Otosclerosis Research Articles

Background. To date, the lack of modern algorithms for the diagnosis and treatment of various forms of otosclerosis (OS) leads to progressive bilateral hearing loss, failures and complication during the operation and disability of the socially active part of the population. The development of a modern therapeutic and diagnostic algorithm for various forms of OS is an urgent topic, the development of which became possible due to the advent of modern medical technologies: high-resolution computed tomographs, microscopes, endoscopes, surgical lasers and motor systems. Aims — to develop an innovative treatment and diagnostic algorithm for various forms of otosclerosis. Methods. In a non-randomized controlled prospective study, the results of the examination, treatment and follow-up of 2,421 patients with OS in the period from 2009 to 2022 were analyzed. Conservative inactivating therapy was performed in 288 patients with active and 28 with cochlear forms of OS. Stapedoplasty was performed in 2,393 patients. A partial stapedectomy was performed in group 1, a piston stapedoplasty technique was performed in group 2, and a wide stapedotomy was performed in group 2. In all cases, the operation was performed with CO2 laser assistance (Acuspot 30C, Lumenis, USA). In the obliterating form of OS, various stapedoplasty techniques were performed, depending on the stage, with various means of assistance (the Skeeter Otologic Drill System motor System (Medtronic Xomed, USA) and a CO2 laser. When the active form was detected, piston stapedoplasty with CO2 laser assay was performed. The evaluation of the functional results of the developed methods of stapeplasty (stapedoplasty) was carried out according to the tonal data. Results. For the first time, based on the results of examination, treatment and treatment of a significant number of patients (2421), a modern therapeutic and diagnostic algorithm and a new clinical and radiological classification for OS have been developed. In a comparative assessment of the functional effectiveness of the developed stapedoplasty techniques, the best results were obtained after performing partial stapedectomy and wide stapedotomy (groups 1 and 3) — “excellent” results were achieved after 3 months in 96% of patients, and with piston (group 2) — after 6 months in 78% with a closure of less than 10 dB (p ≤ 0.05). Cochlear complications in the early postoperative period were detected in 0.8% of patients and recurrence of hearing loss in the long-term period in 1%. Conclusions. The accumulated many years of experience in examining and surgical treatment of patients with OS allowed us to develop an algorithm for diagnosis, treatment and a new clinical and radiological classification, which led to an increase in the frequency of diagnosis of OS and the effectiveness of treatment of hearing loss in patients with various forms of OS.

Otosclerosis (OE) is one of the main causes of hearing loss in young adults, with a preponderance of the female sex, with a 2:1 ratio. High-resolution tomography focused on temporal bone is a fundamental tool for diagnosis, allowing subtle changes in density in the ear capsule to be detected. Depending on the location of these findings, EO can be classified into fenestral and retrofenestral. The fourth turn sign provides valuable information for diagnosis, classification, and surgical planning

BackgroundThe standard methods for diagnosing otosclerosis (OS) include clinical and audiological testing. Radiologic imaging continues to expand with use in diagnosis, staging, surgery planning, and outcomes.ObjectiveTo determine if high resolution computed tomography (HRCT) imaging advances to the audiological findings in the diagnosis of otosclerosis.MethodsThis prospective randomized controlled study was conducted from June 2018 to June 2022. Fifty patients with OS who divided into two subgroups: group 2a, 50 early OS ears, and group 2b, 35 ears with late OS. The controls includes 50 individuals who have healthy ears (group 1). All participants had otorhinolaryngology examination, audiological evaluation and HRCT imaging.ResultsEarly OS had higher air conduction thresholds than control, and late OS had considerably higher air conduction thresholds than either the early or control subjects (p < 0.001). Early OS patients had higher bone conduction threshold (BCT) than control, while late OS patients had higher BCT than both early and control subjects (p < 0.001). In early and late OS, there is a significant association between bone conduction of 11 dB and 21.6 dB, respectively (P = 0.004), and a significant air–bone gap of 25.5 and 31 dB, respectively (P = 0.03). HRCT showed a sensitivity of 75% and high specificity 92% with accuracy 83% in early OS and sensitivity of 78% and high specificity 94% with accuracy 86% in late OS.ConclusionHRCT is a more sensitive and specific diagnostic tool for OS than audiometry. HRCT could discriminate between early and late OS, suggesting that it can be used to do so with a high degree of confidence.

