Genetics of Otosclerosis

Background Otosclerosis is a common ear disease that causes fixation of the stapes and conductive hearing impairment. However, the pathogenesis of otosclerosis is still unknown. Otosclerosis could be associated with the unique bony environment found in the otic capsule. Normal bone remodelling is almost completely absent around the inner ear after birth allowing degenerative changes and dead osteocytes to accumulate. High levels of inner ear anti resorptive osteoprotegerin (OPG) is most likely responsible for this capsular configuration. Studies have demonstrated how osteocyte lifespan variation creates occasional clusters of dead osteocytes, so-called cellular voids, at otosclerotic predilection sites in the human otic capsule. These cellular voids have been suggested as possible starting points of otosclerosis. Aim To describe the cellular viability in otosclerotic lesions and compare it to that of cellular voids. Materials and Methods The study was based on unbiased stereological quantifications in undecalcified human temporal bones with otosclerosis. Results Osteocyte viability was found to vary within the otosclerotic lesions. Furthermore, the results presented here illustrate that inactive otosclerotic lesions consist of mainly dead interstitial bone, much like cellular voids. Conclusions and significance Focal degeneration in the otic capsule may play an important role in the pathogenesis of otosclerosis.

Otosclerosis: From Genetics to Molecular Biology

The cause of otosclerosis is still unknown. Persistent measles virus infection of the otic capsule is supposed to be one of the etiologic factors in otosclerosis. Chronic viral antigen expression on the surface of infected cells can induce a secondary autoimmune reaction against the otic capsule. In the past 15 years, some reports proposed the possible etiologic role of measles virus in otosclerosis. The presence of measles virus was shown in otosclerotic patients by reverse-transcriptase polymerase chain reaction amplification of the viral RNA, detecting the viral proteins by immunohistochemistry and detecting antimeasles immunoglobulin G in the perilymph samples. Many concerns were elicited by these results. Nucleic acid was extracted from pulverized, frozen stapes footplate samples of otosclerotic patients. Measles virus RNA was amplified by reverse-transcriptase polymerase chain reaction: reverse transcription and the first round polymerase chain reaction amplification was performed by heat stable recombinant Thermus thermophilus polymerase, whereas in the nested round, polymerase chain reaction Taq-polymerase was used. Measles virus nucleoprotein RNA-specific oligonucleotide primers were used in these reactions. An Edmonston-type measles virus served as a positive control and cortical bone fragments or stapes superstructures served as negative controls. Among 34 otosclerotic patients, 20 stapes footplate samples contained measles virus RNA. Measles virus RNA was not detected in other bone specimens of the patients. The etiologic role of measles virus in the pathogenesis of otosclerosis should be considered. The 14 negative samples may be genetically determined otosclerotic cases.

Three aspects of brainstem response audiometry were investigated in the present study. (1) The brainstem response threshold was compared with the pure-tone audiogram in 40 patients with conductive hearing loss. The brainstem response threshold has a one-to-one relationship with the mean of the pure-tone thresholds at 2 and 4 kHz. The correlation coefficient in this comparison is 0.84 and the standard error of the estimate is 8.3 dB. Taking into account corresponding results in cochlear hearing loss [Drift et al.: Audiology 26: 1-10, 1987] it is concluded that the brainstem response threshold provides a good estimate of the amount of peripheral hearing loss, independent of the type of hearing loss. (2) It was shown [Drift et al.: Audiology 27: 260-270, 1988] that different types of peripheral hearing loss can be distinguished reliably with brainstem response audiometry. Parameters relevant for this distinction were the horizontal shift of the latency-level curve (1(L) curve), that of its derivative and the response threshold. In the clinical situation measurement of the response threshold is not always possible due to restlessness of the patient. To simulate this situation we randomly truncated the lower parts of the 1(L) curves of quiet patients. The test group consisted of 22 adult normally hearing subjects, 79 patients with cochlear hearing loss, 40 with conductive hearing loss and 22 with mixed hearing loss. Linear discriminant analysis was applied to the horizontal shift of the 1(L) curve and of its derivative. The brainstem diagnosis 'normal hearing' correctly excludes a conductive hearing loss in 98% of the cases and the brainstem diagnosis 'cochlear hearing loss' does so in 79%. The brainstem diagnosis 'conductive hearing loss' correctly predicts a conductive component of hearing loss in 94% of the cases and the brainstem diagnosis 'mixed hearing loss' does so in 90%. The distinction between cochlear hearing loss and normal hearing is not reliable, neither is the distinction between conductive and mixed hearing loss. (3) The amount of the conductive component of hearing loss can be estimated by the horizontal shift of the 1(L) curve. Statistical comparison with the mean of the air-bone gaps at 2 and 4 kHz gave a correlation coefficient of 0.77, a standard error of the estimate of 9.7 dB, and a slope of the regression line of 0.93. An overestimation of about 7 dB has to be taken into account in case of mixed hearing loss.

