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PubMed1998

Localization of a gene for otosclerosis to chromosome 15q25-q26.

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi-generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease-causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.

Adult↗

PubMed1989

The genetics of otosclerosis: a review.

Otosclerosis is a heritable disease affecting the otic capsule. Its genetics have been studied, but remain incompletely elucidated. Presented is a detailed analysis of the literature pertaining to the mode of inheritance and epidemiology of clinical and histologic otosclerosis. Consideration is given to connective tissue abnormalities found in association with the disease. The hypothesis that otosclerosis is an isolated manifestation of a generalized connective tissue disorder is discussed. The author also suggests that otosclerosis, rather than being a discrete entity, may represent a heterogeneous group of diseases.

Adolescent↗

PubMed2003

Why is otosclerosis of low prevalence in Japanese?

OBJECTIVE: This study aimed to clarify the reasons why clinical otosclerosis, a very common disease among Caucasians, is not prevalent among Japanese. STUDY DESIGN: The incidence, site, activity, and volume of otosclerotic foci were examined in 1011 temporal bone sections from 507 Japanese individuals. SETTING: This study was prepared at the temporal bone laboratory, Fukushima Medical University, Fukushima. RESULTS: Otosclerotic foci were observed in 2.56% of individuals and in 1.48% of the ears. The most common site of involvement was anterior to the oval window region, but this was only in 38.9% of the ears with otosclerotic foci. The otosclerotic foci were not involved in the stapediovestibular articulation or the endosteal layer of the otic capsule in any ears. An active change of the otosclerotic focus was seen in 33.3% of ears with otosclerosis. The volume of otosclerotic foci at the site anterior to the oval window region was less than 0.8 mm3 in 5 out of 7 ears. CONCLUSION: The incidence of histologic otosclerosis among Japanese seemed to be almost the same as that among Caucasians. Three reasons why clinical otosclerosis was not as prevalent among Japanese as among Caucasians are suggested: low incidence of involvement of foci anterior to the oval window, low activity, and small lesion without involvement of the footplate and/or membranous labyrinth of the inner ear.

Aged↗

PubMed2004

Spiral ligament and stria vascularis changes in cochlear otosclerosis: effect on hearing level.

OBJECTIVE: To investigate the effect of changes within the spiral ligament and stria vascularis on hearing in cochlear otosclerosis, we examined spiral ligament hyalinization, stria vascularis atrophy, and sensory hearing loss in cochlear otosclerosis and described changes in ion transport molecule expression. STUDY DESIGN: Retrospective. SETTING: Tertiary referral center. PATIENTS: Thirty-two cochleae from 24 temporal bone donors with histologic evidence of cochlear otosclerosis, including spiral ligament hyalinization. INTERVENTION: Audiography. MAIN OUTCOME MEASURES: Measurements of spiral ligament width, stria vascularis, and bone-conduction thresholds were compared by the amount of hyalinization. Expression of the ion transport molecules Na,K-ATPase, connexin 26, and carbonic anhydrase II were assessed by immunohistochemical techniques. RESULTS: Hyalinization most often involved the posterior basal turn (88%) and the posterior middle turn (27%). Spiral ligament hyalinization correlated significantly with stria vascularis atrophy in the posterior middle turn of the cochlea (rho = -0.63, p < 0.01). There was a trend toward a significant association in the posterior basal turn (rho = -0.31, p < 0.08). Bone-conduction thresholds at 2,000 and 4,000 Hz were significantly associated with the amount of stria vascularis atrophy (rho = -0.44, -0.40, p < 0.05). In addition, we observed decreased immunostaining for both carbonic anhydrase II with Type I fibrocytes and Na,K-ATPase with stria vascularis and Type II and Type IV fibrocytes of the spiral ligament in cochlear otosclerosis sections compared with normal cochlea. Na,K-ATPase staining within the stria vascularis was further decreased in the presence of spiral ligament hyalinization. No significant differences were seen with connexin 26 immunostaining. However, immunostaining results were somewhat inconsistent. CONCLUSION: These data suggest that spiral ligament structure and function are essential for stria vascularis survival. In addition, dampened expression of ion transport molecules within the spiral ligament and stria vascularis may disrupt potassium ion recycling, resulting in loss of endocochlear potential and sensory hearing loss.