Objective: To analyze the etiology, diagnosis, and treatment of unexplained conductive hearing loss (UCHL) with intact tympanic membrane. Methods: A systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 642 articles were retrieved from databases such as PubMed, Embase, Web of Science, and Cochrane. Fifty-four research articles and 21 case reports were screened out according to the inclusion and exclusion criteria for analysis of the etiology of UCHL. Seven research articles with UCHL who underwent exploratory tympanotomy were selected for data extraction and analysis of clinical characteristics. Results: UCHL is a common manifestation of various diseases, including congenital ossicular anomalies (COA), otosclerosis (OTS), congenital middle ear cholesteatoma (CMEC), oval window atresia, superior semicircular-canal dehiscence, congenital stapedial footplate fixation, middle ear osteoma or adenoma, congenital ossification of stapedial tendon, and so on. A total of 522 patients were included in the 7 articles; among whom OTS showed a tendency to increase with age. The main symptoms were hearing loss, followed by tinnitus, dizziness, ear fullness, ear pain, facial paralysis. A total of 87.5% to 93.0% patients with COA manifested as nonprogressive deafness that occurred since childhood, with tinnitus incidence of 15.6% to 30.2%, and 86.4% to 96.4% patients with OTS presented with progressive hearing loss, with tinnitus incidence of 60.1% to 90.9%. The diagnosis positive rate of high-resolution computed tomography (HRCT) was 33.8% to 87.1%, and CMEC was higher than that of COA (83.3%-100% vs 28.6%-64%). All the articles reported good hearing recovery. The most common surgical complications included taste abnormalities, tinnitus, and dizziness. Conclusion: UCHL presents with similar clinical manifestations and poses challenges in preoperative diagnosis. Exploratory tympanotomy is the primary method for diagnosis and treatment, with good prognosis after removing the lesion and reconstructing hearing during the operation. Children can also safely undergo the surgery.

To assess the location/number of otic capsule demineralization and hearing outcomes of stapes surgery (SS) for osteogenesis imperfecta (OI) compared with otosclerosis (OS). This study included 11 and 181 consecutive ears from 6 and 152 patients with OI and OS, respectively. Demineralization loci observed as hypodense area of the otic capsule were examined using high-resolution computed tomography. All patients underwent SS. Locations of the hypodense areas were classified into the anterior oval window, anterior internal auditory canal, and pericochlear area. The location/number of hypodense areas and preoperative/postoperative hearing parameters were correlated. Postoperative hearing outcome was evaluated 12 months after surgery. Hypodense area was more frequently observed in OI (9 of 11 ears [81.8%]) than in OS (96 of 181 ears [53.0%]), with significant differences. Multiple sites were involved in 81.8% OI and 18.8% OS patients, showing significant differences. Preoperative air conduction (AC), bone conduction, and air-bone gap (ABG) were 48.9 ± 17.8, 28.0 ± 11.3, and 20.7 ± 8.4 dB, respectively, in OI and 56.2 ± 13.5, 30.5 ± 9.9, and 26.4 ± 9.7 dB, respectively, in OS, demonstrating greater AC and ABG in OS than in OI. Postoperative AC (31.3 ± 20.5 dB), ABG (10.6 ± 10.0 dB), and closure of ABG (12.1 ± 4.7 dB), that is, preoperative ABG minus postoperative ABG of OI, were comparable to those of OS (AC, 30.9 ± 13.3 dB; ABG, 7.0 ± 7.4 dB; closure of ABG, 20.1 ± 11.6 dB). OI ears showed more severe demineralization of otic capsule than OS ears. However, favorable hearing outcomes could be obtained through SS for OI and OS ears.

