Enlarged Vestibular Aqueduct Research Articles

A novel missense mutation in the SLC26A4 gene causes nonsyndromic hearing loss and enlarged vestibular aqueduct

ObjectivesWe aimed to investigate the genetic causes of hearing loss in a Chinese proband with nonsyndromic hearing loss and enlarged vestibular aqueduct syndrome. MethodsWe conducted clinical and genetic evaluations in a deaf proband and his normal-hearing parents. Multiplex PCR technology combined with Ion Torrent™ next-generation sequencing technology was used to detect the pathogenic mutations. As a control, a group of 1500 previously studied healthy newborns from the same ethnic background were subjected to deafness gene screening using the same method as in our previous study. ResultsThe proband harbored two mutations in the SLC26A4 gene in the form of compound heterozygosity. He was found to be heterozygous for a novel mutation named c.1742 G > T (p.Arg581Met) in exon 13 and for the known mutation c.589 G > A (p.Gly197Arg). These variants were carried in the heterozygous state by the parents and therefore co-segregated with the genetic disease. The c.1742 G > T (p.Arg581Met) mutation was absent in 1500 healthy newborns. Protein alignment indicated high evolutionary conservation of the p.R581 residue, and this mutation was predicted by PolyPhen-2 and other online tools to be damaging. ConclusionThis study demonstrates that the novel mutation c.1742 G > T (p.Arg581Met) in compound heterozygosity with c.589 G > A in the SLC26A4 gene is the main cause of deafness in a family clinically diagnosed with enlarged vestibular aqueduct (EVA). Our study will provide a basic foundation for further investigations to elucidate the SLC26A4-related mechanisms of hearing loss.

Cochlear implantation in patients with enlarged vestibular aqueduct. A case series with literature review

Objectives: To report our institutional experience of the management of patients with enlarged vestibular aqueduct (EVA) and compare it to the literature.Methods: We carried out a retrospective review of patients’ records from 1993 to 2015. The age, sex, associated malformations, relevant past medical history, genetic screening results, possible surgical incident, implant model and duration of follow- up, outcome in terms of Categories of Auditory Performance (CAP scores), and integration or resuming mainstream school or work were recorded.Results: We had 11 patients (six boys and five girls) with EVA who underwent cochlear implant surgery in our center during the 22-year study period, out of a total of 827 implanted (1.3%). The mean age at surgery was 8.9 years ranging from 0.6 to 35 years. EVA was bilateral in 10 cases, isolated anatomical finding in seven cases, and associated with other malformations in four. Cochlear implantation was bilateral in five cases and unilateral in six. The mean follow- up duration was 48.3 months (range: 3–120). No postoperative complication was observed and all the patients could regain a serviceable hearing, attending normal school and working normally.Conclusion: EVA is frequently observed in the deaf population without an identifiable cause. The hearing loss is usually progressive and may result in cochlear implantation which has proved its efficiency in rehabilitating EVA patients.

Results of molecular genetic testing in Russian patients with Pendred syndrome and allelic disorders

Pendred syndrome is an autosomal recessive inherited disorder characterized by a combination of sensorineural hearing impairment and euthyroid goiter; its clinical manifestation in children is hardly distinguishable from nonsyndromic hearing loss. Pendred syndrome is one of the most frequent types of syndromic hearing loss. Hearing impairment is accompanied by abnormal development of the bony labyrinth—enlarged vestibular aqueduct (EVA) and occasionally combined with Mondini dysplasia. Mutations in the SLC26A4 gene, which encodes the pendrin protein, are responsible for both Pendred syndrome and for allelic disorder (nonsyndromic enlarged vestibular aqueduct). The present study for the first time conducted molecular genetic analysis in 20 Russian patients with Pendred syndrome, EVA and/or Mondini dysplasia. As a result, six pathogenic mutations in the SLC26A4 gene were revealed in four patients. The mutation c.222G>T (p.Trp74Cys) was detected for the first time. Mutations were found in patients with Pendred syndrome and nonsyndromic EVA with or without Mondini dysplasia. Mutations were not detected in patients with isolated Mondini dysplasia. One proband with clinical diagnosis Pendred syndrome was homozygous for the c.35delG mutation in the GJB2 gene. The absence of frequent mutations, including well-known ones or “hot” exons in the SLC26A4 gene, was reported. Therefore, the optimal method to search for mutations in the SLC26A4 gene in Russian patients is Sanger sequencing of all exons and exon-intron boundaries in the SLC26A4 gene.