Aged↗

PubMed2006

The phenotype of the first otosclerosis family linked to OTSC5.

OBJECTIVE: To report the audiometric and radiologic findings in the first otosclerosis family linked to OTSC5. STUDY DESIGN: A clinical investigation of a family linked to OTSC5, including analyses of audiometric data and of high-resolution computed tomography (CT) images of the temporal bones from genetically affected family members. SETTING: Tertiary referral center. PATIENTS: Family members from a four-generation pedigree with otosclerosis segregating as an autosomal dominant trait. MAIN OUTCOME MEASURE(S): Pre-surgery pure tone audiometric data. Classification of otosclerotic foci on high-resolution spiral CT images of the temporal bones of genetically affected individuals. RESULTS: Audiometric data showed a considerable degree of phenotypic variability. Cross-sectional regression analysis did not disclose any clear age dependence of threshold-related data. Systematic differences between mean parameter values relating to the thresholds in the best or the worst ear were found. High-resolution CT images revealed a fenestral otosclerotic focus in seven of nine (78%) clinically affected individuals and cochlear foci in one of these seven patients. CONCLUSION: The phenotype of OTSC5 seems to be variable. Additional long-term audiometric data are needed to construct age-related typical audiograms, which may also facilitate the comparison between phenotypes of the different otosclerosis loci. The detection rate of otospongiotic foci in our study group is similar or lower compared with previous reports on CT data in consecutive otosclerosis patients who had stapes replacing surgery.

Adult↗

PubMed2005

Histologic otosclerosis is associated with the presence of measles virus in the stapes footplate.

HYPOTHESIS: Persistent measles virus infection of the otic capsule is presumed to be one of the etiologic factors in otosclerosis. The viral pathogenesis of otosclerosis could be established only by correlative analysis: histologic examination of the stapes footplates and reverse-transcriptase polymerase chain reaction amplification of the viral RNA. At present, histologic analysis of the removed stapes footplates is the only appropriate method of distinguishing otosclerotic and nonotosclerotic stapes fixations. BACKGROUND: The presence of measles virus was shown in otosclerotic patients by reverse-transcriptase polymerase chain reaction amplification of the viral RNA and detecting the viral proteins by immunohistochemistry. METHODS: Nucleic acids (mRNA, vRNA, and DNA) were extracted from ankylotic stapes footplates of stapes fixation patients (n = 44). Measles virus genomic nucleoprotein RNA was amplified by seminested reverse-transcriptase polymerase chain reaction. Amplification results were correlated to postoperative histologic findings. RESULTS: Measles virus RNA was detectable only in histologically otosclerotic stapes footplates (n = 32). Histology for virus-negative footplates (n = 12) excluded otosclerosis. Virus-negative stapes footplates showed annular calcification (n = 8), bone resorption with increased numbers of hemosiderophages (n = 2), and mononuclear cell infiltration with osteolysis (n = 2). CONCLUSION: Stapes ankylosis is a heterogenous disease causing conductive hearing loss with different causes. Nonotosclerotic stapes fixations may belong to degenerative disorders with variable histopathology. Otosclerosis is an inflammatory disease resulting from persisting measles virus infection of the otic capsule.

Adult↗

PubMed2005

Bone-conduction hearing and the occlusion effect in otosclerosis and normal controls.

OBJECTIVE: The goal of this study was to better understand bone-conduction hearing in subjects with normal hearing and in those with otosclerosis through the occlusion effect. With this study, the authors hope to lend credence to commonly accepted theories of bone-conduction hearing and the effect of lateralization during the Weber tuning fork test. BACKGROUND: There are three accepted theories defining bone-conduction hearing: compressional bone conduction describes an auditory percept produced by the compression and expansion of the cochlea leading to basilar membrane vibration; inertial bone conduction describes the inertia of the ossicular chain as a result of skull vibration during bone conduction testing; whereas skull vibration may also be transmitted to the external auditory canal, surrounding soft tissues, and para-auditory structures to illicit tympanic membrane vibration known as osseotympanic bone conduction. METHODS: Twenty normal volunteers and 17 unilateral otosclerosis patients underwent external canal sound pressure level measurement during bone-conduction testing using a standardized bone oscillator placement and stimulation paradigm. Sound was detected with a probe microphone placed in the external auditory canal in nonoccluded and occluded conditions after a 50-dB hearing level bone-conduction stimulus. RESULTS: There was no significant difference in sound pressure level between otosclerosis and normal subjects when the external auditory canals were nonoccluded. With occlusion, sound pressure level increased in both groups, but at a statistically significantly higher level for the otosclerosis group. CONCLUSION: Sound measured in the external canal likely represents energy lost to the environment transmitted through the middle and external ear systems, aided by the effect of both inertial and osseotympanic bone conduction. Occluding the ear leads to sound trapping and amplification. Also, the pressure exerted against the tympanic membrane reduces middle ear compliance and increases the impedance mismatch between air and the middle ear system, reflecting sound back into the external canal. This effect is further enhanced by stapes fixation to explain our data in both groups of subjects. The final common pathway in "lateralization" is probably a product of higher than normal impedance mismatch at the oval window.