The article presents various classifications of forms of otosclerosis (OS), which change with the development of diagnostic methods. At the same time, according to the literature, a unified OS classification has not yet been adopted. All existing classifications are imperfect to some extent. The classification of clinical forms of OS according to TPA data makes it possible to determine the indications for surgical treatment and to suggest its possible effect, but not the localization of OS foci. X-ray classifications of localization of OS foci indicate their diversity, distribution, and do not always correlate with the type of hearing loss. At the same time, modern diagnostics of OS should be based on audiological data, localization of foci and their density according to the results of X-ray methods of examination. Based on the examination and treatment of 1532 patients with various forms of OS, a modern clinical and radiological classification of the disease is proposed, based precisely on these provisions. This classification, in our opinion, will improve the quality of diagnosis of various forms of OS, will allow to differentiate the tactics of treating patients with this disease to stabilize hearing loss, indications for surgical treatment, suggest its effectiveness with a reduction in the risk of surgical failures and possible further rehabilitation of the patient.

Otosclerosis (OTSC) is a focal and diffuse bone disorder of the human middle ear characterized by abnormal bone growth and deposition at the stapes' footplate. This hinders the transmission of acoustic waves to the inner ear leading to subsequent conductive hearing loss. The plausible convections for the disease are genetic and environmental factors with yet an unraveled root cause. Recently, exome sequencing of European individuals with OTSCrevealed rare pathogenic variants in the Serpin Peptidase Inhibitor, Clade F (SERPINF1)gene. Here, we sought to investigate the causal variants of SERPINF1 in the Indian population. The gene and protein expression was also evaluated in otosclerotic stapes to ameliorate our understanding of the potential effect of this gene in OTSC. A total of 230 OTSC patients and 230 healthy controls were genotyped by single-strand conformational polymorphism and Sanger sequencing methods. Bycomparing the case controls, we identified five rare variants (c.72 C > T, c.151 G > A, c.242 C > G, c.823 A > T, and c.826 T > A) only in patients. Four variants c.390 T > C (p = 0.048), c.440-39 C > T (p = 0.007), c.643 + 9 G > A (p = 0.035), and c.643 + 82 T > C (p = 0.005) were found to be significantly associated with the disease. Down-regulation of SERPINF1 transcript level in otosclerotic stapes was quantified by qRT-PCR, ddPCR and further validated by in situ hybridization. Similarly, reduced protein expression was observed by immunohistochemistry and immunofluorescence in otosclerotic stapes that corroborate with immunoblotting of patients' plasma samples. Our findings identified that SERPINF1 variants are associated with the disease. Furthermore, reduced expression of SERPINF1 in otosclerotic stapes might contribute to OTSC pathophysiology.

Otosclerosis (OTSC) is the primary form of conductive hearing loss characterized by abnormal bone remodelling within the otic capsule of the human middle ear. A genetic association of the RELN SNP rs3914132 with OTSC has been identified in European population. Previously, we showed a trend towards association of this polymorphism with OTSC and identified a rare variant rs74503667 in a familial case. Here, we genotyped these variants in an Indian cohort composed of 254 OTSC cases and 262 controls. We detected a significant association of rs3914132 with OTSC (OR = 0.569, 95%CI = 0.386–0.838, p = 0.0041). To confirm this finding, we completed a meta-analysis which revealed a significant association of the rs3914132 polymorphism with OTSC (Z = 6.707, p<0.0001) across different ethnic populations. Linkage analysis found the evidence of linkage at RELN locus (LOD score 2.1059) in the OTSC family which has shown the transmission of rare variant rs74503667 in the affected individuals. To understand the role of RELN and its receptors in the development of OTSC, we went further to perform a functional analysis of RELN/reelin. Here we detected a reduced RELN (p = 0.0068) and VLDLR (p = 0.0348) mRNA levels in the otosclerotic stapes tissues. Furthermore, a reduced reelin protein expression by immunohistochemistry was confirmed in the otosclerotic tissues. Electrophoretic mobility shift assays for rs3914132 and rs74503667 variants revealed an altered binding of transcription factors in the mutated sequences which indicates the regulatory role of these variations in the RELN gene regulation. Subsequently, we showed by scanning electron microscopy a change in stapes bone morphology of otosclerotic patients. In conclusion, this study evidenced that the rare variation rs74503667 and the common polymorphism rs3914132 in the RELN gene and its reduced expressions that were associated with OTSC.

