Comparison of vestibular aqueduct visualization on computed tomography and magnetic resonance imaging in patients with Ménière's disease.

BACKGROUND: The vestibular aqueduct (VA) serves an essential role in homeostasis of the inner ear and pathogenesis of Ménière's disease (MD). The bony VA can be clearly depicted by high-resolution computed tomography (HRCT), whereas the optimal sequences and parameters for magnetic resonance imaging (MRI) are not yet established. We investigated VA characteristics and potential factors influencing MRI-VA visibility in unilateral MD patients. METHODS: One hundred patients with unilateral MD underwent MRI with three-dimensional sampling perfection with application optimized contrasts using different flip angle evolutions (3D-SPACE) sequence and HRCT evaluation. The imaging variables included MRI-VA and CT-VA visibility, CT-VA morphology and CT-peri-VA pneumatization. RESULTS: The most frequent type of MRI-VA and CT-VA visualization was invisible VA and continuous VA, respectively. The MRI-VA visibility was significantly lower than CT-VA visibility. MRI-VA visibility had a weak positive correlation with ipsilateral CT-VA visualization. For the affected side, the MRI-VA visualization was negatively correlated with the incidence of obliterated-shaped CT-VA and positively with that of tubular-shaped CT-VA. MRI-VA visualization was not affected by CT-peri-VA pneumatization. CONCLUSION: In patients with MD, the VA visualization on 3D-SPACE MRI is poorer than that observed on CT and may be affected by its osseous configuration. These findings may provide a basis for further characterization of VA demonstrated by MRI and its clinical significance.

[Wideband acoustic immittance characteristics and machine learning-based diagnostic model for children with large vestibular aqueduct syndrome].

Objective:This study was to investigate the wideband acoustic immittance（WAI） characteristics of children with large vestibular aqueduct syndrome（LVAS） and to construct a diagnostic model for LVAS based on WAI and machine learning（ML） techniques. Methods:We performed a retrospective analysis of the data from 38 children（76 ears） with LVAS and 44 children（88 ears） with normal hearing. The data included conventional audiological examination, temporal bone CT scan and WAI test. We performed statistical analysis and developed multivariate diagnostic models based on different ML techniques. Results:The two groups were balanced in terms of ear, gender, and age（P>0.05）. The wideband absorbance（WBA） of the LVAS group was significantly lower than that of the control group at 1 000-2 519 Hz, while the WBA of the LVAS group was significantly higher than that of the control group at 4 000-6 349 Hz（P<0.05）. WBA at 5 039 Hz under ambient pressure had a certain diagnostic value（AUC=0.767）. The multivariate diagnostic model had a high diagnostic value（AUC>0.8）, among which the KNN model performed the best（AUC=0.961）. Conclusion:The WAI characteristics of children with LVAS are significantly different from those of normal children. The diagnostic model based on WAI and ML techniques has high accuracy and reliability, and provides new ideas and methods for intelligent diagnosis of LVAS.

A New Methodology for Evaluation of Large Vestibular Aqueduct in CT and MRI Images.

HYPOTHESIS: Development of a new method for large vestibular aqueduct (LVA)/large endolymphatic sac anomaly (LESA) assessment using magnetic resonance imaging (MRI) and computed tomography (CT)/cone beam CT (CBCT) images. The secondary objective was to compare both modalities. BACKGROUND: The gold standard for LVA diagnosis is the analysis of CT images using Valvassori and Clemis or Cincinnati criteria. The previous studies showed inconclusive results regarding the correlation between audiological and radiological data. METHODS: Retrospective analysis of radiological images from 173 patients (315 ears), who were diagnosed with LVA/LESA based on CT/CBCT and/or MRI images of the temporal bone. The images obtained using both techniques were used to measure the following dimensions of vestibular aqueduct (VA)/endolymphatic duct (ED)/intraosseous endolymphatic sac (ES): width of the opening, length, and width at external aperture. In MRI images, the maximal contact diameters of the extraosseous or intraosseous ES and dura mater were measured as well. RESULTS: LVA has been reported to be bilateral in 82% (142 patients) and unilateral in 18% (31 patients) of cases. Comparison of MRI and CT/CBCT measurements showed a moderate correlation (0.64) in external aperture, a moderate correlation (0.57) in the width of the VA opening, and a weak correlation (0.34) in length measurements (p < 0.05). CONCLUSION: We developed a new method to identify the heterogeneous pathology of LVA/LESA using reconstruction along the VA/ED/intraosseous ES axis, three measurements on two planes, and focus on the maximal contact diameter between the extraosseous or intraosseous ES and dura mater.