Auditory Threshold↗

PubMed1983

Pregnancy and otosclerosis.

A retrospective study has been made of a sample of 479 women with deafness from otosclerosis, classified according to the number of pregnancies they have had and whether there had been a subjective impression of deterioration of hearing during or immediately after at least 1 pregnancy. The study confirms previous reports that pregnancy does involve a risk of aggravating deafness in clinical otosclerosis. The chance of female patients with bilateral otosclerosis reporting a subjective deterioration of hearing in pregnancy can be accurately described by a simple mathematical model and varies from about 33% after 1 pregnancy to about 63% after 6 pregnancies. In women with unilateral otosclerosis pregnancy-related deterioration of hearing is much less commonly perceived. There is no strong evidence that pregnancies cause any alteration to the actual footplate pathology of female patients.

Adult↗

PubMed2000

No evidence of measles virus in stapes samples from patients with otosclerosis.

Otosclerosis is a localized bone dystrophy of unknown etiology mainly involving the stapes. The hypothesis of a persistent infection by the measles virus was based on the inconstant detection of the virus by various methods, including reverse transcription-PCR (RT-PCR) of patients' stapes samples. The aim of this work was to investigate the presence of the measles virus in stapedial otosclerosis foci by different sensitive methods. Pathologic stapes samples were obtained from 35 patients suffering from otosclerosis. Measles virus detection was performed by (i) cocultures of Vero cells and primary cell cultures of bone samples (n = 7), (ii) immunofluorescence study of these cocultures (n = 3), and (iii) RT-PCR on RNA directly obtained from fresh frozen samples (n = 28) and on RNA extracted from the primary cell cultures (n = 2). Viral genomic regions coding for N (nucleoprotein) and M (matrix) proteins were separately amplified. PCR sensitivity was optimized on the measles virus Edmonston strain. Glyceraldehyde-3-phosphate dehydrogenase mRNA was used as a marker of total RNA recovery. PCR products were tested by Southern blot hybridization technique to improve sensitivity and specificity. PCRs amplifying the M and the N protein genes were able to detect the control measles virus RNA at titers as low as 0.1 and 0.01 50% tissue culture infective dose, respectively. With these highly sensitive methods, we could not evidence the presence of the measles virus in any of our bone samples or primary bone cell cultures. Our results do not confirm the hypothesis of persistent measles virus infection in otosclerosis.

Adult↗

PubMed2002

Linkage of otosclerosis to a third locus (OTSC3) on human chromosome 6p21.3-22.3.

Clinical otosclerosis (OMIM 166800/605727) has a prevalence of 0.2-1% among white adults, making it the single most common cause of hearing impairment in this group. It is caused by abnormal bone homeostasis of the otic capsule with the consequent development of sclerotic foci that invade the stapedio-vestibular joint (oval window) interfering with free motion of the stapes. Impaired ossicular chain mobility results in a conductive hearing loss. We identified the first locus for otosclerosis (OTSC1) on chromosome 15 in 1998 and reported a second locus (OTSC2) on chromosome 7 last year. Here we present results of a genome wide linkage study on a large Cypriot family segregating otosclerosis. Results of this study exclude linkage to OTSC1 and OTSC2 and identify a third locus, OTSC3, on chromosome 6p. The defined OTSC3 interval covers the HLA region, consistent with reported associations between HLA-A/HLA-B antigens and otosclerosis.

Chromosome Mapping↗

PubMed1999

Parathyroid hormone-parathyroid hormone-related peptide receptor expression and function in otosclerosis.

