Search Results (18)

Recessive variants of SLC26A4 are a common cause of hereditary hearing impairment and are responsible for non-syndromic enlarged vestibular aqueducts and Pendred syndrome. Patients with bi-allelic SLC26A4 variants often suffer from fluctuating hearing loss and recurrent vertigo, ultimately leading to severe to profound hearing impairment. However, there are currently no satisfactory prevention or treatment options for this condition. The CRISPR/Cas9 genome-editing technique is a well-known tool for correcting point mutations or manipulating genes and shows potential therapeutic applications for hereditary disorders. In this study, we used the homology-independent targeted integration (HITI) strategy to correct the SLC26A4 c.919-2A>G variant, the most common SLC26A4 variant in the Han Chinese population. Next-generation sequencing was performed to evaluate the editing efficiency of the HITI strategy. The results showed that only 0.15% of the reads successfully exhibited HITI integration, indicating that the c.919-2 region may not be a suitable region for HITI selection. This suggests that other site selection or insertion strategies may be needed to improve the efficiency of correcting the SLC26A4 c.919-2A>G variant. This experience may serve as a valuable reference for other researchers considering CRISPR target design in this region. Full article

Background: Wideband tympanometry (WBT) has the potential to distinguish various mechanical middle ear and inner ear pathologies noninvasively. This study investigated the diagnostic value of WBT in the diagnosis of enlarged vestibular aqueduct (EVA). Methods: The absorbance and resonance frequency (RF) of patients with EVA (40 ears, 25 patients) and matched population controls (39 ears, 28 subjects) were compared, alongside receiver operating characteristic (ROC) analysis. Correlations between VA width and RF were also examined. Results: Patients with EVA had higher absorbance at low frequencies (226–917 Hz) and lower absorbance at high frequencies (2520–4896 Hz) compared to controls. The RF of the EVA group was significantly lower versus controls (751 [391–1165] vs. 933 [628–1346] Hz). The ROC analysis revealed area under the curve values of 0.771 and 0.801, respectively, for absorbance and RF. RF had a sensitivity, specificity, positive predictive value, and negative predictive value of 74.4%, 82.5%, 76.7%, and 80.6%, respectively, for diagnosing EVA. In the EVA group, the VA midpoint width (r = −0.334) and VA petrous width (r = −0.402) both significantly correlated with RF. Conclusions: Our findings support the utility of WBT for diagnosing EVA, with RF as the optimal index used. Full article

Conductive hearing loss caused by external or middle ear problems prevents the transmission of sound waves from the external auditory canal to the cochlea, and it is a common condition, especially in pediatric patients aged 1–5 years. The most common etiological factors are otitis media and cerumen during childhood. In some patients, external and middle ear functions and structures may be normal bilaterally despite the air-bone gap on the audiogram. This condition, which is often a missed diagnosis in children, is defined as a pseudo-conductive hearing loss (PCHL) caused by third window syndromes (TWSs) such as semicircular canal dehiscence, inner ear malformations with third window effect, and perilymphatic fistula. In this review of the literature, the authors emphasize the pitfalls of pediatric audio-vestibular evaluation on TWSs as well as the key aspects of this evaluation for the differential diagnosis of PCHL brought on by TWSs. This literature review will provide audiologists and otologists with early diagnostic guidance for TWSs in pediatric patients. Full article

Background: Enlarged vestibular aqueduct (EVA) syndrome can mimic otosclerosis in adults, presenting with an air–bone gap (ABG) and even absent stapedial reflexes. The ABG in inner-ear disorders is currently the object of several authors’ studies and seems to be related to a third mobile window (TMW) phenomenon. This can lead to misdiagnosis and inappropriate treatment. Given that it would be inappropriate and harmful to perform CT scans in all patients with a clinical diagnosis of otosclerosis, this study aims to highlight some clinical features useful for the differential diagnosis between otosclerosis and these rare cases of EVA presenting with an ABG, thus enabling the identification of suspected cases to be tested with CT scans. Methods: Between April and May 2024, a narrative review was conducted focusing on the differential diagnosis between some rare cases of EVA and otosclerosis. Clinical, audiological, and radiologic features of both conditions were investigated. Results: This review demonstrates the diagnostic challenge in differentiating atypical cases of EVA from otosclerosis in a subset of patients. Clinical and audiological features are important for differential diagnosis, but may not always be sufficient. Therefore, high-resolution computed tomography (HRCT) of the temporal bone plays a pivotal role in definitive diagnosis. Conclusions: In some specific cases, pre-operative imaging assessment using HRCT emerges as an essential tool for differentiating these two conditions and avoiding unnecessary stapes surgery. Full article