A novel intronic variant causing aberrant splicing identified in two deaf Chinese siblings with enlarged vestibular aqueducts.

OBJECTIVE: We aimed to evaluate the genotype-phenotype relationship in two Chinese family members with enlarged vestibular aqueduct (EVA). METHODS: We collected blood samples and clinical data from each pedigree family member. Genomic DNA was isolated from peripheral leukocytes using standard methods. Targeted next-generation sequencing and Sanger sequencing were performed to find the pathogenic mutation in this family. Minigene assays were used to verify whether the novel intronic mutation SLC26A4c.765+4A>G influenced mRNA splicing. RESULTS: Hearing loss in the patients with EVA was diagnosed using auditory tests and imaging examinations. Two pathogenic mutations, c.765+4A>G and c.919-2A>G were detected in SLC26A4. In vitro minigene analysis confirmed that c.765+4A>G variant could cause aberrant splicing, resulting in skipping over exon 6. CONCLUSIONS: The SLC26A4c.765+4A>G mutation is the causative variant in the Chinese family with EVA. Particular attention should be paid to intronic variants.

Does CISS MRI Reliably Depict the Endolymphatic Duct in Children with and without Vestibular Aqueduct Enlargement?

BACKGROUND AND PURPOSE: High-resolution CT is the mainstay for diagnosing an enlarged vestibular aqueduct (EVA), but MR imaging may be an appealing alternative, given its lack of ionizing radiation exposure. The purpose of this study was to determine how reliably MR imaging demonstrates the endolymphatic duct and endolymphatic duct enlargement in hearing-impaired children. MATERIALS AND METHODS: We performed a retrospective review of temporal bone high-resolution CT and MR imaging of hearing-impaired children evaluated between 2017 and 2020. Vestibular aqueduct diameter was measured on high-resolution CT. The vestibular aqueducts were categorized as being enlarged (EVA+) or nonenlarged (EVA-) using the Cincinnati criteria. The endolymphatic ducts were assessed on axial high-resolution CISS MR imaging. We categorized endolymphatic duct visibility into the following: type 1 (not visible), type 2 (faintly visible), and type 3 (easily visible). Mixed-effect logistic regression was used to identify associations between endolymphatic duct visibility and EVA. Interreader agreement for the endolymphatic duct among 3 independent readers was assessed using the Fleiss κ statistic. RESULTS: In 196 ears from 98 children, endolymphatic duct visibility on MR imaging was type 1 in 74.0%, type 2 in 14.8%, and type 3 in 11.2%; 20.4% of ears were EVA+ on high-resolution CT. There was a significant association between EVA+ status and endolymphatic duct visibility (P < .01). Endolymphatic duct visibility was type 1 in 87.1%, type 2 in 12.8%, and type 3 in 0% of EVA- ears and type 1 in 22.5%, type 2 in 22.5%, and type 3 in 55.0% of EVA+ ears. The predicted probability of a type 3 endolymphatic duct being EVA+ was 0.997. There was almost perfect agreement among the 3 readers for distinguishing type 3 from type 1 or 2 endolymphatic ducts. CONCLUSIONS: CISS MR imaging substantially underdiagnoses EVA; however, when a type 3 endolymphatic duct is evident, there is a >99% likelihood of an EVA.

Study of the factors related to air-bone gap in enlarged vestibular aqueduct.

BACKGROUND: Over half of patients with enlarged vestibular aqueducts (EVA) will have an air-bonr gap (ABG), however, current research on audiology has focused on the influencing factors of air-conducted. OBJECTIVE: To retrospectively analyse the influencing factors and clinical manifestations of the bone-conduction threshold and ABG in patients with EVA. MATERIALS AND METHODS: We included 286 patients with EVA; among them, 126 had full SLC26A4 gene sequence results. We performed a descriptive analysis of the bone-conduction threshold and explored the effect of age. Finally, we analyzed the relationship of ABG and SLC26A4 genes with the degree of vestibular aqueduct (VA) enlargement. RESULTS: Among 555 ears, 312 (57.8%) ears had ABG; approximately 94% of the patients' bone-conduction hearing is almost completely lost at frequencies of 2 and 4 kHz. There was no linear correlation between age and bone-conduction threshold (p > 0.05). ABG did not significantly differ according to the degree of VA enlargement and number of SLC26A4 allele mutations (p > 0.05). CONCLUSIONS AND SIGNIFICANCE: Among patients with EVA, ABG is mainly produced at low frequencies and is not significantly correlated with age, size of the VA opening or SLC26A4 genes, which could be attributed to the biomechanical effects.

