nonsyndromic hearing loss associated with enlarged vestibular aqueduct. Identification of these mutations is important for accurate diagnosis, proper medical management and appropriate genetic counseling and requires updated information regarding spectrum, clinical characteristics and genotype–phenotype correlations, based on a large cohort. In 100 patients with bilateral enlarged vestibular aqueduct among 1511 Japanese hearing loss probands registered in our gene bank, goiter data were available for 79, of whom 15 had Pendred syndrome and 64 had nonsyndromic hearing loss. We clarified the mutation spectrum for the SLC26A4 mutations and also summarized hearing levels, progression, fluctuation and existence of genotype–phenotype correlation. SLC26A4 mutations were identified in 82 of the 100 patients (82.0%). Of the Pendred syndrome patients, 93% (14/15) were carriers, as were 77% (49/64) of the nonsyndromic hearing loss patients. Clinical characteristics of patients with SLC26A4 mutations were congenital, fluctuating and progressive hearing loss usually associated with vertigo and/or goiter. We found no genotype–phenotype correlations, indicating that, unlike in the case of GJB2 mutations, the phenotype cannot be predicted from the genotype. Our mutation analysis confirmed the importance of mutations in the SLC26A4 gene among hearing loss patients with enlarged vestibular aqueduct and revealed the mutation spectrum, essential information when performing genetic testing.