The aim of this study was to investigate the possibility that an abnormality related to parathyroid hormone (PTH) action is involved in the increased bone turnover observed in otosclerosis. To do so, expression and function of the PTH-PTH-related peptide (PTHrP) receptor were studied in the involved tissue (stapes) and compared with that in control bone sample obtained from the external auditory canal (EAC) in the same patient in 10 cases of otosclerosis and in 1 case of osteogenesis imperfecta. PTH-PTHrP receptor expression was studied by RT-PCR of RNA prepared from cultured cells in three patients and RNA directly extracted from bone samples in four patients. PTH-PTHrP receptor function was assessed by measuring the stimulation of cAMP production by 0.8, 8, and 80 nM PTH in bone cell cultures in seven cases. Results showed that PTH-PTHrP receptor mRNA expression in the otosclerotic stapes was lower than that in EAC samples (P < 0.05), whereas it was higher in stapes than that in EAC in the case of osteogenesis imperfecta. cAMP production after PTH stimulation was lower in bone cells cultured from otosclerotic stapes compared with that in cells cultured from EAC (range of increase in stimulation: 0.8-4.5 and 1.5-7 in stapes and EAC bone cells, respectively, P < 0.05). In contrast, the stimulation of cAMP production by forskolin was not significantly different in otosclerotic stapes and EAC bone cells (range of increase in stimulation: 20.7-83.1 and 4.9-99.8 in stapes and EAC, respectively, P > 0.05). These results show a lower stimulation of cAMP production in response to PTH associated with a lower PTH-PTHrP receptor mRNA expression in pathological stapes from patients with otosclerosis compared with that in control EAC samples. This difference supports the hypothesis that an abnormal cellular response to PTH contributes to the abnormal bone turnover in otosclerosis.

Adult↗

PubMed1990

Pre- and postoperative high-frequency audiometry in otosclerosis. A study of 53 cases.

A study was carried out to evaluate the results of stapes surgery in 53 cases of otosclerosis. The hearing function was measured pre- and postoperatively by means of conventional and high-frequency audiometry (Demlar 20K). The operative findings of the gradation of otosclerosis were compared with the pre- and postoperative audiometrical measurements. The results of this study point out that a clear relation exists between the preoperative high-tone audiogram and the gradation of otosclerosis. Stapedotomy does not influence the high-frequency threshold postoperatively. In conclusion, high-frequency audiometry can predict the state of stapes fixation in otosclerosis and this can be important in stapes surgery.

Audiometry↗

PubMedDate not supplied

Computed tomographic image analysis of ears with otosclerosis.

To evaluate the usefulness of quantitative analysis of computed tomographic images in diagnosing stapedial otosclerosis, high-resolution temporal bone computed tomography (CT) of 32 ears with otosclerosis and 19 control ears was used. The images on the section containing the oval window were digitized using a scanner, and the ratio of the mean gray scale value of 5 areas in the optic capsule including the area anterior to the oval window to that of the cortical bone was calculated. The mean value of the ratio of the area anterior to the oval window was significantly lower in the otosclerosis group (0.85 +/- 0.10) than in the control group (1.03 +/- 0.03; Student t test: t = 7.94, p < 0.0001). In 30 of 32 (93.7%) otosclerotic ears, the values were lower than the normal range calculated in the control group. This method of quantitative CT image analysis comparing the area anterior to the oval window was considered useful in diagnosing stapedial otosclerosis.

Adolescent↗

PubMedDate not supplied

Cochlear and vestibular lesions in capsular otosclerosis as seen in microdissection.