The correlation between deafness progression and SLC26A4 mutations in enlarged vestibular aqueduct patients.

BACKGROUND: The relationship between the hearing phenotype and the SLC26A4 mutation in enlarged vestibular aqueduct cases has not been fully elucidated. OBJECTIVES: To detect SLC26A4 mutation in a group of cases with enlarged vestibular aqueduct who received cochlear implantation and to analyze the correlation between the SLC26A4 genotype and the progression of deafness. MATERIALS AND METHODS: Twenty-nine enlarged vestibular aqueduct patients were selected. Using the Sanger sequence to analyze SLC26A4 gene mutations. The 29 cases were divided into group A (carrying the c.919-2A > G mutation) and group B (not carrying the c.919-2A > G mutation). The difference in the duration of deafness was analyzed between the two groups. RESULTS: The detection rate of the c.1174A > T mutation in the postlingual deafness group was 37.5%, higher than that in the prelingual deafness group (0%). The difference in the duration of deafness between groups A and B was not statistically significant by the Mann-Whitney U test (p > 0.05). CONCLUSIONS: The correlation between the SLC26A4 genotype and the duration of deafness in cases with enlarged vestibular aqueduct is not yet clear. However, the c.1174A > T mutation may be linked to delayed hearing loss and the progression of deafness may be relatively slow in some cases of c.919-2A > G mutation.

Third window lesions of the inner ear: A pictorial review.

PURPOSE: Radiographic review of pathologies that associate with third window syndrome. METHODS: Case series and literature review. RESULTS: Eight unique third window conditions are described and illustrated, including superior, lateral, and posterior semicircular canal dehiscence; carotid-cochlear, facial-cochlear, and internal auditory canal-cochlear dehiscence, labyrinthine erosion from endolymphatic sac tumor, and enlarged vestibular aqueduct. CONCLUSION: The present study highlights the characteristic imaging features and symptoms to differentiate third window pathologies for expedient diagnosis and management planning.

Enlarged Vestibular Aqueduct and Associated Inner Ear Malformations: Hearing Loss Prognostic Factors and Data Modeling from an International Cohort.

ACKGROUND: There is a need to operationalize existing clinical data to support precision medicine in progressive hearing loss (HL). By utilizing enlarged vestibular aqueduct (EVA) and its associated inner ear abnormalities as an exemplar, we model data from a large international cohort, confirm prognostic factors for HL, and explore the potential to generate a prediction model to optimize current management paradigms. METHODS: An international retrospective cohort study. Regression analyses were utilized to model frequency-specific HL and identify prognostic factors for baseline average HL severity and progression. Elastic-net regression and machine learning (ML) techniques were utilized to predict future average HL progression based upon routinely measurable clinical, genetic, and radiological data. RESULTS: Higher frequencies of hearing were lost more severely. Prognostic factors for HL were the presence of incomplete partition type 2 (coefficient 12.95 dB, P=.011, 95% CI 3.0-22 dB) and presence of sac signal heterogeneity (P=.009, 95% CI 0.062-0.429) on magnetic resonance imaging. Elastic-net regression outperformed the ML algorithms (R2 0.32, mean absolute error 11.05 dB) with coefficients for baseline average hearing level and the presence of sac heterogeneity contributing the most to prediction outcomes. CONCLUSION: Incomplete partition type 2 and endolymphatic sac signal heterogeneity phenotypes should be monitored closely for hearing deterioration and need for early audiological rehabilitation/cochlear implant. Preliminary prediction models have been generated using routinely collected health data in EVA. This study showcases how international collaborative research can use exemplar techniques to improve precision medicine in relatively rare disease entities.

[Analysis of 59 cases of large vestibular aqueduct syndrome SLC26A4gene mutation frequency and new mutation sites].

Objective:To study the frequency of SLC26A4 gene mutation sites in children with enlarged vestibular aqueduct deafness in Yunnan, report the new mutation sites of SLC26A4 gene, further clarify the mutation spectrum of SLC26A4gene, and explore the association between biallelic and monoallelic mutations of SLC26A4 gene and CT phenotype of inner ear, so as to provide basis for clinical and genetic diagnosis of deafness. Methods:Review the results of temporal bone CT examination of 390 children after cochlear implantation in the Department of Otolaryngology, Kunming Children's Hospital from August 2016 to September 2021. Sanger sequencing of SLC26A4 gene was performed in 59 children with enlarged vestibular aqueduct. According to the genetic test results, the children who underwent temporal bone CT examination were divided into two groups: SLC26A4 biallelic mutation group（homozygous mutation and compound heterozygous mutation）, monoallelic mutation group, and the association with inner ear CT phenotype was analyzed, and the new sites were summarized and analyzed. Results:The c.919-2a>g mutation was the most common mutation in children with enlarged vestibular aqueduct with SLC26A4 gene mutation. Three new variants of SLC26A4 gene were found; CT examination combined with genetic testing found that a part of children with enlarged vestibular aqueduct was associated with SLC26A4 monoallelic mutation or no SLC26A4 gene mutation was detected. Further research is needed to investigate the involvement of other pathogenic factors in the pathogenesis of EVA.

