Correlation of Endolysmphatic Duct Signal Intensity With Clinical Features in Otological Diseases.

OBJECTIVE: Bilateral high signal intensity (SI) in the endolymphatic duct (ED) on magnetic resonance imaging (MRI) has been reported as a common characteristic in ears with large vestibular aqueduct syndrome (LVAS). However, the significance of bilateral high SI in the ED remains unknown. The present study aimed to compare the correlation between SI in the ED and the clinical manifestations in various otological disorders and consider the significance of the MRI findings. STUDY DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: The study included 2,450 ears from 1,225 patients with various otological disorders. INTERVENTION: All ears underwent 3T enhanced MRI and were evaluated for the degree of endolymphatic hydrops (EH) and the SI ratios (SIRs; i.e., the calculation between SIs in the ED and those in the cerebellum). MAIN OUTCOME MEASURE: The imaging findings were compared with their clinical symptoms. RESULTS: Ears with bilateral high SIRs in the ED tended to have considerably less occurrence of EH in both the cochlea and vestibule than those with bilateral low SIRs. Ears with SIR ≥8 showed significantly elevated hearing thresholds at lower frequencies on pure-tone audiometry, although they exhibited a markedly lower incidence of cochlear EH than those with SIR <8. Moreover, ears with vertigo exhibited notably higher SIRs than those without vertigo. CONCLUSION: Bilateral high SI in the ED on MRI may reflect pathophysiology underlying sensorineural hearing loss and vestibular symptoms, which are not associated with EH formation.

Superior Canal Dehiscence and the Risk of Additional Dehiscences: A Retrospective CT Cohort Study.

OBJECTIVE: Determine if superior canal dehiscence (SCD) found on flat-panel CT increases the risk for other defects in the otic capsule. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary care center. PATIENTS: One hundred ears (50 with SCD and 50 matched controls without SCD). INTERVENTIONS: Flat-panel CT imaging. MAIN OUTCOME MEASURES: (1) Prevalence of other dehiscences in SCD ears, (2) dehiscences in controls, and (3) otic capsule thickness in other reported dehiscence locations (cochlea-carotid, lateral semicircular canal [SCC] and mastoid, facial nerve-lateral SCC, vestibular aqueduct, posterior SCC-jugular bulb, posterior SCC-posterior fossa). Between-group comparisons were considered significant at p < 0.007 after applying the Bonferroni correction for multiple comparisons. RESULTS: Not including the SCD, there was a mean of 0.04 additional dehiscences in the SCD group (n = 2/50, 4%) and 0.04 non-SCD dehiscences in the controls (n = 2/50, 4%, p > 0.007). In the SCD group, there was one dehiscence between the cochlea and carotid artery and one between the posterior SCC and posterior fossa. The control group had one enlarged vestibular aqueduct and one dehiscence between the facial nerve and lateral SCC. As a group, SCD ears had wider vestibular aqueducts (0.68 ± 0.20 vs 0.51 ± 0.30 mm, p < 0.007) and thinner bone between the posterior SCC and posterior fossa (3.12 ± 1.43 vs 4.34 ± 1.67 mm, p < 0.007). The bone between the facial nerve and lateral SCC was thicker in SCD ears (0.77 ± 0.23 vs 0.55 ± 0.27 mm, p < 0.007) and no different for cochlea-carotid, and lateral SCC and mastoid (p > 0.007). CONCLUSIONS: SCD does not increase the likelihood of a second dehiscence in the same otic capsule. SCD patients may have congenitally thinner otic capsule bones compared to controls, particularly near the posterior SCC, where the vestibular aqueduct may be enlarged.

Retrolabyrinthine Bone Thickness as a Radiologic Marker for the Hypoplastic Endotype in Menière Disease.

