{"paper_id":"31cb8a92-7088-4ef2-9cbd-c5ceb3fcee2c","body_text":"Genetic Variants and Audiometric Patterns in Nonsyndromic Enlarged Vestibular Aqueduct Chinese Children with Complete Hearing Loss | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Genetic Variants and Audiometric Patterns in Nonsyndromic Enlarged Vestibular Aqueduct Chinese Children with Complete Hearing Loss Rui-rui Guan, Wan Zhao, Jing-wu Sun, Jia-qiang Sun, Chun-yan Li, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6948944/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Sep, 2025 Read the published version in European Journal of Pediatrics → Version 1 posted 10 You are reading this latest preprint version Abstract Enlarged vestibular aqueduct (EVA) is one of the most common inner ear malformations (IEMs) leading to hearing loss in children. Although its genetic and clinical characteristics have been studied, its manifestations in completely deaf children in China, especially those with or without incomplete partition type II (IP-II), are not yet fully understood. We conducted a comprehensive analysis of 123 pediatric EVA children with complete hearing loss. Participants were classified into isolated EVA (IEVA, n=93) and IP-II with EVA (IP-II & EVA, n=30) groups, with 30 age-, sex-, and hearing status-matched subjects without IEMs. Evaluations included audiologic tests and genetic screening for common deafness-associated variants. Pure tone audiometry revealed significantly lower hearing thresholds in IEVA ears compared to those without IEMs ( p = 0.004). Air-bone gap (ABG) was more prevalent in IEVA than IP-II & EVA cases ( p = 0.019). Acoustically evoked short latency negative response (ASNR) was detected in 66.67% of IEVA and 63.33% of IP-II & EVA ears, significantly higher than controls. Genetic screening of 52 patients revealed pathogenic variants in 66.03%, with SLC26A4 c.919-2A>G being the predominant mutation. Biallelic mutations were significantly more common in IP-II & EVA compared to IEVA patients ( p = 0.022). Conclusions EVA patients exhibit distinct audiometric patterns and genetic variants based on their inner ear morphology. The higher prevalence of biallelic SLC26A4 mutations in IP-II & EVA children suggests a stronger genetic component in this phenotype, potentially influencing clinical management strategies. Enlarged vestibular aqueduct incomplete partition type II genetic screening audiology complete hearing loss Figures Figure 1 Figure 2 Figure 3 Figure 4 What Is Known • The genetic and clinical characteristics of patients with enlarged vestibular aqueduct (EVA) have been studied. However, its manifestations in completely deaf children in China, especially those with or without incomplete partition type II (IP-II), are not yet fully understood. What is New: • Isolated enlarged vestibular aqueduct (IEVA) patients demonstrated lower hearing thresholds but higher air-bone gap (ABG) rates compared to IP-II with EVA (IP-II & EVA) cases. The SLC26A4 c.919-2A>G mutation emerged as predominant, with biallelic mutations occurring more frequently in IP-II & EVA cases. These findings may guide clinical management strategies for affected children. Introduction Enlarged vestibular aqueduct (EVA) is one of the most common inner ear malformations (IEMs) and can be detected by temporal bone computed tomography (CT) and/or magnetic resonance imaging (MRI) [ 1 – 4 ]. EVA patients present with heterogeneous phenotypes, predominantly characterized by progressive, fluctuating hearing loss [ 5 ]. Valvassori and Clemis first established the association between EVA and hearing deficits in their landmark 1978 retrospective analysis of 50 patients with bilateral hearing impairment[ 1 ]. While sensorineural hearing loss (SNHL) is predominant in pediatric EVA cases, audiometric assessments frequently reveal substantial air-bone gap (ABG), even with normal middle ear function [ 6 – 8 ]. In 1979, Cazals and colleagues identified a distinctive negative deflection approximately 3 ms post-stimulus during auditory brainstem response (ABR) testing in EVA patients with severe-to-profound hearing loss [ 9 ]. This response pattern, subsequently termed the acoustically evoked short latency negative response (ASNR) by Nong et al., exhibits significantly higher prevalence in EVA compared to other inner ear malformations or normal anatomy [ 10 – 12 ]. Molecular genetic studies have identified mutations in SLC26A4 as a primary genetic determinant of vestibular aqueduct abnormalities, contributing to both Pendred syndrome (PS) and nonsyndromic sensorineural deafness autosomal recessive type (DFNB4) [ 13 – 15 ]. Despite its autosomal recessive inheritance pattern, the number of identifiable mutant alleles shows considerable variation. The distribution of pathogenic SLC26A4 mutations demonstrates distinct ethnic patterns: p.L236P, p.T416P, and c.1001 + 1G > A mutations predominate in Caucasian populations, and p.H723R is prevalent in Japanese and Korean populations [ 16 – 18 ]. SLC26A4 mutation detection rates vary among ethnic groups, with Korean studies indicating that hearing phenotypes correlate more strongly with mutation type than quantity in bilateral EVA patients [ 19 ]. Studies in Caucasian populations have shown that approximately 25% of subjects carry bilateral mutations, while 75% exhibit either no mutations or single-allele variants [ 20 ]. Carol Mondini first reported a case of congenital deafness, where the cochlea had only 1.5 turns and the absence of the internal partition in the cochlea led to the fusion of the middle and apical turns [ 21 ]. Later, with the development of imaging diagnostic techniques and the precise classification of IEMs, Sennaroglu classified it as incomplete partition type II (IP-II)[ 4 ]. It has been reported that 7.5–34.7% of EVA patients have IP-II [22; 23]. A multicenter international study showed that 84.6% of IP-II patients had EVA[ 15 ]. Some scholars have studied and pointed out that the number of SLC26A4 mutations in patients with EVA is significantly correlated with IP-II & EVA [24; 25]. However, other articles have indicated that whether or not IP-II is present does not have a significant impact on hearing loss in patients with EVA [ 26 ]. Given the relationship between hearing impairment severity and ASNR expression in EVA patients [ 12 ], this study focuses on cochlear implant recipients with complete hearing loss. We aim to elucidate the clinical characteristics of nonsyndromic EVA patients with complete hearing loss, with particular emphasis on with or without IP-II. Materials and methods Participants This study was conducted with approval from the Ethics Committee of Anhui Provincial Hospital. Written informed consent was obtained from all participants or their legal guardians prior to enrollment. The study cohort comprised 123 children (67 males, mean age ± standard deviation (SD): 9.97 ± 2.42 years; age range: 6–17 years) diagnosed with bilateral EVA who underwent cochlear implantation (CI) between January 2019 and October 2023 (Fig. 1 ). A control group of 30 age-, sex-, and hearing status-matched subjects without inner ear malformations (IEMs) was established for comparison. Based on the updated Sennaroglu classification system [ 4 ], participants were stratified into three groups: IEVA (isolated enlarged vestibular aqueduct; n = 93) IP-II & EVA (incomplete partition type II with EVA; n = 30) Control group without IEMs (n = 30) Inclusion criteria: Confirmed bilateral complete hearing loss: pure-tone average (PTA) > 95 dB HL; compliance with required audiological assessments. Exclusion criteria: Presence of thyroid pathologies; presence of concurrent deafness-associated syndromes; non-compliance with the evaluation of audiology and genetic screening. Detailed clinical characteristics of all participants are presented in Table 1 . Table 1 Demographic information of patients with IEVA, IP-II & EVA and without IEMs. Variable IEVA IP-II & EVA Without IEMs N 93 30 30 Sex (F/M, N) 43/50 13/17 14/16 Age at test (mean ± SD, years) 9.96 ± 2.15 10.03 ± 3.16 9.23 ± 2.79 PTA (mean ± SD, dB HL) 101.41 ± 11.36 103.50 ± 18.48 107.08 ± 6.59 Onset of deafness (prelingual/postlingual, N) 65/28 22/8 20/10 IEVA, isolated enlarged vestibular aqueduct; EVA, enlarged vestibular aqueduct; IEMs, inner ear malformations; F, female; M, male; SD, standard deviation; PTA, pure-tone average. The preoperative evaluation protocol included comprehensive audiometric testing, consisting of distortion product otoacoustic emission (DPOAE), tympanometry, ABR, and pure tone audiometry. Additionally, genetic screening for deafness-associated variants was performed in 52 of the 123 children with EVA. Audiologic Evaluation All the subjects were tested for tympanometry via the Titan IMP440 middle ear impedance device (Interacoustics, Denmark, Version 3.4). According to the classification of Jerger, all the patients had type A tympanograms for tympanometry at 226 Hz. DPOAE testing was conducted via Capella equipment (GN Otometrics, Denmark). The DPOAE results of all patients did not pass. The audiometry instrument used was the Madsen Audiometer (Conera, GN Otometrics Inc., Denmark). Audiometric data collected included air conduction thresholds and bone conduction thresholds at 0.25, 0.5, 1, 2, and 4 kHz for both ears. An ABG was defined at each frequency as an air conduction threshold 15 dB higher than the bone conduction threshold from 0.25 to 4 