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.

Transient connection between the vestibular aqueduct and utricle: A study using sagittal sections of human embryonic heads.

BACKGROUND: The aqeductus vestibuli (aqueduct) is believed to connect to the saccule in embryos and adults. However, in embryos, the saccule and utricle are known to communicate widely to provide a common endolymph space "atrium". METHODS: Using sagittal histological sections from five embryos (crown-rump length or CRL, 14-21 mm), nine early fetuses (CRL 24-35 mm) and 12 midterm and near-term fetuses (CRL 82-272 mm), we revisited the development and growth of the human ear aqueduct. RESULTS: The atrium took on a thick tube-like appearance as an antero-inferior continuation of the aqueduct, but soon divided into multiple gulfs. Most of the gulfs corresponded to the ampullae of semicircular ducts, while one gulf at the antero-medio-inferior corner corresponded to the future saccule. Notably, in eight of the 14 embryos and early fetuses, the aqueduct ended at the utricle near the primitive ampulla of the anterior (superior) or posterior semicircular duct. Conversely, an embryo of CRL 21 mm was the smallest specimen in which the aqueduct joined the gulf-like saccule. At midterm and near-term, the growing perilymph space separated the aqueduct from the utricle and appeared to push the aqueduct toward the saccule. A topographical change occurred between the embryonic superiorly located utricle and the inferiorly-located saccule to create the antero-posterior arrangement in adults. CONCLUSIONS: Consequently, the vestibular end of the aqueduct was most likely to migrate anteriorly from the utricle to the saccule at 6-8 weeks possibly due to differential growth of the endothelium. Previous reconstructions of the embryonic aqueduct might be biased by the adult morphology.

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.

Programming Levels and Speech Perception in Pediatric Cochlear Implant Recipients With Enlarged Vestibular Aqueduct or GJB2 Mutation.

OBJECTIVE: To determine the relationship between hearing loss etiology, cochlear implant (CI) programming levels, and speech perception performance in a large clinical cohort of pediatric CI recipients. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care hospitals. PATIENTS: A total of 136 pediatric CI recipients (218 ears) were included in this study. All patients had diagnoses of either enlarged vestibular aqueduct (EVA) or GJB2 (Connexin-26) mutation confirmed via radiographic data and/or genetic reports. All patients received audiologic care at either Boston Children's Hospital or Massachusetts Eye and Ear in Boston, MA, between the years 1999 and 2020. MAIN OUTCOME MEASURES: Electrode impedances and programming levels for each active electrode and speech perception scores were evaluated as a function of etiology (EVA or GJB2 mutation). RESULTS: Children with EVA had significantly higher impedances and programming levels (thresholds and upper stimulation levels) than the children with GJB2 mutation. Speech perception scores did not differ as a function of etiology in this sample; rather, they were positively correlated with duration of CI experience (time since implantation). CONCLUSIONS: Differences in electrode impedances and CI programming levels suggest that the electrode-neuron interface varies systematically as a function of hearing loss etiology in pediatric CI recipients with EVA and those with GJB2 mutation. Time with the CI was a better predictor of speech perception scores than etiology, suggesting that children can adapt to CI stimulation with experience.

Evidence of vestibular dysfunction in children with enlarged vestibular aqueduct.

OBJECTIVE: To investigate the occurrence and characteristics of balance and vestibular deficits in pediatric patients with enlarged vestibular aqueduct (EVA). MATERIALS AND METHODS: Retrospective 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. RESULTS: The 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. CONCLUSIONS: Vestibular 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 the vestibular aqueduct development on the risk for suffering from idiopathic sudden sensorineural hearing loss.