Otosclerosis (OTSC) is a complex bone disorder of the otic capsule, which causes conductive hearing impairment in human adults. The dysregulation of the signaling axis mediated by the receptor activator of nuclear factor-kappa-B (RANK), RANK ligand (RANKL), and osteoprotegerin has been widely attributed to the context of metabolic bone disorders. While genetic associations and epigenetic alterations in the TNFSF11 gene (RANKL) have been well-linked to metabolic bone diseases of the skeleton, particularly osteoporosis, they have never been addressed in OTSC. This study aimed to assess whether the genetic association of rs1021188 polymorphism in the upstream of TNFSF11 and the DNA methylation changes in its promoter CpG-region reveal the susceptibility of OTSC. Peripheral blood DNA samples were collected from unrelated Tunisian-North African subjects for genotyping (109 cases and 120 controls) and for DNA methylation analysis (40 cases and 40 controls). The gender-stratified analysis showed that the TNFSF11 rs1021188 C/T was associated with OTSC in men (p = 0.023), but not in women (p = 0.458). Individuals with CC genotype were more susceptible to OTSC, suggesting an increased risk to disease development. Using publicly available data, the rs1021188 was within a cluster grouping the subpopulations with African ethnicity. Moreover, 26 loci in the TNFSF11 gene were in linkage disequilibrium with rs1021188, revealing relative similarities between different populations. Significant differences in both DNA methylation and unmethylation status were detected with 4.53- and 4.83-fold decreases in the global DNA methylation levels in female and male OTSC groups, respectively. These changes could contribute to an increased risk of OTSC development. Bioinformatic analyses indicated that each of the rs1021188 variations and the DNA methylation changes in the promoter CpG-sites within TNFSF11 may play an important role in its transcription regulation. To our knowledge, this is the first study that investigates an independent effect of the rs1021188 polymorphism and DNA hypomethylation of TNFSF11 promoter in OTSC. Genetic and epigenetic changes in the regulatory regions of TNFSF11 could offer new molecular insights into the understanding of the complexity of OTSC.

An innovative method for trans-impedance matrix interpretation in hearing pathologies discrimination

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

BackgroundThe purpose of this study was to explore the common characteristics of fenestral otosclerosis (OS) which are misdiagnosed, and develop a deep learning model for the diagnosis of fenestral OS based on temporal bone high-resolution computed tomography scans.MethodsWe conducted a study to explicitly analyze the clinical performance of otolaryngologists in diagnosing fenestral OS and developed an explainable deep learning model using 134,574 temporal bone high-resolution computed tomography (HRCT) slices collected from 1,294 patients for the automatic diagnosis of fenestral OS. We prospectively created an external test set with 31,774 CT slices from 144 patients, which contained 86 fenestral OS ears and 202 normal ears and used it to evaluate the performance of our otosclerosis-Logical Neural Network (LNN) model to assess its potential clinical utility. In addition, we compared the diagnostic acumen of seven otolaryngologists with the otosclerosis-LNN approach in the clinical test set, which was mixed with 78 fenestral OS and 62 normal ears. Finally, to evaluate the assisting value of the model, the seven participants were again invited to classify all cases in the clinical test set after referring to the diagnostic results of the model, to which they were blinded.ResultsThe diagnostic performance of otologists was not satisfactory, and those CT samples which were misdiagnosed had similar characteristics. Based on this finding, we defined three subtypes of fenestral OS lesions that are suitable for clinical diagnosis guidance: “focal”, “transitional”, and “typical” fenestral OS. The most encouraging result is that the model achieved an area under the curve (AUC) of 99.5% (per-ear-sensitivity of 96.4%, per-ear-specificity of 98.9%) on the prospective unknown external test. Furthermore, we used this model to assist otologists and observed a consistent and significant improvement in diagnostic performance, especially for the newly defined focal and transitional fenestral OS, which led to the initial high misdiagnosis rate.ConclusionsOur findings of the fine-grained classification of fenestral OS could have implications for future diagnosis and prevention programs. In addition, our deep OS localization network is an effective approach providing assistance to otologists to deal with the significant challenge of the misdiagnosis of fenestral OS.