kHz. When the ABG was > 15 dB at least at the three tested frequencies (0.25, 0.5, and 1 kHz), the patient was classified as having an ABG (EVA with ABG) [27; 28]. Pure tone average (PTA) was calculated as the average of air conduction thresholds at 0.5, 1, 2, and 4 kHz for both ears. The absence of a response at the maximum intensity was recorded as the 120 dB HL threshold. ABR assessments were conducted via ICS Chart EP equipment (GN Otometrics, Denmark) in a soundproof chamber. Testing was performed under sedation with chloral hydrate. The recording electrode, ground electrode, and reference electrode were placed in the middle of the forehead, the base of the nose, and the left/right mastoid processes, respectively. Electrode impedance was maintained below 5 kΩ. ABR testing employed ER-3A insert earphones delivering alternating clicks, beginning at 95 dB nHL with 10 dB decremental steps. The identification criteria for the acoustically evoked short latency negative response (ASNR) in the ABR included the following: [ 29 ] The peak should be reproducible. The peak should appear 3–5 ms after the onset of stimulation. The onset-to-peak amplitude (with onset defined as the starting point of the deflection toward the negative peak) should be more than 0.05 mV. If there were two or more acoustically evoked, short-latency negative responses, we regarded the largest peak as the definitive response. The peak became absent after external auditory canal occlusion. Genetic analysis Prior to genetic testing, we obtained informed consent from all adult participants and from parents/legal guardians of minor participants after thoroughly explaining the purpose and implications of deafness gene screening. Peripheral venous blood samples (3–5 mL) were collected from each participant. Using the Crystal Core platform (Beijing Boao Biological Group Co., Ltd.), we performed microarray analysis to detect nine common pathogenic variants across four deafness-associated genes: GJB2 (35delG, 176del16, 235delC, 299delAT), GJB3 (538C > T), SLC26A4 (2168A > G, 919-2A > G), and mtDNA 12SrRNA (1494 C > T, 1555A > G). Statistical data analysis We used the SPSS software package (version 17.0 for Windows; SPSS Inc., Chicago, IL, USA) to analyze the data. The analysis of variance (ANOVA) was used to analyze the PTA data. In this study, PTA was calculated as the average of air conduction thresholds at 0.5, 1, 2, and 4 kHz for each ear. The Bonferroni test was used in post hoc analysis when significant main effects or interactions were achieved. A chi-Square test was employed to assess the differences between variables (ABG detection rate rates between IEVA ears and IP-II & EVA ears, ASNR detection rates with different inner ear structures, and biallelic/monoallelic SLC26A4 mutations between IEVA patients and IP-II & EVA patients), with statistical significance set at p < 0.05. Results Audiometric Results in Ears with IEVA/ IP-II & EVA Pure-tone audiometry revealed hearing thresholds of 110.36 ± 6.29 dB HL in ears without IEMs, 105.00 ± 5.22 dB HL in the IEVA group, and 107.08 ± 6.59 dB HL in the IP-II with EVA group. Statistical analysis demonstrated significantly higher PTA in ears without IEMs compared to those with IEVA ( p = 0.013). Air-bone gap (ABG) was detected in 130 of 186 ears (69.90%) in the IEVA group and 32 of 60 ears (53.33%) in the IP-II & EVA group. The ABG detection rate was significantly higher in IEVA cases compared to IP-II & EVA cases ( p = 0.019) (Fig. 2 ). ABR testing revealed ASNR in 124 of 186 ears (66.67%) with IEVA, 38 of 60 ears (63.33%) with IP-II & EVA, and 5 of 60 ears (8.33%) without IEMs. Both the IEVA and IP-II & EVA groups demonstrated significantly higher ASNR detection rates compared to the non-IEM group (66.67% vs. 8.33%, p < 0.001; 63.33% vs. 8.33%, p < 0.001, respectively) (Fig. 3 ). Common Mutations in Deafness-Associated Genes in Patients with IEVA/ IP-II & EVA Among 123 patients, genetic screening was performed in 52 cases (43 IEVA and 9 IP-II & EVA) (Table 2 ). Pathogenic variants were identified in 34 patients (66.03%), comprising homozygous SLC26A4 c.919-2A > G mutations (n = 8, 15.09%), heterozygous SLC26A4 c.919-2A > G mutations (n = 17, 32.08%), heterozygous SLC26A4 c.2168A > G mutations (n = 3, 5.67%), compound heterozygous SLC26A4 c.2168A > G/c.919-2A > G mutations (n = 1), and digenic GJB2 c.235delC/ SLC26A4 c.919-2A > G mutations (n = 5, 9.43%). No pathogenic variants were detected in 18 cases using the employed screening methods. In the cohort of 52 EVA patients, ASNR was detected in 27 cases (51.92%). Among these, 16 patients (59.25%) carried pathogenic variants. The remaining eleven ASNR-positive patients showed no detectable pathogenic variants using the current screening methodology. Table 2 Common mutations of deafness genes in 52 patients with IEVA/ IP-II & EVA. Gene Nucleotide change IEVA (N) IP-II&EVA (N) Total (N, %) SLC26A4, total 29(55.77%) Homozygous c.919-2A > G 6 2 8 Heterozygous c.2168A > G 3 3 c.919-2A > G 14 3 17 Double heterozygous c.919-2A > G/ c.2168A > G 1 1 GJB2& SLC26A4, total 5 (9.62%) Heterozygous& Homozygous c.235delC/ c.919-2A > G 3 3 Heterozygous& Heterozygous c.235delC/ c.919-2A > G 2 2 In total 26/43 8/9 34/52(65.38%) In the IEVA cohort (n = 43), 26 patients harbored pathogenic variants: seven with biallelic SLC26A4 mutations (M2) and nineteen with monoallelic SLC26A4 mutations (M1). In the IP-II & EVA cohort (n = 9), eight patients carried pathogenic variants: five with M2 and three with M1. The proportion of M2 mutations was significantly higher in IP-II & EVA patients compared to IEVA patients (55.56% vs. 16.28%, p = 0.022). Conversely, M1 mutations were more frequent in IEVA patients than in IP-II & EVA patients, though this difference was not statistically significant (44.19% vs. 33.33%, p = 0.717) (Fig. 4 ). Discussion EVA is a significant congenital anomaly of the inner ear, characterized by an expanded vestibular aqueduct and associated sensorineural or mixed hearing loss. The condition accounts for approximately 1–8% of SNHL cases [2; 3]. EVA demonstrates a strong genetic association with mutations in the SLC26A4 gene, which encodes the anion transport protein pendrin—a critical mediator of endolymphatic fluid homeostasis. These SLC26A4 mutations can manifest in two distinct phenotypes: the non-syndromic form DFNB4 and PS, both following an autosomal recessive inheritance pattern [ 16 ]. IP-II was originally described by Carlo Mondini, and together with a minimally dilated vestibule as well as EVA, constitutes the Mondini deformity [ 4 ]. Our clinical investigation of 123 EVA patients revealed that 24.3% (30/123) exhibited concurrent IP-II, which is consistent with the findings of previous studies [22; 23]. Our study indicated that ears affected by IEVA demonstrate superior hearing capabilities compared to those lacking IEMs, while no notable hearing differences exist between no IEMs ears and those with IP-II & EVA. Research has documented that individuals with IP-II typically experience earlier onset of hearing deterioration, whereas those presenting with isolated vestibular aqueduct enlargement show a more gradual progression of hearing loss. Biomechanical analysis suggests that the cochlea's spiral configuration provides resistance against internal fluid dynamics. The reduced number of cochlear turns in IP-II results in heightened susceptibility to biomechanical stress, consequently leading to more pronounced hearing impairment. The syndrome of EVA typically manifests as sensorineural or mixed hearing loss. Various researchers have documented air-bone gap (ABG) occurrence at lower frequencies in 15–100% of EVA cases [7; 8; 27; 28]. Our research revealed that ABG was present in more than half of the examined ears across both the IEVA and IP-II&EVA groups. The underlying mechanism responsible for ABG development in EVA syndrome continues to be debated. The prevalent explanation among researchers centers on the \"third window\" theory to explain conductive hearing loss in patients with enlarged vestibular aqueduct [27; 28]. Unlike the normal vestibular aqueduct's third window, the pathological third window created by EVA diverts acoustic energy away from the cochlea while enhancing bone conduction's compressional mechanism. This results in diminished air conduction hearing alongside improved bone conduction. Our findings revealed that ABG detection rates were considerably higher in IEVA patients compared to IP-II&EVA patients (69.90% vs. 53.33%, p = 0.019). This disparity may be attributed to the distinct cochlear structural characteristics observed in IP-II, which increases vulnerability to biomechanical forces [23; 30]. Genetic analysis of our 52 EVA patients revealed that 66.03% (34 patients) harbored mutations in known deafness-associated genes, consistent with findings by Archibald et al., who reported similar genetic variations in 64% of their cohort [ 31 ]. The remaining 34% (18 patients) showed no detectable mutations using conventional screening methods, suggesting potential involvement of yet-unidentified genetic factors. In our SLC26A4 mutation analysis, the 919-2A > G variant emerged as predominant, with heterozygous alterations frequently observed. Current genetic understanding indicates that EVA syndrome typically manifests through either homozygous or compound heterozygous SLC26A4 mutations [ 32 ]. The presence of apparently unaffected single heterozygous carriers suggests the existence of additional mutation sites or regulatory mechanisms that warrant further investigation. 