OBJECTIVE: Large vestibular aqueduct syndrome (LVAS) is one of the etiology of hearing loss. Clinically, we observed that the VA size of patients with idiopathic sudden sensorineural hearing loss (ISSNHL) did not meet the diagnostic criteria of VA enlargement, but there were individual variations. Through this study, we want to understand the VA development and explore its risk for suffering from ISSNHL. METHODS: 74 patients with ISSNHL were retrospectively reviewed in our department from June 2018 to September 2021. Meanwhile, 57 people with no ear diseases were randomly selected as the control group. All their clinical information were systematically collected. The axial thin-slice CT images of temporal bone were used to observe and measure the VA in ISSNHL and controls. ISSNHL were classified as different types and grades according to pure tone audiometry and the degree of hearing loss, respectively. Logistic regression analysis was adopted to evaluate the risk factors of different types and grades of ISSNHL. RESULTS: The operculum morphology could be funnel-shaped, tubular and invisible, but they had no statistical difference in the morbidity of ISSNHL. The operculum width of the affected sides in the case group was significantly wider than that of the matched sides in the control group (0.84±0.35mm vs 0.68±0.34mm, p=0.009), but the midpoint width had no statistical difference (p=0.447). The operculum width was an independent risk factor for the total hearing loss type (p=0.036, OR=4.49, 95% CI=1.10-18.29), moderate (p=0.013, OR=17.62, 95% CI=1.82-170.95) and profound (p=0.031, OR=4.50, 95% CI=1.14-17.67) grade of ISSNHL. Hypertension was an independent risk factor for the severe grade (p=0.004, OR=12.44, 95% CI=2.19-70.64) of ISSNHL. Both the operculum width (p=0.048, OR=7.14, 95% CI=1.02-50.26) and hypertension (p=0.014, OR=6.73, 95% CI=1.46-30.97) were the risk factors for the flat type of ISSNHL. The midpoint width of the VA, gender, age, diabetes mellitus, hyperlipidemia, and plasma fibrinogen concentration had no significant effect on the risk for suffering from ISSNHL. CONCLUSION: The development of the VA operculum is a risk factor for some types and grades of ISSNHL. Hypertension remained a risk factor for ISSNHL.

Newborn Hearing Screening Results in Patients with Enlarged Vestibular Aqueduct.

OBJECTIVES: Enlarged vestibular aqueduct (EVA) is the most common anatomic abnormality contributing to permanent hearing loss (HL) in children. Although the association between EVA and HL is well-documented, the pass rate for the newborn hearing screening (NBHS) for patients with EVA-related HL is not. Our objective was to investigate the association between NBHS results and audiologic and clinical outcomes in a large cohort of pediatric patients with EVA. METHODS: This was a retrospective chart review of patients seen in the Boston Children's Hospital (BCH) Department of Otolaryngology and Communication Enhancement with confirmed HL, known NBHS results, and confirmed EVA. Demographic, clinical, audiologic, and imaging data were collected from the medical record. Frequency-specific data points from pure-tone audiograms and/or automated auditory brainstem response tests were recorded, and four-frequency pure tone average was calculated using air conduction thresholds at 500, 1000, 2000, and 4000 Hz. RESULTS: Of the 183 patients included in the study, 84 (45.9%) passed their NBHS, whereas 99 (54.1%) did not pass. Compared with patients who did not pass, patients who passed were more likely to have unilateral EVA and unilateral HL, whereas they were less likely to undergo cochlear implantation and to have causative SLC26A4 variants. CONCLUSIONS: EVA-associated HL may be identified at birth or during childhood, with nearly half the patients in this cohort passing their NBHS. Our results provide prognostic information for patients with EVA who pass their NBHS and highlight the importance of regular hearing monitoring for children not initially suspected of having HL. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2786-2791, 2023.

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.

[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.

Method to estimate the basal turn length in inner ear malformation types.

The mathematical equations to estimate cochlear duct length (CDL) using cochlear parameters such as basal turn diameter (A-value) and width (B-value) are currently applied for cochleae with two and a half turns of normal development. Most of the inner ear malformation (IEM) types have either less than two and a half cochlear turns or have a cystic apex, making the current available CDL equations unsuitable for cochleae with abnormal anatomies. Therefore, this study aimed to estimate the basal turn length (BTL) from the cochlear parameters of different anatomical types, including normal anatomy; enlarged vestibular aqueduct; incomplete partition types I, II, and III; and cochlear hypoplasia. The lateral wall was manually tracked for 360° of the angular depth, along with the A and B values in the oblique coronal view for all anatomical types. A strong positive linear correlation was observed between BTL and the A- (r2 = 0.74) and B-values (r2 = 0.84). The multiple linear regression model to predict the BTL from the A-and B-values resulted in the following equation (estimated BTL = [A × 1.04] + [B × 1.89] - 0.92). The manually measured and estimated BTL differed by 1.12%. The proposed equation could be beneficial in adequately selecting an electrode that covers the basal turn in deformed cochleae.