ZASTOSOWANIE POMIARU ABSORBANCJI W OCENIE POSZERZONEGO WODOCIĄGU PRZEDSIONKA: OPIS PRZYPADKU

There is a limited number of diagnostic procedures to verify the presence of large vestibular aqueduct syndrome (LVAS) in humans. The wideband absorbance (WBA) measurement technique is a non-invasive and objective tool for assessing the amount of sound energy absorbed by the tympanic membrane over a wide frequency range. We suggest that WBA could be an aid for detecting LVAS in some hearing-impaired subjects. We report use of WBA on a patient who had bilateral sensorineural hearing loss associated with LVAS and cochlear abnormalities in both ears.

Long-term Observation of Three Cases of Large Vestibular Aqueduct Syndrome

Long-term Observation of Three Cases of Large Vestibular Aqueduct Syndrome

The audiological characteristics of large vestibular aqueduct syndrome in infants and young children

Objective:To investigate the audiological characteristics of large vestibular aqueduct syndrome(LVAS) in infants and young children, and to provide suggestion for the early diagnosis and early intervention.Method:One hundred and twenty-four cases diagnosed as LVAS were enrolled in our study. Acoustic immittance, pediatric audiometry and(or) auditory steady state responses and auditory brainstem response test were tested to analyze the degree and configuration of hearing loss, and air-bone threshold difference and short latency negative response in auditory brainstem response.Result:The configuration of the hearing loss, includes 44.8%(111/248) of high frequency loss, 19.0%(47/248) of flat, 13.7%(34/248) of rising, 3.6%(9/248) of U type, and 19.0%(47/248) of the configuration which cannot be distinguished. The distribution of the degree of the hearing loss in total 124 cases (248 ears) includes 73.4%(182/248) of profound hearing loss, 16.9%(42/248) of severe hearing loss, 6.9%(17/248) of moderate hearing loss, and 2.8%(7/248)of mild hearing loss. The acoustically evoked short latency negative response in ABR accounted for 27.4%(68/248). The emergence of ABR air-bone threshold difference accounted for 24.6%(61/248), and the mean difference was(19.3±14.2) dB nHL.Conclusion:Infants and young children with large vestibular aqueduct syndrome mostly has the characteristics of high frequency hearing loss curve, acoustically evoked short latency negative response in ABR and ABR bone-air threshold difference, that will remind clinicians of LVAS.

Management of surgical difficulties during cochlear implant with inner ear anomalies

ObjectiveTo review the difficulties that can occur during cochlear implant surgery in patients with inner ear abnormalities and the management thereof. MethodsA retrospective chart review of 316 patients who received cochlear implants was conducted. The data collected included the types of inner ear anomalies, intraoperative findings, and the clinical management strategies. A review of the literature was also performed. ResultsA total of 24 patients with inner ear malformations who underwent 28 total cochlear implant procedures were identified. The anomalies included isolated large vestibular aqueducts in 8 (33.3%) patients, isolated semicircular canal dysplasia in 8 (33.3%) patients, classical Mondini malformation in 7 (29.1%) patients, and cochlear hypoplasia in 1 (4.1%) patient. Four (14.2%) patients exhibited intraoperative cerebrospinal fluid (CSF) gushers. One patient experienced delayed facial nerve paralysis, and an electrode was partially inserted into one patient. In 2 (7.14%) cases, the surgeries were aborted because of difficulties. ConclusionCochlear implantation for inner ear anomalies can be performed safely. Special attention should be given to preoperative imaging to anticipate the potential intraoperative risks that can occur in inner ear anomaly cases. Every surgery should be planned with a safe approach and specific requirements, e.g., regarding electrode type, and the surgeries must be performed by experienced surgeons who are capable of modifying their technique according to the surgical findings.