BACKGROUND AND PURPOSE: Menière disease (MD) manifests in 2 major endotypes: one with a hypoplastic, underdeveloped endolymphatic sac (MD-hp) and the other with a normally developed sac that degenerates over time (MD-dg). Determining the specific endotype in patients is important for predicting disease progression, tailoring patient counseling, and optimizing treatment strategies. Endotype diagnosis involves measuring an angular trajectory of the vestibular aqueduct (ATVA), with an ATVA ≥140° indicative of MD-hp and an ATVA ≤120° of MD-dg. However, assessing the ATVA can be challenging. This study aimed to explore the link between ATVA and the thickness of the retrolabyrinthine bone as an alternative diagnostic measure that could provide differentiation between MD endotypes using CT and MR imaging. MATERIALS AND METHODS: Retrospective review of CT temporal bone imaging from 32 adult patients with definite MD (60 ears) and 33 age-matched controls without MD or other inner ear symptoms (61 ears) was performed. The ATVA and retrolabyrinthine bone thickness were measured using uniform methodology on standardized axial CT images. Comparative analyses were performed to determine the correlation between ATVA and retrolabyrinthine bone thickness. Additionally, from a separate cohort of 11 patients (22 ears), CT and MR examinations of the temporal bone were retrospectively reviewed for retrolabyrinthine bone thickness measurements, to verify the correlation across the 2 modalities. RESULTS: The average retrolabyrinthine bone thickness was statistically significantly different between MD endotypes, being a mean of 0.8 (SD, 0.3) mm in patients with MD-hp (ATVA ≥140°) and 2.0 (SD, 0.9) mm in patients with MD-dg (ATVA ≤120°), with a consistent pattern of thin retrolabyrinthine bone in MD-hp and variable thickness in MD-dg. Receiver operating characteristic curve analysis within the MD cohort revealed that a retrolabyrinthine bone thickness ≥1.2 mm effectively rules out MD-hp. Excellent interrater reliability was noted for the retrolabyrinthine measurement, and there was near-perfect correlation between CT and MR measurements. CONCLUSIONS: Retrolabyrinthine bone thickness proved to be a useful and straightforward alternative marker for distinguishing MD endotypes, being particularly useful for excluding MD-hp. Including information on retrolabyrinthine bone thickness should be considered a routine part of reporting in the context of MD imaging.

Association Between Vestibular Aqueduct Morphology and Meniere's Disease.

OBJECTIVE: To investigate the relationship between vestibular aqueduct (VA) morphology and Meniere's disease (MD) using ultrahigh-resolution computed tomography (U-HRCT). METHODS: Retrospective data were collected from 34 patients (40 ears) diagnosed with MD in our hospital who underwent temporal bone U-HRCT with isotropic 0.05-mm resolution, magnetic resonance with gadolinium-enhanced, and pure-tone audiometry; 34 age- and sex-matched controls (68 ears) who underwent U-HRCT were also included. VA patency was qualitatively classified as locally not shown (grade 1), locally faintly shown (grade 2), or clearly shown throughout (grade 3). The width of the outer orifice and VA length and angle were quantitatively measured. Differences in VA morphology between the MD and control groups were analyzed. The correlations between VA morphology and the degrees of hearing loss and endolymphatic hydrops (EH) were also analyzed. RESULTS: VA was classified as grades 1-3 in 11, 17, and 12 ears in the MD group and 5, 26, and 37 ears in the control group, respectively. The patency differed significantly between the groups (p < 0.01). The width of the outer orifice and length of VA were significantly smaller in the MD group than those in the control group (p < 0.05). Both VA patency and length were correlated with the degree of EH in the cochlea and the vestibule (p < 0.05). No difference was found between VA morphology and the degree of hearing loss (p > 0.05). CONCLUSION: The morphological characteristics of VA were found to be associated with the occurrence of MD and the degree of EH. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3349-3354, 2024.

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.

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 SLC26A4, FOXI1, and KCNJ10 Gene Variants in Patients with Incomplete Partition of the Cochlea and Enlarged Vestibular Aqueduct (EVA) Anomalies

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 etiologic spectrum of pediatric severe to profound hearing loss of consecutive 119 cases.