In 24 temporal bones from patients with otosclerosis prepared by the method of microdissection and surface preparations, otosclerotic foci could be clearly seen during removal of the otic capsule. The state of activity of each focus was estimated on the basis of its consistency and vascularity. Small anterior foci constituted the most common form of involvement of the otic capsule. All were judged to be inactive, and none of them appeared to have caused obvious sensorineural degeneration. No cases of "pure cochlear otosclerosis" were seen. Sensorineural degeneration was associated with large anterior foci which reached the upper basal turn. One specimen displayed a circumscribed sensorineural degeneration in the upper basal turn, with an almost exact correspondence between the location and extent of the cochlear lesion and the site of invasion by the otosclerotic process in the bone and endosteum bordering on scala media and scala tympani. It is postulated that a toxic factor had diffused from the focus and acted directly on the organ of Corti. When multiple foci were present they were usually poorly defined. The otosclerotic process involved the round window, with new lamellar bone formation in the scala tympant of the lower half of the basal turn. The most extensive sensorineural degeneration in the entire material was seen in this group. One specimen also had severe cochlear hydrops. In three specimens large shunts were observed to connect the otosclerotic foci with the cochlear vasculature, which was severely dilated. Where otosclerosis involved the endosteum of the scala tympani, loss of vessels was observed. One specimum with extensive active capsular otosclerosis had severe sensorineural degeneration of the vestibular system. Vestibular pathology in fenestrated ears is also described. In a specimen from a patient with no caloric reaction, numerous hair cells were present in the macular organs.

Aged↗

PubMedDate not supplied

Histologically proven cochlear otosclerosis with pure sensorineural hearing loss.

This paper discusses cochlear otosclerosis without stapedial fixation as a cause of sensorineural hearing loss. Because many cases of cochlear otosclerosis may remain undiagnosed, we believe that patients with a progressive sensorineural hearing loss and a family history of cochlear otosclerosis should be suspected of having cochlear otosclerosis. A positive stapedial reflex on-off effect or polytomographic findings help make the diagnosis. We prescribe sodium fluoride, calcium, and vitamin D for these patients in an effort to prevent progression of the loss.

Aged↗

PubMed1990

Immunohistologic findings in otosclerosis.

The cause of otosclerosis is still unclear. Between 1981 and 1988 we obtained 186 biopsy specimens of otosclerotic bone during the course of stapedectomies. Serial sections of the specimens were examined histologically (H & E) and immunohistologically (peroxidase-antiperoxidase technique) for immunoglobulin G, immunoglobulin M, and C1q and C3 complements. Active otosclerotic foci were found in 61 cases, 43 of which had IgG deposits. IgM antibodies were absent. In specimens with inactive otosclerosis, IgG and IgM were not evident, C1q and C3 complements were demonstrated together with IgG, but sometimes also in the mucosa independent of the phase of the otosclerosis. Our findings suggest that an immunologic process may be important in the pathogenesis of otosclerosis.

Acute Disease↗

PubMed1990

Otosclerosis involving the vestibular aqueduct and Menière's disease.

The coexistence of otosclerosis and endolymphatic hydrops in the temporal bone have been described; however, the mechanism for the development of endolymphatic hydrops in otosclerosis remains unknown. Among 128 temporal bones with otosclerosis, involvement of the vestibular aqueduct by otosclerosis was observed in four temporal bones from two patients. In all four, the vestibular aqueduct was filled with active otosclerotic foci; the lumen of the endolymphatic duct and sac was narrowed as a result of fibrosis, and endolymphatic hydrops, more severe in the pars inferior than the pars superior, was observed. Collapse of the ductus reuniens and dilated saccule was seen in three temporal bones. Our study indicates that otosclerotic obstruction of the vestibular aqueduct may create a disturbance of the outflow and/or absorption of endolymph, leading to the development of endolymphatic hydrops and Meniere's disease, thus supporting the theory of longitudinal flow of endolymph.

Aged↗

PubMed1984

Otosclerosis and otospongiosis: clinical and histological comparisons.

The simultaneous occurrence of otosclerosis and otospongiosis in the same lesion is well documented. The logical sequence of events would seem to be softening and destruction of the bone by the otospongiotic lesion, which is subsequently converted to otosclerosis. Examination of 46 temporal bones has led us to further classify the lesion as: 1. an active lesion, both otospongiotic and otosclerotic, 2. an inactive lesion, also both otosclerotic and otospongiotic, or 3. a fibrous lesion. Hyalinization of the spiral ligament only occurs adjacent to active otospongiotic or very large otosclerotic lesions. If the lesion adjacent to the spiral ligament is inactive, there is no hyalinization. It seems illogical that a hyalinized spiral ligament will return to normal when the lesion changes from active otospongiosis to inactive otosclerosis. Otospongiotic and otosclerotic lesions are found side by side at the periphery of lesions, and both are adjacent to normal bone. These findings have implications concerning the mode of action of sodium fluoride and other medications that are under evaluation for the control of the sensorineural hearing loss due to otosclerosis.

Aged↗