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 [ 33 ]. Our investigation revealed a significantly higher prevalence of M2 mutations in IP-II & EVA patients compared to IEVA cases (55.56% vs. 16.28%, p = 0.022). This finding aligns with previous research correlating specific mutation patterns with hearing loss severity [19; 34]. Notably, patients carrying M2 mutations typically present with more limited residual hearing and more pronounced inner ear structural abnormalities. This correlation is further supported by Jane et al., who documented increased rates of CI among EVA patients with M2 mutations compared to those with M1 or no detected mutations [ 35 ]. EVA manifests through diverse clinical presentations, characterized by progressive or sudden-onset hearing deterioration. Although high-resolution CT and MRI enable definitive diagnosis, early detection in neonates remains challenging. Notably, affected infants may pass initial hearing screenings, with their auditory impairment remaining undetected without supplementary diagnostic modalities. Nong et al. documented ASNR in 80 of 653 cases with severe hearing impairment, suggesting its association with vestibular function [ 10 ]. Among our 52 patients with EVA, ASNR was detected in 27 patients (51.92%), and 34 patients (66.03%) carried known deafness-related gene mutations. Sixteen of these patients had both ASNR and deafness gene mutations, whereas seven patients had neither ASNR nor deafness gene mutations. Although the presence of ASNR and deafness gene screening is a good reference in the clinical diagnosis of EVA, it should not be used as the sole diagnostic criterion. A definitive EVA diagnosis necessitates an integrated approach incorporating genetic analysis, audiological evaluation, and complementary diagnostic methodologies. Conclusion This comprehensive study of pediatric EVA patients undergoing CI revealed distinct audiometric and genetic patterns. IEVA patients demonstrated lower hearing thresholds but higher ABG rates compared to IP-II & EVA cases. The SLC26A4 c.919-2A > G mutation emerged as predominant, with M2 mutations occurring more frequently in IP-II & EVA cases. ASNR detection rates were significantly elevated in both EVA groups compared to controls, supporting its potential diagnostic value. These findings enhance our understanding of genotype-phenotype correlations in EVA and may guide clinical management strategies for affected children. Abbreviations EVA Enlarged vestibular aqueduct IEVA Isolated enlarged vestibular aqueduct IP-II Incomplete partition type II IEMs Inner ear malformations ABG Air-bone gap ASNR Acoustically evoked short latency negative response CI cochlear implantation DPOAE Distortion product otoacoustic emission ABR Auditory brainstem response SNHL Sensorineural hearing loss CT Computed tomography MRI Magnetic resonance imaging SD Standard deviation ANOVA Analysis of variance. Declarations Acknowledgments We would like to thank all the patients for allowing us to review their medical findings and records. Author contribution R.-R.G. collected and analyzed data and approved the final version of this paper. W.Zh. analyzed data, and approved the final version of this paper. J.-W.S. designed this study, provided critical comments, and approved the final version of this paper. J.-Q. S analyzed data, and approved the final version of this paper. C.-Y.L. designed this study, analyzed data, and approved the final version of this paper. X.-T.G. designed this study, provided critical comments, and approved the final version of this paper. Funding This work was supported by the National Natural Science Foundation of China (Grants 82301299, 82471172, 82271180, 82471179, 82201278, and 82471162), the Excellent Young Scientists Fund of the Natural Science Foundation of China (Grant 82322020), and the National Key R&D Program of China (Grant 2023YFC2509800). Data availability No datasets were generated or analyzed during the current study. Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the local Ethics Committee (reference number: 2019-KY-60). Informed consent Informed consent was taken from the patients. Competing interests The authors have no conflicts of interest to disclose. 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Clin Endocrinol (Oxf) 52:279–285 Roesch S, Rasp G, Sarikas A, Dossena S (2021) Genetic Determinants of Non-Syndromic Enlarged Vestibular Aqueduct: A Review. Audiol Res 11:423–442 Rose J, Muskett JA, King KA, Zalewski CK, Chattaraj P, Butman JA, Kenna MA, Chien WW, Brewer CC, Griffith AJ (2017) Hearing loss associated with enlarged vestibular aqueduct and zero or one mutant allele of SLC26A4. Laryngoscope 127:E238–E243 Okamoto Y, Mutai H, Nakano A, Arimoto Y, Sugiuchi T, Masuda S, Morimoto N, Sakamoto H, Ogahara N, Takagi A, Taiji H, Kaga K, Ogawa K, Matsunaga T (2014) Subgroups of enlarged vestibular aqueduct in relation to SLC26A4 mutations and hearing loss. Laryngoscope 124:E134–140 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 04 Sep, 2025 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Revision requested 23 Jul, 2025 Reviews received at journal 18 Jul, 2025 Reviews received at journal 15 Jul, 2025 Reviewers agreed at journal 01 Jul, 2025 Reviewers agreed at journal 28 Jun, 2025 Reviewers agreed at journal 26 Jun, 2025 Reviewers invited by journal 26 Jun, 2025 Editor assigned by journal 25 Jun, 2025 Submission checks completed at journal 24 Jun, 2025 First submitted to journal 22 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-6948944\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":477833238,\"identity\":\"856c3bbd-e4a6-4ead-b704-c25f0b4b96f5\",\"order_by\":0,\"name\":\"Rui-rui Guan\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Rui-rui\",\"middleName\":\"\",\"lastName\":\"Guan\",\"suffix\":\"\"},{\"id\":477833239,\"identity\":\"10ba3633-73ac-4dd3-a0e7-2aa8a361c853\",\"order_by\":1,\"name\":\"Wan Zhao\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The First Affiliated Hospital of USTC, University of Science and Technology of China\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Wan\",\"middleName\":\"\",\"lastName\":\"Zhao\",\"suffix\":\"\"},{\"id\":477833240,\"identity\":\"84ec14f1-a54f-45c4-a201-c6f39d0ef339\",\"order_by\":2,\"name\":\"Jing-wu Sun\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The First Affiliated Hospital of USTC, University of Science and Technology of China\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jing-wu\",\"middleName\":\"\",\"lastName\":\"Sun\",\"suffix\":\"\"},{\"id\":477833243,\"identity\":\"c965df4a-8944-4595-a51d-e8f668673669\",\"order_by\":3,\"name\":\"Jia-qiang Sun\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The First Affiliated Hospital of USTC, University of Science and Technology of China\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jia-qiang\",\"middleName\":\"\",\"lastName\":\"Sun\",\"suffix\":\"\"},{\"id\":477833247,\"identity\":\"77b4ec13-6c3a-4af9-8ad7-1e8e7f241c55\",\"order_by\":4,\"name\":\"Chun-yan Li\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Chun-yan\",\"middleName\":\"\",\"lastName\":\"Li\",\"suffix\":\"\"},{\"id\":477833248,\"identity\":\"8b5766f7-5007-4cd1-94db-529e57fb27c8\",\"order_by\":5,\"name\":\"Xiao-tao Guo\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYHACxgcJBjZyQLrxAExIAr8OZmaDDwVpxkAtDQdgqglpYZOc8eFwYgOQSZwW+Yj8A9I8Bszpa9sPNxxgbKur429gPnibh8EuD5cWwzOHGYx5DNhyt51JBGk5LCFxgC3ZmochuRinlvZmhmQeA57cbQfAWg5IGDDwmEnzMBwAOxWrlmZmhsM8BhLpZucfgh0G1ML/Da8WefZmxsYZBgYJZjfAtjCDbGHDq8WA57AxwweDBMNtN4C2JJw7LDnjMJux5RyDZNy2zEh8/iPhz395s/PpDx98KKvj529vfnjjTYUdblsOIPMSQAQzWByHepAtuMwaBaNgFIyCUQAHAHgeV2cf3Gs7AAAAAElFTkSuQmCC\",\"orcid\":\"\",\"institution\":\"The First Affiliated Hospital of USTC, University of Science and Technology of China\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Xiao-tao\",\"middleName\":\"\",\"lastName\":\"Guo\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-06-22 10:23:13\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-6948944/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-6948944/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1007/s00431-025-06445-6\",\"type\":\"published\",\"date\":\"2025-09-04T15:57:57+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":85756068,\"identity\":\"2d2d2923-1cf0-434e-8472-0c0264393446\",\"added_by\":\"auto\",\"created_at\":\"2025-07-01 10:47:10\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":351484,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eHigh-resolution computed tomography (CT) of two patients. IEVA, isolated enlarged vestibular aqueduct; IP-II \\u0026amp; EVA, incomplete partition type II with enlarged vestibular aqueduct.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Fig.1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6948944/v1/df4d6722a69f6ff4e5c3a99a.png\"},{\"id\":85757398,\"identity\":\"4ab4f62b-46d9-4246-bceb-5c0720db4741\",\"added_by\":\"auto\",\"created_at\":\"2025-07-01 10:55:10\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":82686,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e(A) The PTA of children in different inner ear structures.\\u003cstrong\\u003e \\u003c/strong\\u003e(B)\\u003cstrong\\u003e \\u003c/strong\\u003eThe ABG detection rate in IEVA/IP-II \\u0026amp; EVA cases. IEVA, isolated enlarged vestibular aqueduct; IP-II \\u0026amp; EVA, incomplete partition type II with enlarged vestibular aqueduct; IEMs, inner ear malformations.