Determining the etiology of severe-to-profound sensorineural hearing loss (SP-SNHL) in pediatric subjects is particularly important in aiding the decision for auditory rehabilitation. We aimed to update the etiologic spectrum of pediatric SP-SNHL by combining internal auditory canal (IAC)-MRI with comprehensive and state-of-the-art genetic testings. From May 2013 to September 2020, 119 cochlear implantees under the age of 15 years with SP-SNHL were all prospectively recruited. They were subjected to genetic tests, including exome sequencing, and IAC-MRI for etiologic diagnosis. Strict interpretation of results were made based on ACMG/AMP guidelines and by an experienced neuroradiologist. The etiology was determined in of 65.5% (78/119) of our cohort. If only one of the two tests was done, the etiologic diagnostic rate would be reduced by at least 21.8%. Notably, cochlear nerve deficiency (n = 20) detected by IAC-MRI topped the etiology list of our cohort, followed by DFNB4 (n = 18), DFNB1 (n = 10), DFNB9 (n = 10) and periventricular leukomalacia associated with congenital CMV infection (n = 8). Simultaneous application of state-of-the-art genetic tests and IAC-MRI is essential for etiologic diagnosis, and if lesions of the auditory nerve or central nerve system are carefully examined on an MRI, we can identify the cause of deafness in more than 65% of pediatric SP-SNHL cases.

High jugular bulb with a diverticulum and vestibular aqueduct dehiscence: an anatomical variant to be aware in patients with hearing loss.

PURPOSE: To describe an anatomical variant that should be consider in patients with hearing loss. METHODS: An 8-year-old girl underwent to temporal bone computed tomography for the evaluation of bilateral conductive hearing loss and further assessment of possible enlarged vestibular aqueduct or high jugular bulb on brain magnetic resonance imaging (MRI). RESULTS: CT of temporal bone showed a cystic cavity with bony sclerotic margins extending from the right jugular foramen to the vestibular aqueduct. Bony dehiscence of the jugular foramen with the right carotid canal was also noted. On brain MRI, there was no evidence of enlargement of the endolymphatic duct and sac on T2 thin-section gradient echo sequence. Time of flight MR angiography did not show arterial flow in the cavity. Contrast enhanced MR venography confirmed the presence of a high right jugular bulb with a diverticulum extending into the vestibular aqueduct due to jugular bulb-vestibular aqueduct dehiscence. CONCLUSION: Knowledge of high jugular bulb-vestibular aqueduct dehiscence is important in the assessment of patients with otologic symptoms such as vertigo, tinnitus and hearing loss.

Vestibular Aqueduct Size Correlates With the Degree of Cochlear Hydrops in Patients With and Without Menière's Disease.

OBJECTIVE: To correlate the CT imaging findings of the visibility and size of the vestibular aqueduct (VA) with the degree of the cochlear hydrops determined in MRI late imaging of the hydrops. Study Design: Retrospective study. Setting: Tertiary referral center. Patients: A total of 127 patients (62 women, 65 men, average age 55.6 yrs): 86 of these were diagnosed with Menière's disease (American Academy of Otolaryngology-Head and Neck Surgery [AAO-HNS] criteria; 67 unilateral, 19 bilateral). INTERVENTIONS: Temporal bone CT and hydrops MRI were performed in all patients. MAIN OUTCOME MEASURES: Visibility/width of the VA in temporal bone CT and grade of cochlear hydrops evaluated by MRI. RESULTS: The width of the VA is significantly smaller in patients diagnosed with Menière's disease (30% non-visible VA), compared with the patients who did not fulfill the diagnostic criteria of Menière's disease (12% non-visible VA) (double sided Spearman correlation, p < 0.001). In all ears of patients diagnosed with Menière's disease the width of the VA was significantly correlated with the degree of the cochlear hydrops (in cases of non-visible VA 65% [34/52] ears presented with hydrops grade 3 or 4; 13% [7/52] ears presented with hydrops grade 1 or 2 and 21% [11/52] ears showed no hydrops) (Spearman correlation p = 0.001/p < 0.01). This is also true for all ears that can be summarized as hydrophic ear disease (symptomatic ears that present with a hydrops in MRI). CONCLUSIONS: The results of our study could confirm the importance of the VA in the pathogenesis of the endolymphatic hydrops in vivo.