Our aim was to evaluate the relationship of the dimensions of the facial canal (FC) and cochlear aqueduct (CA) in otosclerosis (OS) with the type and severity of OS. Two radiologists retrospectively evaluated temporal bone high-resolution computed tomography (HRCT) images obtained from 48 healthy individuals and 94 OS patients between January 2015 and July 2020. In the study group, the CA width, funnel base width, and funnel length, in addition to the FC transverse length, were measured in the axial plane. The CA length was measured in the coronal plane on HRCT images. The FC craniocaudal length was measured in the same plane as the fissula ante fenestram (FAF) in coronal reformatted HRCT images. Grading of OS was based on otosclerotic plaque density and new bone formation extending toward the tympanic cavity at the FAF level. In the OS patients, the CA width and FC craniocaudal and FC transverse diameters were significantly decreased on both sides compared to those in the control group (p < 0.001). In fenestral OS, the FC craniocaudal and transverse widths on both sides were statistically significantly lower than the FC widths in the control group (p < 0.0001). A statistically negative correlation was found in the FC craniocaudal (r = -0.831/-0.818) and transverse (r = -0.742/-0.750) measurements on both sides in accordance with an increase in the otosclerotic plaque density (p < 0.0001). The presence of narrowing in the FC and CA adjacent to the FAF supports the role of autoimmunity theory in the etiology of OS.

The article briefly presents the physiology of the stapes muscle tendon (SMT), and features in its defeat. Its length was studied using high-resolution multispiral computed tomography of the temporal bones. We also studied the possibility of its restoration using the author's method of tendoplasty using metallized stapes prostheses. Tendoplasty with stapedoplasty was performed in 74 patients with otosclerosis (OS), and 48 patients had stapedoplasty without tendoplasty. As a result of research, the average length of the SMT was 2.38±0.02 mm, which explains the need to use a 3 mm long venous autograft for tendoplasty. The author's method of tendoplasty for stapedoplasty allows restoring the acoustic reflex in 54.1% of OS patients using artificial stapes prostheses. The preservation of the vascular bed in the thickness of the restored tendon can improve the trophy of the long incus process and reduce the risk of its dystrophic changes in the postoperative period. In addition, this fact confirms the importance of the stapes muscle in the acoustic reflex.

Concomitant otosclerosis (OTS) and superior semicircular canal dehiscence (SSCD) is a rare, but difficult-to-identify and treat diagnosis. A systematic review of the literature was performed to analyze the diagnostic and therapeutic approaches of concurrent OTS and SSCD cases and to identify possible factors that may help in predicting the surgical outcome. PubMed, Scopus, Medscape, Ovid databases. Studies showing diagnosis of OTS documented by audiometric test with or without associated radiological signs (computed tomography), and concomitant diagnosis of SSCD, documented at least by high-resolution computed tomography (and possibly supported by neurophysiological testing) were included. Both surgically treated and untreated patients were considered for data analysis. The general characteristics of each study were recorded, when available. Clinical, audiological, vestibular testing, surgical, and radiological data were extracted from the published case reports and series, and recorded on a database. For each case, the diagnostic steps that confirmed OTS and concomitant SSCD in the same ear were extracted. Twelve studies were included in the review and 18 cases affected simultaneously by the 2 conditions were extracted and analyzed. Seven of 12 ears (58.3%) undergoing stapes surgery experienced a hearing improvement. In four (33.3%) cases, vestibular symptoms (with or without associated acoustic symptoms) of SSCD were unmasked or worsened by stapes surgery. A reliable preoperative diagnosis of the two concomitant conditions is possible with a proper interpretation of clinical signs, audiometric, and vestibular testing, in association with the radiologic assessment. Despite that the length and the location of the dehiscence may guide the surgical decision, definitive conclusions regarding the appropriate indications for surgical treatment cannot be drawn due to the limited number of cases with adequate data reported in the literature.