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Fig.2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6948944/v1/a9a125ad6ee9c11b4a473e28.png\"},{\"id\":85756066,\"identity\":\"789ad84b-8702-4977-b6c1-7088264bad27\",\"added_by\":\"auto\",\"created_at\":\"2025-07-01 10:47:10\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":87963,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e(A) A characteristic ASNR was observed in a patient diagnosed with EVA. (B) Absence of the ASNR in a patient without IEMs. (C) Percentage of ears with an ASNR in different inner ear structures. ***\\u003cem\\u003ep\\u003c/em\\u003e \\u0026lt; 0. 001. IEVA, isolated enlarged vestibular aqueduct; IP-II \\u0026amp; EVA, incomplete partition type II with enlarged vestibular aqueduct; IEMs, inner ear malformations.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Fig.3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6948944/v1/84725a77816466f6d679939c.png\"},{\"id\":85759226,\"identity\":\"074b7dad-6d3f-4f4e-b9b4-df2bd63ba68a\",\"added_by\":\"auto\",\"created_at\":\"2025-07-01 11:11:10\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":74561,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eThe number of \\u003cem\\u003eSLC26A4\\u003c/em\\u003emutations in IEVA/IP-II \\u0026amp; EVA cases. M2, biallelic \\u003cem\\u003eSLC26A4\\u003c/em\\u003e mutations; M1, monoallelic \\u003cem\\u003eSLC26A4\\u003c/em\\u003emutation. IEVA, isolated enlarged vestibular aqueduct; IP-II \\u0026amp; EVA, incomplete partition type II with enlarged vestibular aqueduct.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Fig.4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6948944/v1/401c53a6a5efadd603c76d54.png\"},{\"id\":90828123,\"identity\":\"15c35ce1-b9dd-4093-b391-d0661a935f55\",\"added_by\":\"auto\",\"created_at\":\"2025-09-08 16:05:54\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1301865,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6948944/v1/9816027d-3026-4a4b-be56-df251f0373b7.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Genetic Variants and Audiometric Patterns in Nonsyndromic Enlarged Vestibular Aqueduct Chinese Children with Complete Hearing Loss\",\"fulltext\":[{\"header\":\"What Is Known\",\"content\":\"\\u003cp\\u003e\\u0026bull; The genetic and clinical characteristics of patients with enlarged vestibular aqueduct (EVA) have been studied. However, its manifestations in completely deaf children in China, especially those with or without incomplete partition type II (IP-II), are not yet fully understood.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eWhat is New:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026bull; Isolated enlarged vestibular aqueduct (IEVA) patients demonstrated lower hearing thresholds but higher air-bone gap (ABG) rates compared to IP-II with EVA (IP-II \\u0026amp; EVA) cases. The \\u003cem\\u003eSLC26A4\\u003c/em\\u003e c.919-2A\\u0026gt;G mutation emerged as predominant, with biallelic mutations occurring more frequently in IP-II \\u0026amp; EVA cases. These findings may guide clinical management strategies for affected children.\\u003c/p\\u003e\"},{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eEnlarged vestibular aqueduct (EVA) is one of the most common inner ear malformations (IEMs) and can be detected by temporal bone computed tomography (CT) and/or magnetic resonance imaging (MRI) [\\u003cspan additionalcitationids=\\\"CR2 CR3\\\" citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. EVA patients present with heterogeneous phenotypes, predominantly characterized by progressive, fluctuating hearing loss [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. Valvassori and Clemis first established the association between EVA and hearing deficits in their landmark 1978 retrospective analysis of 50 patients with bilateral hearing impairment[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. While sensorineural hearing loss (SNHL) is predominant in pediatric EVA cases, audiometric assessments frequently reveal substantial air-bone gap (ABG), even with normal middle ear function [\\u003cspan additionalcitationids=\\\"CR7\\\" citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]. In 1979, Cazals and colleagues identified a distinctive negative deflection approximately 3 ms post-stimulus during auditory brainstem response (ABR) testing in EVA patients with severe-to-profound hearing loss [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. This response pattern, subsequently termed the acoustically evoked short latency negative response (ASNR) by Nong et al., exhibits significantly higher prevalence in EVA compared to other inner ear malformations or normal anatomy [\\u003cspan additionalcitationids=\\\"CR11\\\" citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eMolecular genetic studies have identified mutations in \\u003cem\\u003eSLC26A4\\u003c/em\\u003e as a primary genetic determinant of vestibular aqueduct abnormalities, contributing to both Pendred syndrome (PS) and nonsyndromic sensorineural deafness autosomal recessive type (DFNB4) [\\u003cspan additionalcitationids=\\\"CR14\\\" citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. Despite its autosomal recessive inheritance pattern, the number of identifiable mutant alleles shows considerable variation. The distribution of pathogenic \\u003cem\\u003eSLC26A4\\u003c/em\\u003e mutations demonstrates distinct ethnic patterns: p.L236P, p.T416P, and c.1001\\u0026thinsp;+\\u0026thinsp;1G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A mutations predominate in Caucasian populations, and p.H723R is prevalent in Japanese and Korean populations [\\u003cspan additionalcitationids=\\\"CR17\\\" citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. \\u003cem\\u003eSLC26A4\\u003c/em\\u003e mutation detection rates vary among ethnic groups, with Korean studies indicating that hearing phenotypes correlate more strongly with mutation type than quantity in bilateral EVA patients [\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e]. Studies in Caucasian populations have shown that approximately 25% of subjects carry bilateral mutations, while 75% exhibit either no mutations or single-allele variants [\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eCarol Mondini first reported a case of congenital deafness, where the cochlea had only 1.5 turns and the absence of the internal partition in the cochlea led to the fusion of the middle and apical turns [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. Later, with the development of imaging diagnostic techniques and the precise classification of IEMs, Sennaroglu classified it as incomplete partition type II (IP-II)[\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. It has been reported that 7.5\\u0026ndash;34.7% of EVA patients have IP-II [22; 23]. A multicenter international study showed that 84.6% of IP-II patients had EVA[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. Some scholars have studied and pointed out that the number of \\u003cem\\u003eSLC26A4\\u003c/em\\u003e mutations in patients with EVA is significantly correlated with IP-II \\u0026amp; EVA [24; 25]. However, other articles have indicated that whether or not IP-II is present does not have a significant impact on hearing loss in patients with EVA [\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]. Given the relationship between hearing impairment severity and ASNR expression in EVA patients [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e], this study focuses on cochlear implant recipients with complete hearing loss. We aim to elucidate the clinical characteristics of nonsyndromic EVA patients with complete hearing loss, with particular emphasis on with or without IP-II.\\u003c/p\\u003e\"},{\"header\":\"Materials and methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eParticipants\\u003c/h2\\u003e \\u003cp\\u003e This study was conducted with approval from the Ethics Committee of Anhui Provincial Hospital. Written informed consent was obtained from all participants or their legal guardians prior to enrollment. The study cohort comprised 123 children (67 males, mean age\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;standard deviation (SD): 9.97\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.42 years; age range: 6\\u0026ndash;17 years) diagnosed with bilateral EVA who underwent cochlear implantation (CI) between January 2019 and October 2023 (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). A control group of 30 age-, sex-, and hearing status-matched subjects without inner ear malformations (IEMs) was established for comparison. Based on the updated Sennaroglu classification system [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e], participants were stratified into three groups:\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eIEVA (isolated enlarged vestibular aqueduct; n\\u0026thinsp;=\\u0026thinsp;93)\\u003c/p\\u003e \\u003cp\\u003eIP-II \\u0026amp; EVA (incomplete partition type II with EVA; n\\u0026thinsp;=\\u0026thinsp;30)\\u003c/p\\u003e \\u003cp\\u003eControl group without IEMs (n\\u0026thinsp;=\\u0026thinsp;30)\\u003c/p\\u003e \\u003cp\\u003eInclusion criteria: Confirmed bilateral complete hearing loss: pure-tone average (PTA)\\u0026thinsp;\\u0026gt;\\u0026thinsp;95 dB HL; compliance with required audiological assessments. Exclusion criteria: Presence of thyroid pathologies; presence of concurrent deafness-associated syndromes; non-compliance with the evaluation of audiology and genetic screening. Detailed clinical characteristics of all participants are presented in Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eDemographic information of patients with IEVA, IP-II \\u0026amp; EVA and without IEMs.