Toward the Pathogenicity of the SLC26A4 p.C565Y Variant Using a Genetically Driven Mouse Model.

Recessive variants of the SLC26A4 gene are globally a common cause of hearing impairment. In the past, cell lines and transgenic mice were widely used to investigate the pathogenicity associated with SLC26A4 variants. However, discrepancies in pathogenicity between humans and cell lines or transgenic mice were documented for some SLC26A4 variants. For instance, the p.C565Y variant, which was reported to be pathogenic in humans, did not exhibit functional pathogenic consequences in cell lines. To address the pathogenicity of p.C565Y, we used a genotype-based approach in which we generated knock-in mice that were heterozygous (Slc26a4+/C565Y), homozygous (Slc26a4C565Y/C565Y), and compound heterozygous (Slc26a4919-2A>G/C565Y) for this variant. Subsequent phenotypic characterization revealed that mice with these genotypes demonstrated normal auditory and vestibular functions, and normal inner-ear morphology and pendrin expression. These findings indicate that the p.C565Y variant is nonpathogenic for mice, and that a single p.C565Y allele is sufficient to maintain normal inner-ear physiology in mice. Our results highlight the differences in pathogenicity associated with certain SLC26A4 variants between transgenic mice and humans, which should be considered when interpreting the results of animal studies for SLC26A4-related deafness.

Diagnostic Value of 3D Segmentation in Understanding the Anatomy of Human Inner Ear Including Malformation Types.

OBJECTIVE: To understand the anatomical and dimensional variations of the human inner ear using 3-dimensional (3D) segmentation within the Middle East population. DESIGN: Retrospective study. SETTING: King Abdullah Ear Specialist Center (KAESC) Riyadh, Saudi Arabia. PARTICIPANT: Forty computed tomography (CT) images of patients with sensorineural hearing loss who underwent cochlear implant (CI) were taken for analysis. MAIN OUTCOME MEASURES: Three-dimensional images showing the anatomical variations of the inner ear including various pathological conditions, cochlear parameters including basal turn diameter ("A" value), "B" value which is perpendicular to "A" value, cochlear height, length, and width of the internal auditory canal (IAC), intercochlear spacing, and electrode angular insertion depth (AID). RESULTS: Out of 40 CT image data sets, 12 had normal inner-ear anatomy (NA), 4 with enlarged vestibular aqueduct syndrome (EVAS), 8 with only 2 turns of the cochlea (2TL), 7 with incomplete partition (IP) type II, 5 with cochlear hypoplasia, 1 with common cavity, and 3 with abnormal IAC. Taking the NA, EVAS, 2TL, and the IP type II cases altogether, age of the patient had no correlation with the "A" value; however, the "A" value had a linear correlation with the "B" value. The age of the patient had an increasing logarithmic correlation with the IAC length and the intercochlear spacing. The "A" value did not have any meaningful correlation with the cochlear height. Three data sets showed asymmetric inner-ear malformation types on either side of the ears. All these 40 cases were implanted with various CI electrode array variants and the corresponding postoperative plain film X-ray images showing the electrode AID are given separately in figures. CONCLUSIONS: Three-dimensional segmentation of the inner ear from the temporal bone CT is a valuable clinical and training tool for surgeons and radiologists especially in difficult cases which will certainly help to understand the overall anatomical and dimensional variations.

Correlation of air-bone gap and size of Enlarged Vestibular Aqueduct in children.