A review on reversal stapedotomy outcome and associated factors

Otosclerosis (OTSC) is one of the most common causes of progressive adult-onset hearing loss in the Caucasian population, with a female preponderance. The etiology of OTSC is complex and there are a number of genetic variants reported to be associated with OTSC susceptibility, but no data on the genetic background of OTSC in patients originating from the central-eastern part of Europe have been available. The purpose of our study was to investigate in Polish patients the frequency of genetic variants previously reported to be most strongly associated with OTSC. Genomic DNA was isolated from blood samples or buccal swabs. Variants in TGFB1 (rs1800472) and RELN (rs39335, rs39350, rs39374) were genotyped in surgically confirmed OTSC patients (n = 94) and a control group (n = 198) using custom TaqMan SNP genotyping assays and real-time PCR. Allele and genotype frequencies were compared between the groups in statistical analysis and the odds ratios with 95% confidence intervals were calculated to estimate the risk. For all of the tested variants the distributions of alleles and genotypes were not statistically significantly different between OTCS patients and the control group. There were also no statistically significant differences in relation to gender of the tested subjects. Despite multiple confirmatory studies on TGFB1 and RELN association with OTSC development in some populations, no significant association between the studied variants and OTSC was found in Polish patients. Our results indicate the presence of inter-population differences in OTSC susceptibility factors and confirm the large genetic heterogeneity of this disorder.

This work on otospongios is to evaluate our experience in management. It is a rare pathology in our context more precisely in the black race. The studies on this pathology concerned the study on whites. The prevalence of this pathology remains obscure in our context. In our structure we have tried to highlight the diagnostic and therapeutic aspects. We collected fourteen cases of otosclerosis. The clinical examination and the computed tomography allowed us to choose the operable cases in 85.8% with favorable consequences. Our study highlights the lack of management familiarity of these cases especially in the black race.

Background/aim To emphasize the role of cochlear implantation (CI) in the auditory rehabilitation of patients with otosclerosis (OS) and share our surgical experiences on this rare group of patients. Materials and methodsRetrospective analysis of the patients who have a diagnosis of otosclerosis and implanted between January 1998–May 2019 was performed. Preoperative and postoperative clinical, radiological, audiological and surgical findings are presented. ResultsAmong 2195 patients who have been implanted in our institution, 12 (0.54%) met the diagnostic criteria of OS according to their preoperative (clinical, radiological, audiological) and peroperative (surgical) findings. Electrode insertion was performed via “round window membrane and cochleostomy” in 8 and 4 patients, respectively. No major complications occured. All patients showed satisfactory performances by means of audiometric scores postoperatively. Nonauditory stimulation (NAS) which manifested as “facial twitching” was a challenging problem in one patient during the surgery and subsided after the operation.ConclusionOur experience on CI in patients with OS revealed that the implantation was a relatively safe procedure and had satisfactory impact on audiological performances.

Background: Otosclerosis (OTSC) is a genetically heterogeneous disorder, characterized by abnormal bone growth in the middle ear, affecting the stapes bone. Previous studies have shown that single nucleotide polymorphisms (SNPs) of the COL1A1, BMP2, and BMP4 genes are linked to susceptibility of OTSC, musculoskeletal degenerative diseases, and bone remodeling. Aims: To evaluate the genetic association and expression levels of COL1A1, BMP2, and BMP4 genes with OTSC in the Indian population. Methods: A total of 320 otosclerotic and 320 control samples were screened for four SNPs (rs1107946, rs11327935, rs2269336, and rs1800012) of the COL1A1 gene; rs3178250 of the BMP2 gene; and rs17563 of the BMP4 gene using single-strand conformation polymorphism analysis, and restriction fragment length polymorphism analyses. Genotypic, haplotypic, and linkage disequilibrium analyses were performed to assess the potential associations of these SNPs with OTSC. COL1A1, BMP2, and BMP4 mRNA expression levels were analyzed by semiquantitative RT-PCR and real-time PCR. Results: Genotypes of two SNPs, rs1800012 and rs17563, were found to be associated with OTSC (the rs1800012 GT genotype, p = 0.0022, OR = 0.481; and the rs17563 TC genotype, p = 0.0225, OR = 1.471). Haplotypic analyses revealed that the COL1A1 haplotype G-T-C-T (p = 0.021) was significantly increased among controls. Functional studies revealed an unexpected decrease in mRNA expression of COL1A1 but an increased expression of the BMP2 and BMP4 genes in otosclerotic stapes tissues. Conclusions: Our findings suggest that OTSC is a heterogeneous disorder, but that the GT genotype of the rs1800012 locus is protective and that the TC genotype at the rs17563 locus is a risk factor. In addition, our studies indicate that changes in the expression of the COL1A1, BMP2, and BMP4 genes may contribute to the genetic susceptibility of OTSC by regulating their mRNA levels.