Fibrous dysplasia (FD) and McCune-Albright syndrome (MAS) are rare bone and endocrine disorders in which expansile fibro-osseous lesions result in deformity, pain, and functional impairment. The effect of FD on hearing and otologic function has not been established. To characterize audiologic and otologic manifestations in a large cohort of individuals with FD/MAS and to investigate potential mechanisms of hearing loss. In this natural history study, individuals with craniofacial FD seen at a clinical research center underwent clinical, biochemical, computed tomographic, audiologic, and otolaryngologic evaluations. Clinical and radiologic features associated with hearing loss and otologic disease were evaluated. Conductive hearing loss was hypothesized to be associated with narrowing of the external auditory canal (EAC), FD involving the epitympanum, and FD crowding the ossicular chain. Sensorineural hearing loss was hypothesized to be associated with FD affecting the internal auditory canal (IAC) and otic capsule. Of the 130 study participants with craniofacial FD who were evaluated, 116 (89.2%) had FD that involved the temporal bone (median age, 19.6 years; range, 4.6-80.3 years; 64 female [55.2%]), whereas 14 (10.8%) had craniofacial FD that did not involve the temporal bone. Of the 183 ears with temporal bone FD, hearing loss was identified in 41 ears (22.4%) and was conductive in 27 (65.9%), sensorineural in 12 (29.3%), and mixed in 2 (4.9%). Hearing loss was mild and nonprogressive in most participants. Whereas EACs were narrower in ears with FD (mean difference [MD], 0.33 mm; 95% CI, 0.11-0.55 mm), this finding was associated with conductive hearing loss in only 4 participants. Fibrous dysplasia crowding of the ossicles was associated with conductive hearing loss (odds ratio [OR], 5.0; 95% CI, 2.1-11.6). The IAC length was not different between ears with and without FD (MD, -0.37; 95% CI, -0.95 to 0.211); however, canals were elongated in ears with sensorineural hearing loss (MD, -1.33; 95% CI, -2.60 to -0.07). Otic capsule involvement was noted in only 4 participants, 2 of whom had sensorineural hearing loss. Both MAS-associated growth hormone excess (OR, 3.1; 95% CI, 1.3-7.5) and neonatal hypercortisolism (OR, 11; 95% CI, 2.5-55) were associated with an increased risk of hearing loss . Hearing loss in craniofacial FD is common and mild to moderate in most individuals. It typically arises from FD crowding of the ossicular chain and elongation of the IAC, whereas EAC stenosis and otic capsule invasion are less common causes. Individuals with craniofacial FD should undergo otolaryngologic evaluation and monitoring, including assessment to identify those with high-risk features.

Genetics of progressive hearing loss: a link between hearing impairment and dysfunction of mechanosensory hair cells

Is Preoperative Computed Tomography Necessary or Useful for Primary Stapes Surgery?

Characterization of hearing loss in pediatric patients with osteogenesis imperfecta

1) Characterize the current presentation of pediatric temporal bone fractures, 2) compare two classification schemes for temporal bone fractures and illustrate complications in each fracture type. Retrospective medical record review. Tertiary-care, academic children's hospital. All children presenting from 1999 to 2009 with CT-proven temporal bone fracture and audiology examination with follow-up. All CT scans were reinterpreted by a dedicated head and neck radiologist. All fractures were characterized as otic capsule sparing (OCS) or otic capsule violating (OCV), as well as transverse (T) or longitudinal (L). CT findings, mechanisms of injury, sensorineural hearing loss (SNHL), conductive hearing loss (CHL), and facial nerve injury (FNI). Seventy-one children met inclusion criteria. Fifty-four (76%) children had longitudinal fractures versus 17 (24%) with transverse fractures. Sixty-four (90%) had OCS versus 7 (10%) with OCV. The otic capsule was involved in 7.4% of longitudinal fractures and 17.6% of transverse fractures. Eleven (15%) had facial weakness, 72% of whom had a visualized fracture through the facial nerve course. SNHL was detected in 14 (20%) patients and CHL in 17(23.9%). All patients with fractures classified as both transverse and OCV had SNHL. The OCS versus OCV and T versus L classification schemes were directly compared for statistical significance in predicting SNHL, CHL, and FNI using the Fisher's exact test. Both OCS/OCV and T/L were predictors of SNHL (P = .0025 and P = .0143, respectively), but the OCS/OCV scheme was more accurate. Neither classification significantly predicted CHL or FNI (P = .787 versus .825; P = .705 vs. .755). In this pediatric series, approximately 75% of the fractures are longitudinal and 25% are transverse. The otic capsule is spared in 90% and violated in 10%. Both OCS/OCV and L/T classification schemes predict SNHL, but the OCV/OCS scheme is more accurate in this prediction. Although the negative predictive value of the two schemes is similar, the positive predictive value is higher with the OCS/OCV system. The presence of conductive hearing loss and facial nerve symptoms was not predicted by either classification system.