OBJECTIVE: Enlarged vestibular aqueduct (EVA) is an inner ear malformation that represents an important cause of pediatric hearing loss. While certain elements in the history or audiogram may suggest EVA, it is most often diagnosed using computed tomography (CT). The present investigation was conducted to determine if the size of the audiometric air-bone gap (ABG) is correlated with the size of the vestibular aqueduct in the pediatric population using three vestibular aqueduct measurements. These included the fundus, midpoint, and porous widths of the vestibular aqueduct. STUDY DESIGN: This is a retrospective cohort study. SETTING: This study took place at a tertiary care referral center. PATIENTS: Fifty-five children (33 female; 22 male) with a confirmed diagnosis of unilateral or bilateral EVA as determined by prior imaging of the inner ear were included in the study. MAIN OUTCOME MEASURES: Associations of EVA measurements with ABGs at 0.5 and 1 kHz were evaluated using Pearson correlation coefficients. RESULTS: All of the correlation coefficients were positive, indicating that as EVA measurements increased so did the ABG. Only the correlation between fundus width and ABG at 1 kHz was not statistically significant. CONCLUSIONS: ABGs measured during audiometric testing correlate with the size of the EVA and ABGs can be clinical predictors of the severity of the bony abnormality. These data support the third window theory of conductive hearing loss in pediatric EVA.

The vestibular aqueduct sign: Magnetic resonance imaging can detect abnormalities in both ears of patients with unilateral Meniere's disease.

BACKGROUND AND PURPOSE: In patients with Meniere's disease (MD), saccular hydrops can only be studied by magnetic resonance imaging (MRI) at a late stage when the disease is already responsible for moderate to severe hearing loss. However, these patients may also present vestibular aqueduct (VA) abnormalities. MATERIALS AND METHODS: In this prospective study (38RC14.428 for healthy subjects/38RC15.173 for patients), imaging was carried out on a 3T MRI scanner. Twenty healthy subjects (13 women, median age 53.5 [52.2-66.7]) and twenty MD patients (9 women, median age 54.5 [52-66.7]) had MRI scans with 3D-FLAIR sequences without injection, then 4 hours after a single intra-venous dose of contrast agent. Two radiologists independently ranked the morphology of the VA in the healthy subjects and in MD patients, using a three-level score (completely visible, discontinuous and not visible). Each subject was then graded, based on both the VA's appearance and on saccular hydrops presence. Inter-reader agreement tests were performed. RESULTS: In controls and patients, VA modifications were symmetrical without significant difference between the symptomatic and asymptomatic ears. The presence of at least one ear with discontinuous VA showed a correlation with clinical MD (P < 0.001) with a sensitivity of 90%. Ten patients had saccular hydrops, but only in the symptomatic ears. The evaluation of VA did not differ between MRI, both within MRI series or between the two radiologists (kappa without and with contrast agent = 0.9 and 0.92 respectively). CONCLUSION: Analysis of the vestibular aqueduct by MRI detects abnormalities in both ears of patients with unilateral MD.

Association of SLC26A4 mutations, morphology, and hearing in pendred syndrome and NSEVA.

OBJECTIVE: To investigate the relations of monoallelic (M1), biallelic (M2), or the absence of mutations (M0) in SLC26A4 to inner ear morphology and hearing levels in individuals with Pendred syndrome (PS) or nonsyndromic enlarged vestibular aqueduct (NSEVA) associated with hearing loss. METHODS: In a cohort of 139 PS/NSEVA individuals, 115 persons from 95 unrelated families had full genetic sequencing of SLC26A4, and 113 had retrievable images for re-assessment of inner ear morphology. The association between the number of mutant alleles in SLC26A4, inner ear morphology (including endolymphatic sac size and protein content on magnetic resonance imaging), and hearing level (pure tone average) was explored. RESULTS: Biallelic SLC26A4 mutations (M2) occurred in three-quarters of the cohort and was invariably associated with poor hearing; in 87%, it was associated with incomplete partition type II of the cochlea as well as enlarged endolymphatic sac and vestibular aqueduct. M1 or M0 individuals exhibited a greater variability in inner ear morphology. Endolymphatic sac size and presence of "high-protein" sac contents were significantly higher in M2 individuals compared to M1 and M0 individuals. CONCLUSION: The number of SLC26A4 mutations is associated with severity and variability of inner ear morphology and hearing level in individuals with PS or NSEVA. M2 individuals have poorer hearing and present largely incomplete partition type II of the cochleas with enlarged endolymphatic sacs, whereas individuals with M1 and no detectable SLC26A4 mutations have less severe hearing loss and more diverse inner ear morphology. LEVEL OF EVIDENCE: 4. Laryngoscope, 129:2574-2579, 2019.