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"6\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eVariable\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eIEVA\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003eIP-II \\u0026amp; EVA\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eWithout IEMs\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eN\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e93\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e30\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e30\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eSex (F/M, N)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e43/50\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e13/17\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e14/16\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAge at test (mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD, years)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c4\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e9.96\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.15\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e10.03\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;3.16\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e9.23\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.79\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePTA (mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD, dB HL)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c4\\\" namest=\\\"c2\\\"\\u003e \\u003cp\\u003e101.41\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;11.36\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e103.50\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;18.48\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e107.08\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.59\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eOnset of deafness (prelingual/postlingual, N)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e65/28\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c5\\\" namest=\\\"c4\\\"\\u003e \\u003cp\\u003e22/8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e20/10\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eIEVA, isolated enlarged vestibular aqueduct; EVA, enlarged vestibular aqueduct; IEMs, inner ear malformations; F, female; M, male; SD, standard deviation; PTA, pure-tone average.\\u003c/p\\u003e \\u003cp\\u003eThe preoperative evaluation protocol included comprehensive audiometric testing, consisting of distortion product otoacoustic emission (DPOAE), tympanometry, ABR, and pure tone audiometry. Additionally, genetic screening for deafness-associated variants was performed in 52 of the 123 children with EVA.\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eAudiologic Evaluation\\u003c/h3\\u003e\\n\\u003cp\\u003eAll the subjects were tested for tympanometry via the Titan IMP440 middle ear impedance device (Interacoustics, Denmark, Version 3.4). According to the classification of Jerger, all the patients had type A tympanograms for tympanometry at 226 Hz. DPOAE testing was conducted via Capella equipment (GN Otometrics, Denmark). The DPOAE results of all patients did not pass. The audiometry instrument used was the Madsen Audiometer (Conera, GN Otometrics Inc., Denmark). Audiometric data collected included air conduction thresholds and bone conduction thresholds at 0.25, 0.5, 1, 2, and 4 kHz for both ears. An ABG was defined at each frequency as an air conduction threshold 15 dB higher than the bone conduction threshold from 0.25 to 4 kHz. When the ABG was \\u0026gt;\\u0026thinsp;15 dB at least at the three tested frequencies (0.25, 0.5, and 1 kHz), the patient was classified as having an ABG (EVA with ABG) [27; 28]. Pure tone average (PTA) was calculated as the average of air conduction thresholds at 0.5, 1, 2, and 4 kHz for both ears. The absence of a response at the maximum intensity was recorded as the 120 dB HL threshold.\\u003c/p\\u003e \\u003cp\\u003eABR assessments were conducted via ICS Chart EP equipment (GN Otometrics, Denmark) in a soundproof chamber. Testing was performed under sedation with chloral hydrate. The recording electrode, ground electrode, and reference electrode were placed in the middle of the forehead, the base of the nose, and the left/right mastoid processes, respectively. Electrode impedance was maintained below 5 kΩ. ABR testing employed ER-3A insert earphones delivering alternating clicks, beginning at 95 dB nHL with 10 dB decremental steps. The identification criteria for the acoustically evoked short latency negative response (ASNR) in the ABR included the following: [\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e]\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003eThe peak should be reproducible.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eThe peak should appear 3\\u0026ndash;5 ms after the onset of stimulation.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eThe onset-to-peak amplitude (with onset defined as the starting point of the deflection toward the negative peak) should be more than 0.05 mV.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eIf there were two or more acoustically evoked, short-latency negative responses, we regarded the largest peak as the definitive response.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eThe peak became absent after external auditory canal occlusion.\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e\\n\\u003ch3\\u003eGenetic analysis\\u003c/h3\\u003e\\n\\u003cp\\u003ePrior to genetic testing, we obtained informed consent from all adult participants and from parents/legal guardians of minor participants after thoroughly explaining the purpose and implications of deafness gene screening. Peripheral venous blood samples (3\\u0026ndash;5 mL) were collected from each participant. Using the Crystal Core platform (Beijing Boao Biological Group Co., Ltd.), we performed microarray analysis to detect nine common pathogenic variants across four deafness-associated genes: \\u003cem\\u003eGJB2\\u003c/em\\u003e (35delG, 176del16, 235delC, 299delAT), \\u003cem\\u003eGJB3\\u003c/em\\u003e (538C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T), \\u003cem\\u003eSLC26A4\\u003c/em\\u003e (2168A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G, 919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G), and \\u003cem\\u003emtDNA 12SrRNA\\u003c/em\\u003e (1494 C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T, 1555A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G).\\u003c/p\\u003e\\n\\u003ch3\\u003eStatistical data analysis\\u003c/h3\\u003e\\n\\u003cp\\u003eWe used the SPSS software package (version 17.0 for Windows; SPSS Inc., Chicago, IL, USA) to analyze the data. The analysis of variance (ANOVA) was used to analyze the PTA data. In this study, PTA was calculated as the average of air conduction thresholds at 0.5, 1, 2, and 4 kHz for each ear. The Bonferroni test was used in post hoc analysis when significant main effects or interactions were achieved. A chi-Square test was employed to assess the differences between variables (ABG detection rate rates between IEVA ears and IP-II \\u0026amp; EVA ears, ASNR detection rates with different inner ear structures, and biallelic/monoallelic \\u003cem\\u003eSLC26A4\\u003c/em\\u003e mutations between IEVA patients and IP-II \\u0026amp; EVA patients), with statistical significance set at \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eAudiometric Results in Ears with IEVA/ IP-II \\u0026amp; EVA\\u003c/h2\\u003e \\u003cp\\u003ePure-tone audiometry revealed hearing thresholds of 110.36\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.29 dB HL in ears without IEMs, 105.00\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;5.22 dB HL in the IEVA group, and 107.08\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;6.59 dB HL in the IP-II with EVA group. Statistical analysis demonstrated significantly higher PTA in ears without IEMs compared to those with IEVA (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.013).