The aim of the study was to compare the traditional and newer temporal bone fracture classification systems and their reliability in predicting serious outcomes of hearing loss and facial nerve (FN) injury. We queried the medical record database for hospital visits from 2002 to 2013 related to the search term temporal. A total of 1144 records were identified, and of these, 46 records with documented temporal bone fractures were reviewed for patient age, etiology and classification of the temporal bone fracture, FN examination, and hearing status. Of these records, radiology images were available for 38 patients and 40 fractures. Thirty-eight patients with accessible radiologic studies, aged 10 months to 16 years, were identified as having 40 temporal bone fractures for which the otolaryngology service was consulted. Twenty fractures (50.0%) were classified as longitudinal, 5 (12.5%) as transverse, and 15 (37.5%) as mixed. Using the otic capsule sparing (OCS)/violating nomenclature, 32 (80.0%) of fractures were classified as OCS, 2 (5.0%) otic capsule violating (OCV), and 6 (15.0%) could not be classified using this system. The otic capsule was involved in 1 (5%) of the longitudinal fractures, none of the transverse fractures, and 1 (6.7%) of the mixed fractures. Sensorineural hearing loss was found in only 2 fractures (5.0%) and conductive hearing loss (CHL) in 6 fractures (15.0%). Two fractures (5.0%) had ipsilateral facial palsy but no visualized fracture through the course of the FN canal. Neither the longitudinal/transverse/mixed nor OCS/OCV classifications were predictors of sensorineural hearing loss (SNHL), CHL, or FN involvement by Fisher exact statistical analysis (for SNHL: P = 0.37 vs 0.16; for CHL: P = 0.71 vs 0.33; for FN: P = 0.62 vs 0.94, respectively). In this large pediatric series, neither classification system of longitudinal/transverse/mixed nor OCS/OCV was predictive of SNHL, CHL, or FN palsy. A more robust database of audiologic results would be helpful in demonstrating this relationship.

ObjectiveTo identify the relationship of pediatric temporal fractures to the incidence and type of hearing loss present. To analyze the timing and utility of audiometric testing in children with temporal bone fractures. MethodsRetrospective case series of 50 pediatric patients with temporal bone fractures who were treated at an urban, tertiary care children's hospital from 2008 to 2014. A statistical analysis of predictors of hearing loss after temporal bone fracture was performed. ResultsFifty-three fractures (69.7%) in 50 patients involved the petrous portion of the temporal bone. The mean age of patients was 7.13 years, and 39 (73.6%) were male. A fall was the most common mechanism of injury in 28 (52.8%) patients, followed by crush injury (n=14, 26.2%), and vehicular trauma (n=10, 18.9%). All otic capsule violating fractures were associated with a sensorineural hearing loss (n=4, 7.5%, p=0.002). Three of four otic capsule sparing fractures were associated with ossicular dislocation, with a corresponding mixed or conductive hearing loss on follow up audiometric testing. The majority of otic capsule sparing fracture patients (n=19/43, 44.2%) who had follow up audiograms had normal hearing, and those with otic capsule violating fractures were statistically more likely to have persistent hearing loss than those with otic capsule sparing fractures (p=0.01). ConclusionsPatients with otic capsule violating fractures or those with ossicular disruption are at higher risk for persistent hearing loss. Cost-saving may be accrued by selecting only those patients at high risk for persistent hearing loss for audiometric testing after temporal bone fractures.