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

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

Large Vestibular Aqueduct Syndrome: Parents' and Audiologists' Perspectives.

BACKGROUND: Large vestibular aqueduct syndrome (LVAS) is an auditory disorder that is difficult to diagnose and manage; it is confirmed when the vestibular aqueduct is >1.5 mm in diameter. Diagnosis of LVAS in children can devastate parents and challenge healthcare professionals who serve these patients and their families. PURPOSE: This study surveyed parents of children with LVAS about their knowledge of and experiences with LVAS and their attitudes about the support provided to them by healthcare professionals. This study also surveyed audiologists about their knowledge of and experiences with LVAS and their level of confidence in serving families with children having this disorder. RESEARCH DESIGN: Cross-sectional survey. STUDY SAMPLE: 100 parents, mostly mothers, and 144 audiologists responded to invitations to participate in surveys designed to elicit information about their knowledge of, experiences with, and attitudes toward LVAS. DATA COLLECTION AND ANALYSIS: Invitations via links to participate in a survey on surveymonkey.com were posted in LVAS support group pages on Facebook.com for parents and sent to audiologists randomly selected from the American Academy of Audiology Membership Directory. Descriptive statistics were used to analyze trends in parents' and audiologists' responses. RESULTS: A response rate could not be obtained for the parents' survey because it was impossible to know how many parents actually viewed the invitation to participate via Facebook.com. The response rate for the audiologists' survey was 10%. Most of the parents reported that their children had clinical trajectories similar to those of cases reported in the literature, and said they needed more information from their healthcare providers, especially pediatricians and primary care physicians. Most of the audiologists felt confident in their knowledge of and/or skills in aiding in the diagnosis and/or treatment of LVAS, except for issues surrounding cochlear implants. Audiologists were interested in obtaining continuing education about LVAS from multiple sources. CONCLUSIONS: Parents of children having LVAS need greater support from their healthcare providers, who in turn need additional information on the topic and should collaborate for supportive and appropriate interprofessional care.

Application of multiplanar reconstruction of spiral CT in the diagnosis and treatment of enlarged vestibular aqueducts.

Background: Multiplanar reconstruction (MPR) of High Resolution Computed Tomography (HRCT) makes it possible to achieve a clear view of inner ear structures. However, no agreement was reached on the standard measurement of inner ear. Objectives: To establish standard inner ear measurements for building criteria for cochlear structure evaluation. Material and Methods: HRCT scanning of the temporal bones of 82 cases with normal inner ear structures and 104 cases with an EVA and bilaterally sensorineural hearing loss (SNHL) was performed. Three standard cochlear plane and one vestibular plane were reconstructed by MPR. Results: Normative data of inner ear was measured and formulated. The most common malformation found in cases with EVA was incomplete partition type II (IP-II; 90.4%). The IP-II group had significantly greater modiolar height, cochlear aperture width, vestibular area, and vestibule width than did the control group. Different degrees of IP-II modiolar defects were observed using MPR. Conclusions and Significance: Standard cochlear plane can help us to evaluate the cochlear structure. The MPR standard measurement of inner ear is clinically valuable for the diagnosis and cochlear implant of EVA.