Prevalence of inner ear anomalies among cochlear implant candidates.

Objectives:To determine the prevalence of inner ear anomalies and the frequency of different anomaly types among cochlear implant recipients.Methods:This study included a retrospective chart review of all patients who received cochlear implants between January 2009 and January 2013 in King Abdulaziz University Hospital cochlear implant program in Riyadh, Saudi Arabia. All subjects underwent thin-cut CT of the temporal bone and MRI. The collected data included age, gender, and CT and MRI findings regarding temporal bone anomalies. Patients with any identified congenital inner ear anomalies were included in the study.Results:In total, 316 patients’ cases were reviewed. Inner ear malformations were identified in 24 patients, which represented a prevalence of 7.5%. Among these 24 patients, 8 (33.3%) presented with a large vestibular aqueduct (LVA), 8 (33.3%) semicircular canal (SCC) dysplasia, 7 (29.1%) classical Mondini deformity, and one (4.1%) cochlear hypoplasia.Conclusion:The prevalence of inner ear anomalies among cochlear implant recipients was 7.5%. This result is consistent with findings worldwide. The most common anomalies were LVA and SCC hypoplasia; by contrast, in other regions, the most common anomaly is either the Mondini deformity, or LVA.

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.

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.

Identification of SLC26A4 mutations p.L582LfsX4, p.I188T and p.E704K in a Chinese family with large vestibular aqueduct syndrome (LVAS)

Large vestibular aqueduct syndrome (LVAS) is a type of hearing loss characterized by an autosomal recessive inheritance. LVAS has been shown to be associated with mutations in SLC26A4 gene. In the present study, we report the clinical, genetic and molecular characterization of a Chinese family with LVAS. By using the targeted sequence capture and next-generation sequencing, we identified heterozygous mutations of SLC26A4 p.I188T (c.563T > C), p.L582LfsX4 (c.1746 delG) and p.E704K (c.2110G > A) in the affected individual of this family, of which SLC26A4 p.E704K is a novel mutation associated with LVAS. By tracing the transmission and functional prediction of these mutations in the pedigree, the heterozygous mutations of p.I188T, p.L582LfsX4 and p.E704K in SLC26A4 gene were responsible for the LVAS of the affected individual. This is the first case of LVAS caused by these mutations.

A Novel Frameshift Mutation of SLC26A4 in a Korean Family With Nonsyndromic Hearing Loss and Enlarged Vestibular Aqueduct.

ObjectivesWe aimed to identify the causative mutation for siblings in a Korean family with nonsyndromic hearing loss (HL) and enlarged vestibular aqueduct (EVA). The siblings were a 19-year-old female with bilateral profound HL and an 11-year-old male with bilateral moderately severe HL.MethodsWe extracted genomic DNA from blood samples of the siblings with HL, their parents, and 100 controls. We performed mutation analysis for SLC26A4 using direct sequencing.ResultsThe two siblings were compound heterozygotes with the novel mutation p.I713LfsX8 and the previously described mutation p.H723R. Their parents had heterozygous mono-allelic mutations. Father had p.I713LfsX8 mutation as heterozygous, and mother had p.H723R mutation as heterozygous. However, novel mutation p.I713LfsX8 was not detected in 100 unrelated controls.ConclusionBoth mutations identified in this study were located in the sulfate transporter and anti-sigma factor antagonist domain, the core region for membrane targeting of SulP/SLC26 anion transporters, which strongly suggests that failure in membrane trafficking by SLC26A4 is a direct cause of HL in this family. Our study could therefore provide a foundation for further investigations elucidating the SLC26A4-related mechanisms of HL.

Minimally invasive surgical techniques of cochlear implantation withround window pathways in young children

Objective:To discuss the minimally invasive surgical techniques and the effect of cochlear implantation with round window pathways in young children(≤3 years).Method:One hundred and sixty patients with bilateral profound sensorineural hearin loss received MED-EL cochlear implantation,including 144 cases of normal middle and inner ear,4 cases of Mondini deformity,12 cases of large vestibular aqueduct syndrome.Result:Of 160 patients underwent CIs,148 patients were performed with round window pathways,the rate was 92.5%. Iit's difficult to exposure round window in 12 patients,performing from promontory.All electrodes of 158 cases with unilateral CI and 2 cases with bilateral CI were implanted successfully,in which the CI went normally and electrode array were protected well.All implant devices had worked normally and all patients had performed well during an average follow-up period of 8 month-3 years.Post-operatively complications of cerebrospinal fluid leakage,facial nerve injury haven't been found.Conclusion:Cochlear implantation could be performed in patients wit with round window pathways,and it is a safe and effective way in young children.