Introduction: Temporal bone fractures in adults are invariably due to motor vehicle accidents or road traffic accidents. Hearing loss is a common complaint following temporal bone fractures, but attention to it is frequently overlooked as there may be other life-threatening complications associated with it that may require immediate attention of the caregiver. Immediate detection of temporal bone fracture and its complications helps in providing early and effective treatment. Aim: The main objective of our study is to observe various types of fractures on multidetector computed tomography (CT), difference between various types, and classification of fractures of temporal bone with correlation between types of fracture and clinical hearing loss. Methods: Two-year (2019–2021) prospective study of head injured patients with temporal bone fracture presented to the Department of Radio-diagnosis (AVBRH, DMIMS, Wardha) with complaints of hearing loss was subjected for study. Temporal bone fracture patients satisfying inclusion and exclusion criteria having hearing loss were evaluated audiologically after a gap of 3 months following the initial injury once the patient was stable. Age and gender distribution, cause of injury, radiological findings, and clinical presentations were analyzed. Data were entered into Microsoft Excel data sheet and were analyzed using SPSS 22 version software. Results: Out of 173 patients having hearing loss with temporal bone fracture, majority of the patients were male (84.97%) and were between 20 and 39 years (46.24%) with a mean age of 41 years. The major cause of injury was motor vehicle accidents (84.39%). The right side was involved (49.1%) more than the left side (46.0%). Longitudinal type fracture was most frequent (64.74%). Otic capsule involvement was present in 9.25%. Conductive hearing loss was more common in otic capsule sparing and sensorineural hearing loss was more common in otic capsule-involved fractures. Otic capsule sparing was more common in (95.54%) longitudinal type of fracture. Otic capsule violation was more common in (26.09%) transverse type of fracture. Conclusion: This study suggests that image analysis of high-resolution CT can be used in fracture of temporal bone either to detect the hearing loss or to know the type and classify the fracture or to find the correlation between the types of fracture and clinical hearing loss.

Otosclerosis is a common form of hearing loss characterized by abnormal bone remodeling in the otic capsule. It is considered a complex disease caused by both genetic and environmental factors. In a previous study, we identified a region on chr7q22.1 located in the RELN gene that is associated with otosclerosis in Belgian-Dutch and French populations. Evidence for allelic heterogeneity was found in this chromosomal region in the form of two independent signals. To confirm this finding, we have completed a replication study that includes four additional populations from Europe (1,141 total samples). Several SNPs in this region replicated in these populations separately. While the power to detect significant association in each population is small, when all four populations are combined, six of seven SNPs replicate and show an effect in the same direction as in the previous populations. We also confirmed the presence of allelic heterogeneity in this region. These data further implicate RELN in the pathogenesis of otosclerosis. Functional research is warranted to determine the pathways through which RELN acts in the pathogenesis of otosclerosis.

The number of potential options for rehabilitation of patients with conductive or mixed hearing loss is continually expanding. To be able to inform patients and other stakeholders, there is a need to identify and develop patient-centred outcomes for treatment of hearing loss. To identify outcome measures in the physical core area used when reporting the outcome after treatment of conductive and mixed hearing loss in adult patients. Systematic review. Systematic review of the literature related to reported physical outcome measures after treatment of mixed or conductive hearing loss without restrictions regarding type of intervention, treatment or device. Any measure reporting the physical outcome after treatment or intervention of mixed or conductive hearing loss was sought and categorised. The physical outcome measures that had been extracted were then grouped into domains. The literature search resulted in the identification of 1434 studies, of which 153 were selected for inclusion in the review. The majority (57%) of papers reported results from middle ear surgery, with the remainder reporting results from either bone conduction hearing devices or middle ear implants. Outcomes related to complications were categorised into 17 domains, whereas outcomes related to treatment success was categorised into 22 domains. The importance of these domains to patients and other stakeholders needs to be further explored in order to establish which of these domains are most relevant to interventions for conductive or mixed hearing loss. This will allow us to then assess which outcome measures are most suitable for inclusion in the core set.

Otosclerosis is a common form of conductive hearing loss characterized by abnormal bone remodeling exclusively in the otic capsule. The prevalence of otosclerosis varies in racial populations and is described as being rare in black African populations. In this paper we aim to report five cases of clinical, and surgically confirmed, otosclerosis in black individuals, in São Tomé and Príncipe. Since February 2011, Ear, Nose and Throat consultations and surgeries specialty have been carried out at Dr. Ayres de Menezes Hospital in cooperation with the project 'Health for all'. A retrospective analysis was undertaken of the records of all patients subjected either to stapedectomy or partial stapedectomy until February 2014. Information regarding clinical presentation, audiometric data and surgery reports was recorded. Five adult patients underwent stapedectomy or partial stapedectomy. All of them presented with normal otoscopy, conductive or mixed hearing loss on audiogram and normal tympanometry with absent stapedial reflexes. None of the patients had signs of infection or history of head trauma. Three cases showed improvement in the air-bone gap after surgery. The other two were lost to follow-up. We documented and surgically confirmed five cases of clinical otosclerosis in this population. A thematic review was carried out and concluded that, despite being described as a rare event in this race, available literature on this topic is not enough to state that there is lower prevalence of otosclerosis amongst the African population. Even if not common, otosclerosis cannot be disregarded as a possible cause for conductive hearing loss among the population of São Tomé and Principe.