Objective: This study aimed to evaluate the effectiveness of endolymphatic duct blockage (EDB) on dizziness control in patients with a large vestibular aqueduct (LVA) and to evaluate its effect on hearing. Study design: This is a prospective nonrandomized study. Setting: Five adults and one child with dizziness and five children with progressive hearing loss were referred to our tertiary centers. Methods: The dizziness handicap inventory (DHI) and DHI-PC (dizziness handicap inventory—patient caregiver) questionnaires were used before and after surgery. All patients underwent a preoperative temporal bone HRCT scan and pure tone audiometry one day before surgery, then four and twelve months after surgery and at the last follow-up. The mean follow-up time was 5.6 years. Student’s t-test was used to compare DHI/-PC results. Results: The DHI scores were 44, 24, 84, 59 and 56 before surgery, respectively, for Patients 1 to 5. The DHI scores at four months was significantly different, i.e., 4, 6, 0, 7 and 18 (p = 0.001). No differences were found between 4 and 12 months. Patient 6 (child) had Trisomy 21; their DHI-PC score dropped from 38 (preoperative score) to 8 (postoperative score), showing no activity limitations; clinical evaluation showed the complete resolution of symptoms. We found no significant differences between hearing loss before the surgery and at 1 and 12 months post operation for four adult patients. Our fifth adult patient’s hearing changed from severe to profound SNHL. For 5 out of 6 pediatric patients, preoperative PTA and mean ABG were 63 dB and 20 dB, respectively; postoperatively, they improved to 42 dB and 16 dB, respectively. The hearing loss level for the sixth pediatric patient dropped from moderate (PTA = 42 dB) to severe (PTA = 85 dB) due to an opening of the endolymphatic sac and a sudden leak of the endolymph. Conclusions: EDB, using two titanium clips, seems to be helpful for controlling vestibular symptoms and for stabilizing hearing or even to improve hearing in 82% of cases. Nevertheless, there is a risk of hearing worsening. Full article

We present the case of a patient treated as affected by conductive hearing loss due to recurrent otitis, then as a juvenile otosclerosis, who was finally diagnosed as affected by bilateral ossicular chain fixation and enlarged vestibular aqueduct by means of cone-beam CT. Full article

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. Full article

This study aimed to validate the role of 3D segmentation in measuring the volume of the vestibular aqueduct (VAD), and the inner ear, and to study the correlation between VAD volume and VAD linear measurements at the midpoint and operculum. The correlation with other cochlear metrics was also studied. We retrospectively recruited 21 children (42 ears) diagnosed with Mondini dysplasia (MD) plus enlarged vestibular aqueduct (EVA) from 2009 to 2021 and who underwent cochlear implantation (CI). Patients’ sociodemographic data were collected, and linear cochlear metrics were measured using Otoplan. Vestibular aqueduct width and vestibular aqueduct and inner ear volumes were measured by two independent neuro-otologists using 3D segmentation software (version 4.11.20210226) and high-resolution CT. We also conducted a regression analysis to determine the association between these variables and CT VAD and inner ear volumes. Among the 33 cochlear implanted ears, 13 ears had a gusher (39.4%). Regarding CT inner ear volume, we found that gender, age, A-value, and VAD at the operculum were statistically significant (p-Value = 0.003, <0.001, 0.031, and 0.027, respectively) by regression analysis. Moreover, we found that Age, H value, VAD at the midpoint, and VAD at the operculum were significant predictors of CT VAD volume (p-Value < 0.04). Finally, gender (OR: 0.092; 95%CI: 0.009–0.982; p-Value = 0.048) and VAD at the midpoint (OR: 0.106; 95%CI: 0.015–0.735; p-Value = 0.023) were significant predictors of gusher risk. Patients’ gusher risk was significantly differentiated by gender and VAD width at the midpoint. Full article