What is the role of preoperative imaging for cochlear implants in adults with postlingual deafness?

What is the role of preoperative imaging for cochlear implants in adults with postlingual deafness?

Cochlear implantation in Pendred syndrome and non-syndromic enlarged vestibular aqueduct – clinical challenges, surgical results, and complications

Objective: To explore specific clinical issues, surgical results, and complications of 80 cochlear implantations (CI) in 55 patients with Pendred syndrome (PS) or non-syndromic enlarged vestibular aqueduct (NSEVA).Background: Previous studies have focused either on unselected case series or on populations with mixed cochlear malformations. PS/NSEVA accounts for up to 10% of congenital SNHL, rendering this a large group of cochlear implant candidates. The abnormal inner ear anatomy of these patients may be associated with a lower surgical success rate and a higher rate of complications.Study design: Retrospective review of patients’ medical records and CT/MRI.Setting: Tertiary referral center.Materials and methods: The medical records and CT/MRI images of 55 PS/NSEVA patients receiving 80 cochlear implantations from 1982–2014 were reviewed. Demographic data, surgical results, intra-operative incidents, and post-operative complications were retrieved.Results: Complications occurred in 36% of implantations; 5% hereof major complications. Gushing/oozing from the cochleostoma occurred in 10% of implantations and was related to transient, but not prolonged post-operative vertigo.Conclusion: Intra-operative risks of gushing/oozing and post-operative vertigo are the primary clinical issues in PS/NSEVA patients regarding CI. Nonetheless, the surgical success rate is high and the major complication rate is low; similar to studies of unselected series of CI recipients.

CSF Gusher in Cochlear Implant Surgery–does it affect surgical outcomes?

ObjectivesThe purpose of this prospective study was to measure surgical outcomes in cases of cerebrospinal fluid gusher in cochlear implant surgery. Materials and methodsDemographic, radiological, neurophysiological and surgical results were evaluated in nine cases of patients with cerebrospinal fluid gusher during cochlear implant surgery, out of 164 unilateral cochlear implant procedures. Review of literature and our management technique is discussed. ResultsNine cases had cerebrospinal fluid leak during surgery. Out of three cases of incomplete partition type II, two had cerebrospinal fluid gusher while one had milder ooze. Two cases with large vestibular aqueduct syndrome had intraoperative cerebrospinal fluid gusher. Four cases of gusher had no predictable risk factors on clinical history, examination or preoperative radiology. All cases were managed with meticulous packing of round window site without any other additional measures such as lumbar drain or use of tissue glue. These cases showed no symptoms or signs of cerebrospinal fluid leak in the follow-up period. ConclusionWe recommend careful meticulous packing of the round window around the electrode using periosteum until cerebrospinal fluid leak is controlled in all cases of cerebrospinal fluid gushers. We also recommend a very conservative approach to managing these patients in the immediate postoperative period.

Genotypes and phenotypes of a family with a deaf child carrying combined heterozygous mutations in SLC26A4 and GJB3 genes.

Mutations in the SLC26A4 gene have been shown to cause a type of deafness referred to as large vestibular aqueduct syndrome (LVAS), whereas mutations in the GJB3 gene have been associated with nonsyndromic deafness. However, the clinical phenotypes of these mutations vary and remain to be fully elucidated. The present study performed genetic analysis of a Chinese family, in which the child was deaf and the parents were healthy. Sanger sequencing demonstrated that the affected individual harbored three heterogeneous mutations in the SLC26A4 and GJB3 genes, as follows: SLC26A4 IVS-2 A>G, SLC26A4 c.2168 A>G and GJB3 c.538 C>T. The affected individual exhibited hearing loss and was diagnosed with LVAS by computed tomography scan. The mother and father of the affected individual harbored the heterogeneous mutations of SLC26A4 IVS-2 A>G and GJB3 c.538 C>T, and the heterozygous mutation of SLC26A4 c.2168 A>G, respectively. Neither parents exhibited any hearing loss. The results obtained from the deaf patient provided genetic and clinical evidence that carrying combined heterogeneous mutations in the GJB3 and SLC26A4 genes may be involved in the etiology of severe hearing loss, of which the mechanism requires further examination.