\\u003c/p\\u003e \\u003cp\\u003eAir-bone gap (ABG) was detected in 130 of 186 ears (69.90%) in the IEVA group and 32 of 60 ears (53.33%) in the IP-II \\u0026amp; EVA group. The ABG detection rate was significantly higher in IEVA cases compared to IP-II \\u0026amp; EVA cases (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.019) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eABR testing revealed ASNR in 124 of 186 ears (66.67%) with IEVA, 38 of 60 ears (63.33%) with IP-II \\u0026amp; EVA, and 5 of 60 ears (8.33%) without IEMs. Both the IEVA and IP-II \\u0026amp; EVA groups demonstrated significantly higher ASNR detection rates compared to the non-IEM group (66.67% vs. 8.33%, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001; 63.33% vs. 8.33%, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001, respectively) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eCommon Mutations in Deafness-Associated Genes in Patients with IEVA/ IP-II \\u0026 EVA\\u003c/h3\\u003e\\n\\u003cp\\u003eAmong 123 patients, genetic screening was performed in 52 cases (43 IEVA and 9 IP-II \\u0026amp; EVA) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Pathogenic variants were identified in 34 patients (66.03%), comprising homozygous \\u003cem\\u003eSLC26A4\\u003c/em\\u003e c.919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G mutations (n\\u0026thinsp;=\\u0026thinsp;8, 15.09%), heterozygous \\u003cem\\u003eSLC26A4\\u003c/em\\u003e c.919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G mutations (n\\u0026thinsp;=\\u0026thinsp;17, 32.08%), heterozygous \\u003cem\\u003eSLC26A4\\u003c/em\\u003e c.2168A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G mutations (n\\u0026thinsp;=\\u0026thinsp;3, 5.67%), compound heterozygous \\u003cem\\u003eSLC26A4\\u003c/em\\u003e c.2168A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G/c.919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G mutations (n\\u0026thinsp;=\\u0026thinsp;1), and digenic \\u003cem\\u003eGJB2\\u003c/em\\u003e c.235delC/\\u003cem\\u003eSLC26A4\\u003c/em\\u003e c.919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G mutations (n\\u0026thinsp;=\\u0026thinsp;5, 9.43%). No pathogenic variants were detected in 18 cases using the employed screening methods. In the cohort of 52 EVA patients, ASNR was detected in 27 cases (51.92%). Among these, 16 patients (59.25%) carried pathogenic variants. The remaining eleven ASNR-positive patients showed no detectable pathogenic variants using the current screening methodology.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eCommon mutations of deafness genes in 52 patients with IEVA/ IP-II \\u0026amp; EVA.\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGene\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNucleotide change\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eIEVA (N)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eIP-II\\u0026amp;EVA (N)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eTotal (N, %)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eSLC26A4, total\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e29(55.77%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHomozygous\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e8\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHeterozygous\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.2168A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e14\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e17\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDouble heterozygous\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G/ c.2168A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eGJB2\\u0026amp; SLC26A4, total\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e5 (9.62%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHeterozygous\\u0026amp; Homozygous\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.235delC/ c.919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHeterozygous\\u0026amp; Heterozygous\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ec.235delC/ c.919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eIn total\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e26/43\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e8/9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e34/52(65.38%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eIn the IEVA cohort (n\\u0026thinsp;=\\u0026thinsp;43), 26 patients harbored pathogenic variants: seven with biallelic \\u003cem\\u003eSLC26A4\\u003c/em\\u003e mutations (M2) and nineteen with monoallelic \\u003cem\\u003eSLC26A4\\u003c/em\\u003e mutations (M1). In the IP-II \\u0026amp; EVA cohort (n\\u0026thinsp;=\\u0026thinsp;9), eight patients carried pathogenic variants: five with M2 and three with M1. The proportion of M2 mutations was significantly higher in IP-II \\u0026amp; EVA patients compared to IEVA patients (55.56% vs. 16.28%, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.022). Conversely, M1 mutations were more frequent in IEVA patients than in IP-II \\u0026amp; EVA patients, though this difference was not statistically significant (44.19% vs. 33.33%, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.717) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eEVA is a significant congenital anomaly of the inner ear, characterized by an expanded vestibular aqueduct and associated sensorineural or mixed hearing loss. The condition accounts for approximately 1\\u0026ndash;8% of SNHL cases [2; 3]. EVA demonstrates a strong genetic association with mutations in the \\u003cem\\u003eSLC26A4\\u003c/em\\u003e gene, which encodes the anion transport protein pendrin\\u0026mdash;a critical mediator of endolymphatic fluid homeostasis. These \\u003cem\\u003eSLC26A4\\u003c/em\\u003e mutations can manifest in two distinct phenotypes: the non-syndromic form DFNB4 and PS, both following an autosomal recessive inheritance pattern [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]. IP-II was originally described by Carlo Mondini, and together with a minimally dilated vestibule as well as EVA, constitutes the Mondini deformity [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. Our clinical investigation of 123 EVA patients revealed that 24.3% (30/123) exhibited concurrent IP-II, which is consistent with the findings of previous studies [22; 23].\\u003c/p\\u003e \\u003cp\\u003eOur study indicated that ears affected by IEVA demonstrate superior hearing capabilities compared to those lacking IEMs, while no notable hearing differences exist between no IEMs ears and those with IP-II \\u0026amp; EVA. Research has documented that individuals with IP-II typically experience earlier onset of hearing deterioration, whereas those presenting with isolated vestibular aqueduct enlargement show a more gradual progression of hearing loss. Biomechanical analysis suggests that the cochlea's spiral configuration provides resistance against internal fluid dynamics. The reduced number of cochlear turns in IP-II results in heightened susceptibility to biomechanical stress, consequently leading to more pronounced hearing impairment. The syndrome of EVA typically manifests as sensorineural or mixed hearing loss. Various researchers have documented air-bone gap (ABG) occurrence at lower frequencies in 15\\u0026ndash;100% of EVA cases [7; 8; 27; 28]. Our research revealed that ABG was present in more than half of the examined ears across both the IEVA and IP-II\\u0026amp;EVA groups. The underlying mechanism responsible for ABG development in EVA syndrome continues to be debated. The prevalent explanation among researchers centers on the \\\"third window\\\" theory to explain conductive hearing loss in patients with enlarged vestibular aqueduct [27; 28]. Unlike the normal vestibular aqueduct's third window, the pathological third window created by EVA diverts acoustic energy away from the cochlea while enhancing bone conduction's compressional mechanism. This results in diminished air conduction hearing alongside improved bone conduction. Our findings revealed that ABG detection rates were considerably higher in IEVA patients compared to IP-II\\u0026amp;EVA patients (69.90% vs. 53.33%, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.019). This disparity may be attributed to the distinct cochlear structural characteristics observed in IP-II, which increases vulnerability to biomechanical forces [23; 30].\\u003c/p\\u003e \\u003cp\\u003eGenetic analysis of our 52 EVA patients revealed that 66.03% (34 patients) harbored mutations in known deafness-associated genes, consistent with findings by Archibald et al., who reported similar genetic variations in 64% of their cohort [\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e]. The remaining 34% (18 patients) showed no detectable mutations using conventional screening methods, suggesting potential involvement of yet-unidentified genetic factors. In our \\u003cem\\u003eSLC26A4\\u003c/em\\u003e mutation analysis, the 919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G variant emerged as predominant, with heterozygous alterations frequently observed. Current genetic understanding indicates that EVA syndrome typically manifests through either homozygous or compound heterozygous \\u003cem\\u003eSLC26A4\\u003c/em\\u003e mutations [\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e]. The presence of apparently unaffected single heterozygous carriers suggests the existence of additional mutation sites or regulatory mechanisms that warrant further investigation. Genes that have been linked to non-syndromic EVA are \\u003cem\\u003eSLC26A4\\u003c/em\\u003e, \\u003cem\\u003eGJB2\\u003c/em\\u003e, \\u003cem\\u003eFOXI1\\u003c/em\\u003e, \\u003cem\\u003eKCNJ10\\u003c/em\\u003e, and \\u003cem\\u003ePOU3F4\\u003c/em\\u003e. \\u003cem\\u003eSLC26A4\\u003c/em\\u003e and \\u003cem\\u003eFOXI1\\u003c/em\\u003e are also involved in determining syndromic forms of hearing loss with EVA [\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e]. Our investigation revealed a significantly higher prevalence of M2 mutations in IP-II \\u0026amp; EVA patients compared to IEVA cases (55.56% vs. 16.28%, \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.022). This finding aligns with previous research correlating specific mutation patterns with hearing