Pathogenic variants in the SLC26A4, FOXI1, and KCNJ10 genes are associated with hearing loss (HL) and specific inner ear abnormalities (DFNB4). In the present study, phenotype analyses, including clinical data collection, computed tomography (CT), and audiometric examination, were performed on deaf individuals from the Sakha Republic of Russia (Eastern Siberia). In cases with cochleovestibular malformations, molecular genetic analysis of the coding regions of the SLC26A4, FOXI1, and KCNJ10 genes associated with DFNB4 was completed. In six of the 165 patients (3.6%), CT scans revealed an incomplete partition of the cochlea (IP-1 and IP-2), in isolation or combined with an enlarged vestibular aqueduct (EVA) anomaly. Sequencing of the SLC26A4, FOXI1, and KCNJ10 genes was performed in these six patients. In the SLC26A4 gene, we identified four variants, namely c.85G>C p.(Glu29Gln), c.757A>G p.(Ile253Val), c.2027T>A p.(Leu676Gln), and c.2089+1G>A (IVS18+1G>A), which are known as pathogenic, as well as c.441G>A p.(Met147Ile), reported previously as a variant with uncertain significance. Using the AlphaFold algorithm, we found in silico evidence of the pathogenicity of this variant. We did not find any causative variants in the FOXI1 and KCNJ10 genes, nor did we find any evidence of digenic inheritance associated with double heterozygosity for these genes with monoallelic SLC26A4 variants. The contribution of biallelic SLC26A4 variants in patients with IP-1, IP-2, IP-2+EVA, and isolated EVA was 66.7% (DFNB4 in three patients, Pendred syndrome in one patient). Seventy-five percent of SLC26A4-biallelic patients had severe or profound HL. The morphology of the inner ear anomalies demonstrated that, among SLC26A4-biallelic patients, all types of incomplete partition of the cochlea are possible, from IP-1 and IP-2, to a normal cochlea. However, the dominant type of anomaly was IP-2+EVA (50.0%). This finding is very important for cochlear implantation, since the IP-2 anomaly does not have an increased risk of “gushers” and recurrent meningitis. Full article

SLC26A4 is one of the most common genes causing autosomal recessive non-syndromic sensorineural hearing loss (SNHL). It has been reported to cause Pendred Syndrome (PDS) and DFNB4 which is deafness with enlarged vestibular aqueduct (EVA). However, mutated SLC26A4 is not conclusive for having either DFNB4 or PDS. Three unrelated Jordanian families consisting of eight affected individuals with congenital bilateral hearing loss (HL) participated in this study. Whole-exome and Sanger sequencing were performed to investigate the underlying molecular etiology of HL. Further clinical investigations, including laboratory blood workup for the thyroid gland, CT scan for the temporal bone, and thyroid ultrasound were performed. Three disease-causing variants were identified in SLC26A4 in the three families, two of which were novel. Two families had a novel pathogenic homozygous splice-site accepter variant (c.165-1G>C), while the third family had compound heterozygous pathogenic variants (c.1446G>A; p.Trp482* and c.304G>A; p.Gly102Arg). Our approach helped in redirecting the diagnosis of several affected members of three different families from non-syndromic HL to syndromic HL. Two of the affected individuals had typical PDS, one had DFNB4, while the rest had atypical PDS. Our work emphasized the intra- and inter-familial variability of SLC26A4-related phenotypes. In addition, we highlighted the variable phenotypic impact of SLC26A4 on tailoring a personalized healthcare management. Full article

Is cochlear implant (CI) electrode selection for cochleae with an enlarged vestibular aqueduct (EVA) the same as that for patent cochleae with a normal inner ear structure? Preoperative high-resolution computed tomography (HRCT) images of 247 ears were assessed retrospectively. The A-value, B-value, and H-value were measured with OTOPLAN, and Bell curves were created to show the distribution. All ears with EVA were re-evaluated using a 3D slicer to confirm whether incomplete partition type II (IP II) existed. The Mann–Whitney U-test was applied to determine a statistically significant difference. After adjustment with the Bonferroni correction method, a p-value ≤ 0.006 was considered significant. In total, 157 ears with patent cochlea and 90 ears with EVA were assessed. Seventy (82%) of the EVA ears had an IP II malformation, and 14 (19%) of these were not detected by CT scan but were later seen through the 3D reconstruction. A significant difference was found for the A value and B value between the patent cochleae and EVA-only and between the patent cochleae and EVA with IP II. Most EVA cases had an IP II malformation. The basal turn of the cochlea may be smaller in EVA cases than in the patent cochleae. Electrode selection should be adjusted accordingly. Full article