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.

Prevention and management of hearing loss in syndromic craniosynostosis: A case series

ObjectiveTo assess the audiological profile in a cohort of children affected by syndromic craniosynostosis. MethodsEleven children with Apert syndrome (n=4), Saethre-Chotzen syndrome (n=3), Muenke syndrome (n=2), Crouzon syndrome (n=1) and Pfeiffer syndrome type 1 (n=1) were submitted to a complete audiologic evaluation including otoscopy, pure-tone audiometry, tympanometry and acoustic reflex testing, ABR, otoacustic emissions, temporal bone High Resolution CT (HRCT) scan. The main outcome measures were prevalence, type and severity of hearing loss, prevalence of chronic otitis media, correlation with the time of first surgical correction. ResultsSeven of 11 patients (64%) presented hearing loss (HL), conductive in 3/7 patients (43%) and mixed in 4/7 (57%). No patients showed a purely sensorineural HL. All hearing impaired patients displayed middle ear disorders: the patients with conductive HL had otitis media with effusion (OME) and 3/4 patients with mixed HL showed tympanic alterations or cholesteatoma. A bilateral vestibular aqueduct enlargement was detected by HRCT scan in one normal hearing patient. The ABRs resulted normal in all cases. ConclusionOur study confirms the high prevalence of otologic diseases in such patients. In contrast with previous studies, middle ear disorders were responsible for the hearing impairment also in patients with mixed HL due to secondary inner ear damage. These findings restate the necessity of a close audiologic follow-up. We did not detect the specific ABR abnormalities previously reported, possibly because of an early correction of the cranial vault malformations.

Identification of a novel mutation in SLC26A4 gene in a Chinese family with enlarged vestibular aqueduct syndrome

ObjectiveTo investigate the genetic causes of hearing loss in a two generation Chinese family with enlarged vestibular aqueduct syndrome (EVAS). MethodsClinical and genetic evaluations were conducted in a deaf proband and her normal-hearing parents. Sanger sequencing analysis of all the 21 exons, the exon–intron boundaries and the promoter in SLC26A4 gene was performed to detect the pathogenic mutations. PCR-restricted fragment length polymorphism (PCR-RFLP) was used to further identify the mutation. Phylogenetic analysis was carried out with multiple sequence alignment using BioEdit software. Three-dimensional (3D) modeling of the human wild-type and mutant SLC26A4 (NP_000432.1) was carried out using I-TASSER (http://zhanglab.ccmb.med.umich.edu/). ResultsClinical examinations showed that the proband suffered from typical features of sensorineural hearing loss with enlarged vestibular aqueduct. A novel nonsense mutation c.2118C>A (p.C706X) in exon 19 was identified in compound heterozygosity with the splice-site mutation c.919-2A>G in the proband by using Sanger sequencing. The mother was a heterozygous carrier of c.919-2A>G in intron 7, while the father was a heterozygous carrier of c.2118C>A. The mutation c.2118C>A was not found in 200 unrelated controls using Sanger sequencing. PCR-RFLP showed the PCR product of the proband was not digested at 2110 by Fau I because of the c.2118C>A mutation. 3D-structure modeling indicated that the mutation c.2118C>A resulted in a truncate Pendrin protein. Protein alignment indicated high conservation of p.C706 residue in healthy Homo, Nomascus, Pan, Macaca, Canis, Sus, Mus, Rattus, Cricetulus and Xenopus. ConclusionsThis study revealed a novel heterozygous mutation c.2118C>A (p.C706X) compound with c.919-2A>G in SLC26A4 gene in a patient with EVAS.