loss severity [19; 34]. Notably, patients carrying M2 mutations typically present with more limited residual hearing and more pronounced inner ear structural abnormalities. This correlation is further supported by Jane et al., who documented increased rates of CI among EVA patients with M2 mutations compared to those with M1 or no detected mutations [\\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eEVA manifests through diverse clinical presentations, characterized by progressive or sudden-onset hearing deterioration. Although high-resolution CT and MRI enable definitive diagnosis, early detection in neonates remains challenging. Notably, affected infants may pass initial hearing screenings, with their auditory impairment remaining undetected without supplementary diagnostic modalities. Nong et al. documented ASNR in 80 of 653 cases with severe hearing impairment, suggesting its association with vestibular function [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]. Among our 52 patients with EVA, ASNR was detected in 27 patients (51.92%), and 34 patients (66.03%) carried known deafness-related gene mutations. Sixteen of these patients had both ASNR and deafness gene mutations, whereas seven patients had neither ASNR nor deafness gene mutations. Although the presence of ASNR and deafness gene screening is a good reference in the clinical diagnosis of EVA, it should not be used as the sole diagnostic criterion. A definitive EVA diagnosis necessitates an integrated approach incorporating genetic analysis, audiological evaluation, and complementary diagnostic methodologies.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eThis comprehensive study of pediatric EVA patients undergoing CI revealed distinct audiometric and genetic patterns. IEVA patients demonstrated lower hearing thresholds but higher ABG rates compared to IP-II \\u0026amp; EVA cases. The \\u003cem\\u003eSLC26A4\\u003c/em\\u003e c.919-2A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G mutation emerged as predominant, with M2 mutations occurring more frequently in IP-II \\u0026amp; EVA cases. ASNR detection rates were significantly elevated in both EVA groups compared to controls, supporting its potential diagnostic value. These findings enhance our understanding of genotype-phenotype correlations in EVA and may guide clinical management strategies for affected children.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eEVA Enlarged vestibular aqueduct\\u003c/p\\u003e\\u003cp\\u003eIEVA Isolated enlarged vestibular aqueduct\\u003c/p\\u003e\\u003cp\\u003eIP-II Incomplete partition type II\\u003c/p\\u003e\\u003cp\\u003eIEMs Inner ear malformations\\u003c/p\\u003e\\u003cp\\u003eABG Air-bone gap\\u003c/p\\u003e\\u003cp\\u003eASNR Acoustically evoked short latency negative response\\u003c/p\\u003e\\u003cp\\u003eCI cochlear implantation\\u003c/p\\u003e\\u003cp\\u003eDPOAE Distortion product otoacoustic emission\\u003c/p\\u003e\\u003cp\\u003eABR Auditory brainstem response\\u003c/p\\u003e\\u003cp\\u003eSNHL Sensorineural hearing loss\\u003c/p\\u003e\\u003cp\\u003eCT Computed tomography\\u003c/p\\u003e\\u003cp\\u003eMRI Magnetic resonance imaging\\u003c/p\\u003e\\u003cp\\u003eSD Standard deviation\\u003c/p\\u003e\\u003cp\\u003eANOVA Analysis of variance.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments\\u003c/strong\\u003e We would like to thank all the patients for allowing us to review their medical findings and records.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contribution\\u003c/strong\\u003e R.-R.G. collected and analyzed data and approved the final version of this paper. W.Zh. analyzed data, and approved the final version of this paper. J.-W.S. designed this study, provided critical comments, and approved the final version of this paper. J.-Q. S analyzed data, and approved the final version of this paper. C.-Y.L. designed this study, analyzed data, and approved the final version of this paper. X.-T.G. designed this study, provided critical comments, and approved the final version of this paper.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e This work was supported by the National Natural Science Foundation of China (Grants 82301299, 82471172, 82271180, 82471179, 82201278, and 82471162), the Excellent Young Scientists Fund of the Natural Science Foundation of China (Grant 82322020), and the National Key R\\u0026amp;D Program of China (Grant 2023YFC2509800).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData availability\\u003c/strong\\u003e No datasets were generated or analyzed during the current study.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval\\u003c/strong\\u003e This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the local Ethics Committee (reference number: 2019-KY-60).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eInformed consent\\u003c/strong\\u003e Informed consent was taken from the patients.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e The authors have no conflicts of interest to disclose.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eValvassori GE, Clemis JD (1978) The large vestibular aqueduct syndrome. Laryngoscope 88:723\\u0026ndash;728\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eJackler RK, De La Cruz A (1989) The large vestibular aqueduct syndrome. Laryngoscope 99:1238\\u0026ndash;1242 discussion 1242\\u0026thinsp;\\u0026ndash;\\u0026thinsp;1233\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLevenson MJ, Parisier SC, Jacobs M, Edelstein DR (1989) The large vestibular aqueduct syndrome in children. A review of 12 cases and the description of a new clinical entity. Arch Otolaryngol Head Neck Surg 115:54\\u0026ndash;58\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSennaroglu L, Bajin MD (2017) Classification and Current Management of Inner Ear Malformations. Balkan Med J 34:397\\u0026ndash;411\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMadden C, Halsted M, Benton C, Greinwald J, Choo D (2003) Enlarged vestibular aqueduct syndrome in the pediatric population. Otol Neurotol 24:625\\u0026ndash;632\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eZhou G, Gopen Q, Kenna MA (2008) Delineating the hearing loss in children with enlarged vestibular aqueduct. Laryngoscope 118:2062\\u0026ndash;2066\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMerchant SN, Nakajima HH, Halpin C, Nadol JB Jr., Lee DJ, Innis WP, Curtin H, Rosowski JJ (2007) Clinical investigation and mechanism of air-bone gaps in large vestibular aqueduct syndrome. Ann Otol Rhinol Laryngol 116:532\\u0026ndash;541\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMimura T, Sato E, Sugiura M, Yoshino T, Naganawa S, Nakashima T (2005) Hearing loss in patients with enlarged vestibular aqueduct: air-bone gap and audiological Bing test. Int J Audiol 44:466\\u0026ndash;469\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCazals Y, Aran JM, Erre JP, Guilhaume A, Hawkins JE Jr. (1979) Neural responses to acoustic stimulation after destruction of cochlear hair cells. Arch Otorhinolaryngol 224:61\\u0026ndash;70\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNong DX, Ura M, Owa T, Noda Y (2000) An acoustically evoked short latency negative response in profound hearing loss patients. Acta Otolaryngol 120:960\\u0026ndash;966\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLiu L, Yang B (2013) Acoustically evoked short latency negative responses in hearing loss patients with enlarged vestibular aqueduct. Acta Neurol Belg 113:157\\u0026ndash;160\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eChen J, Chen Y, Zhang Q, Ma X, Mei L, Wang W, Shen J, Zhang Q, Wang L, Shen M, He K, Chen X, Yang J (2020) Grades of hearing loss affect the presence of acoustically evoked short latency negative responses in children with large vestibular aqueduct syndrome. Int J Pediatr Otorhinolaryngol 138:110159\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eEverett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E, Nassir E, Baxevanis AD, Sheffield VC, Green ED (1997) Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 17:411\\u0026ndash;422\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eUsami S, Abe S, Weston MD, Shinkawa H, Van Camp G, Kimberling WJ (1999) Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations. Hum Genet 104:188\\u0026ndash;192\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eD'Arco F, Kandemirli SG, Dahmoush HM, Alves C, Severino M, Dellepiane F, Robson CD, Lequin MH, Rossi-Espagnet C, O'Brien WT, Nash R, Clement E, Juliano AF (2024) Incomplete partition type II in its various manifestations: isolated, in association with EVA, syndromic, and beyond; a multicentre international study. Neuroradiology 66:1397\\u0026ndash;1403\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCampbell C, Cucci RA, Prasad S, Green GE, Edeal JB, Galer CE, Karniski LP, Sheffield VC, Smith RJ (2001) Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations. Hum Mutat 17:403\\u0026ndash;411\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eTsukamoto K, Suzuki H, Harada D, Namba A, Abe S, Usami S (2003) Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese. Eur J Hum Genet 11:916\\u0026ndash;922\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePark HJ, Lee SJ, Jin HS, Lee JO, Go SH, Jang HS, Moon SK, Lee SC, Chun YM, Lee HK, Choi JY, Jung SC, Griffith AJ, Koo SK (2005) Genetic basis of hearing loss associated with enlarged vestibular