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder in which genetics play a major role. Molecular diagnosis may lead to a more accurate prognosis, improved clinical management, and potential treatment of the condition. Both copy number variations (CNVs) and single nucleotide variations (SNVs) have been reported to contribute to the genetic etiology of ASD. The effectiveness and validity of clinical targeted panel sequencing (CTPS) designed to analyze both CNVs and SNVs can be evaluated in different ASD cohorts. CTPS was performed on 573 patients with the diagnosis of ASD. Medical records of positive CTPS cases were further reviewed and analyzed. Additional medical examinations were performed for a group of selective cases. Positive molecular findings were confirmed by orthogonal methods. The overall positive rate was 19.16% (109/569) in our cohort. About 13.89% (79/569) and 4.40% (25/569) of cases had SNVs only and CNVs only findings, respectively, while 0.9% (5/569) of cases had both SNV and CNV findings. For cases with SNVs findings, the SHANK3 gene has the greatest number of reportable variants, followed by gene MYT1L. Patients with MYT1L variants share common and specific clinical characteristics. We found a child with compound heterozygous SLC26A4 variants had an enlarged vestibular aqueduct syndrome and autistic phenotype. Our results showed that CTPS is an effective molecular diagnostic tool for ASD. Thorough clinical and genetic evaluation of ASD can lead to more accurate diagnosis and better management of the condition. Full article

Both Pendred syndrome (PS) and nonsyndromic hearing loss with an enlarged vestibular aqueduct (EVA) are autosomal recessive disorders caused by SLC26A4 pathogenic variants. The spectrum of SLC26A4 pathogenic variants varies with the ethnic background. Among the patients with EVA in Okinawa, 94% had some combination of NM_000441.2(SLC26A4):c.1707+5G>A and NM_000441.2(SLC26A4):c.2168A>G(p.His723Arg), the two SLC26A4 pathogenic variants that are the most common in this population. We identified these two pathogenic variants using a novel genotyping method that employed an allele-specific polymerase chain reaction (PCR) from a gDNA and single-stranded tag hybridization chromatographic printed-array strip (STH-PAS) in DNA samples obtained from 48 samples in Okinawa, including 34 patients with EVA and 14 carriers of c.1707+5G>A or c.2168A>G. In addition, whole blood and saliva samples were used for analysis in this genotyping method with direct PCR. The results of STH-PAS genotyping were consistent with those obtained using standard Sanger sequencing for all samples. The accuracy of the STH-PAS method is 100% under the optimized conditions. STH-PAS genotyping provided a diagnosis in 30 out of 34 patients (88%) in Okinawan patients with EVA in under 3 h. The turn-around time for STH-PAS genotyping used with direct PCR was 2 h as a result of the omission of the DNA extraction and purification steps. Using information about the ethnic distribution of pathogenic variants in the SLC26A4 gene, STH-PAS genotyping performs a rapid genetic diagnosis that is simple and has a considerably improved efficiency. Full article

Enlarged vestibular aqueduct is the most common inner ear malformation in pediatric patients with sensorineural hearing loss. Here, we report a new presentation of enlarged vestibular aqueduct in a Korean family. The family consists of two parents and five daughters, and the first and second daughters were diagnosed with bilateral enlarged vestibular aqueducts. The third daughter, who showed no signs of hearing deterioration, came to medical attention with incomplete Horner syndrome. Evaluations for localization of Horner syndrome on the patient and Sanger sequencing of SLC26A4 on the family members were performed. Although auditory brainstem response and pure tone audiometry of the third daughter were normal, temporal bone computed tomography demonstrated bilateral enlarged vestibular aqueducts. Sanger sequencing of SLC26A4 revealed compound heterozygous variants c.2168A>G and c.919-2A>G in the first, second, and third daughters. Diagnosis of enlarged vestibular aqueduct is often delayed because the degree of hearing loss can vary, and a considerable phenotypic variability can be shown even in family members with the same SLC26A4 variations. Fluctuations of CSF pressure into the cochlear duct and recurrent microruptures of the endolymphatic membrane could result in damage of sympathetic nerve supplying to the inner ear, which could explain the mechanism of Horner syndrome associated with enlarged vestibular aqueduct. Full article

Hearing loss is the most common sensorial deficit in humans and one of the most common birth defects. In developed countries, at least 60% of cases of hearing loss are of genetic origin and may arise from pathogenic sequence alterations in one of more than 300 genes known to be involved in the hearing function. Hearing loss of genetic origin is frequently associated with inner ear malformations; of these, the most commonly detected is the enlarged vestibular aqueduct (EVA). EVA may be associated to other cochleovestibular malformations, such as cochlear incomplete partitions, and can be found in syndromic as well as non-syndromic forms of hearing loss. Genes that have been linked to non-syndromic EVA are SLC26A4, GJB2, FOXI1, KCNJ10, and POU3F4. SLC26A4 and FOXI1 are also involved in determining syndromic forms of hearing loss with EVA, which are Pendred syndrome and distal renal tubular acidosis with deafness, respectively. In Caucasian cohorts, approximately 50% of cases of non-syndromic EVA are linked to SLC26A4 and a large fraction of patients remain undiagnosed, thus providing a strong imperative to further explore the etiology of this condition. Full article