aqueducts in Koreans. Clin Genet 67:160\\u0026ndash;165\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRah YC, Kim AR, Koo JW, Lee JH, Oh SH, Choi BY (2015) Audiologic presentation of enlargement of the vestibular aqueduct according to the SLC26A4 genotypes. Laryngoscope 125:E216\\u0026ndash;222\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAlbert S, Blons H, Jonard L, Feldmann D, Chauvin P, Loundon N, Sergent-Allaoui A et al (2006) SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations. Eur J Hum Genet 14:773\\u0026ndash;779\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMondini C (1997) Minor works of Carlo Mondini: the anatomical section of a boy born deaf. Am J Otol 18:288\\u0026ndash;293\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRuthberg J, Ascha MS, Kocharyan A, Gupta A, Murray GS, Megerian CA, Otteson TD (2019) Sex-specific enlarged vestibular aqueduct morphology and audiometry. Am J Otolaryngol 40:473\\u0026ndash;477\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHan JW, Wang L, Zhao H, Yang SM (2020) Biomechanical analysis of the clinical characteristics of enlarged vestibular aqueduct syndrome with Mondini malformation. Acta Otolaryngol 140:813\\u0026ndash;817\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHuang S, Han D, Yuan Y, Wang G, Kang D, Zhang X, Yan X, Meng X, Dong M, Dai P (2011) Extremely discrepant mutation spectrum of SLC26A4 between Chinese patients with isolated Mondini deformity and enlarged vestibular aqueduct. J Transl Med 9:167\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMey K, Muhamad AA, Tranebj\\u0026aelig;rg L, Rendtorff ND, Rasmussen SH, Bille M, Cay\\u0026eacute;-Thomasen P (2019) Association of SLC26A4 mutations, morphology, and hearing in pendred syndrome and NSEVA. Laryngoscope 129:2574\\u0026ndash;2579\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAhadizadeh E, Ascha M, Manzoor N, Gupta A, Semaan M, Megerian C, Otteson T (2017) Hearing loss in enlarged vestibular aqueduct and incomplete partition type II. Am J Otolaryngol 38:692\\u0026ndash;697\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSeo YJ, Kim J, Choi JY (2016) Correlation of vestibular aqueduct size with air-bone gap in enlarged vestibular aqueduct syndrome. Laryngoscope 126:1633\\u0026ndash;1638\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eVan Beck J, Chinnadurai S, Morrison AK, Zuniga MG, Smith B, Lohse CM, McCaslin D (2020) Correlation of air-bone gap and size of Enlarged Vestibular Aqueduct in children. Int J Pediatr Otorhinolaryngol 132\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eEmara AA (2010) Acoustically evoked, short latency negative response in children with sensorineural hearing loss. J Laryngol Otol 124:141\\u0026ndash;146\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWang R, Zhuang BX, Guo W, Li J, Lin C, Yang S (2024) Study of the factors related to air-bone gap in enlarged vestibular aqueduct. Acta Otolaryngol 144:39\\u0026ndash;43\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eArchibald HD, Ascha M, Gupta A, Megerian C, Otteson T (2019) Hearing loss in unilateral and bilateral enlarged vestibular aqueduct syndrome. Int J Pediatr Otorhinolaryngol 118:147\\u0026ndash;151\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBogazzi F, Raggi F, Ultimieri F, Campomori A, Cosci C, Berrettini S, Neri E, La Rocca R, Ronca G, Martino E, Bartalena L (2000) A novel mutation in the pendrin gene associated with Pendred's syndrome. Clin Endocrinol (Oxf) 52:279\\u0026ndash;285\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRoesch S, Rasp G, Sarikas A, Dossena S (2021) Genetic Determinants of Non-Syndromic Enlarged Vestibular Aqueduct: A Review. Audiol Res 11:423\\u0026ndash;442\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRose J, Muskett JA, King KA, Zalewski CK, Chattaraj P, Butman JA, Kenna MA, Chien WW, Brewer CC, Griffith AJ (2017) Hearing loss associated with enlarged vestibular aqueduct and zero or one mutant allele of SLC26A4. Laryngoscope 127:E238\\u0026ndash;E243\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eOkamoto Y, Mutai H, Nakano A, Arimoto Y, Sugiuchi T, Masuda S, Morimoto N, Sakamoto H, Ogahara N, Takagi A, Taiji H, Kaga K, Ogawa K, Matsunaga T (2014) Subgroups of enlarged vestibular aqueduct in relation to SLC26A4 mutations and hearing loss. Laryngoscope 124:E134\\u0026ndash;140\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"european-journal-of-pediatrics\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"ejpe\",\"sideBox\":\"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)\",\"snPcode\":\"431\",\"submissionUrl\":\"https://submission.nature.com/new-submission/431/3\",\"title\":\"European Journal of Pediatrics\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"Enlarged vestibular aqueduct, incomplete partition type II, genetic screening, audiology, complete hearing loss\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-6948944/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-6948944/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eEnlarged vestibular aqueduct (EVA) is one of the most common inner ear malformations (IEMs) leading to hearing loss in children. Although its genetic and clinical characteristics have been studied, its manifestations in completely deaf children in China, especially those with or without incomplete partition type II (IP-II), are not yet fully understood. We conducted a comprehensive analysis of 123 pediatric EVA children with complete hearing loss. Participants were classified into isolated EVA (IEVA, n=93) and IP-II with EVA (IP-II \\u0026amp; EVA, n=30) groups, with 30 age-, sex-, and hearing status-matched subjects without IEMs. Evaluations included audiologic tests and genetic screening for common deafness-associated variants. Pure tone audiometry revealed significantly lower hearing thresholds in IEVA ears compared to those without IEMs (\\u003cem\\u003ep \\u003c/em\\u003e= 0.004). Air-bone gap (ABG) was more prevalent in IEVA than IP-II \\u0026amp; EVA cases (\\u003cem\\u003ep\\u003c/em\\u003e = 0.019). Acoustically evoked short latency negative response (ASNR) was detected in 66.67% of IEVA and 63.33% of IP-II \\u0026amp; EVA ears, significantly higher than controls. Genetic screening of 52 patients revealed pathogenic variants in 66.03%, with \\u003cem\\u003eSLC26A4\\u003c/em\\u003ec.919-2A\\u0026gt;G being the predominant mutation. Biallelic mutations were significantly more common in IP-II \\u0026amp; EVA compared to IEVA patients (\\u003cem\\u003ep\\u003c/em\\u003e= 0.022).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusions \\u003c/strong\\u003eEVA patients exhibit distinct audiometric patterns and genetic variants based on their inner ear morphology. The higher prevalence of biallelic \\u003cem\\u003eSLC26A4\\u003c/em\\u003e mutations in IP-II \\u0026amp; EVA children suggests a stronger genetic component in this phenotype, potentially influencing clinical management strategies.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Genetic Variants and Audiometric Patterns in Nonsyndromic Enlarged Vestibular Aqueduct Chinese Children with Complete Hearing Loss\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-07-01 10:47:05\",\"doi\":\"10.21203/rs.3.rs-6948944/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2025-07-23T11:24:28+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-07-18T15:24:27+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2025-07-15T12:25:39+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"276386938697080337107277290453546092463\",\"date\":\"2025-07-01T17:43:28+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"207537435722785299405606310360124448133\",\"date\":\"2025-06-28T22:14:24+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"250688094601843816599301908616233451612\",\"date\":\"2025-06-26T13:46:44+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-06-26T08:14:15+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-06-26T00:06:05+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-06-25T02:32:42+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"European Journal of Pediatrics\",\"date\":\"2025-06-22T10:13:57+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"european-journal-of-pediatrics\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"ejpe\",\"sideBox\":\"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)\",\"snPcode\":\"431\",\"submissionUrl\":\"https://submission.nature.com/new-submission/431/3\",\"title\":\"European Journal of Pediatrics\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"525c1909-e24e-4a59-9946-473c8375cc5e\",\"owner\":[],\"postedDate\":\"July 1st, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-09-08T16:05:12+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-6948944\",\"link\":\"https://doi.org/10.1007/s00431-025-06445-6\",\"journal\":{\"identity\":\"european-journal-of-pediatrics\",\"isVorOnly\":false,\"title\":\"European Journal of Pediatrics\"},\"publishedOn\":\"2025-09-04 15:57:57\",\"publishedOnDateReadable\":\"September 4th, 2025\"},\"versionCreatedAt\":\"2025-07-01 10:47:05\",\"video\":\"\",\"vorDoi\":\"10.1007/s00431-025-06445-6\",\"vorDoiUrl\":\"https://doi.org/10.1007/s00431-025-06445-6\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-6948944\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-6948944\",\"identity\":\"rs-6948944\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}