Dataset Information

Association of Hearing Loss and Otologic Outcomes With Fibrous Dysplasia.

ABSTRACT: Importance: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. Objectives:To characterize audiologic and otologic manifestations in a large cohort of individuals with FD/MAS and to investigate potential mechanisms of hearing loss. Design, Setting, and Participants:In this natural history study, individuals with craniofacial FD seen at a clinical research center underwent clinical, biochemical, computed tomographic, audiologic, and otolaryngologic evaluations. Main Outcomes and Measures: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. Results: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 . Conclusions and Relevance: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.

SUBMITTER: Boyce AM

PROVIDER: S-EPMC5839293 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Association of Hearing Loss and Otologic Outcomes With Fibrous Dysplasia.

Boyce Alison M AM Brewer Carmen C DeKlotz Timothy R TR Zalewski Christopher K CK King Kelly A KA Collins Michael T MT Kim H Jeffrey HJ

JAMA otolaryngology-- head & neck surgery 20180201 2

<h4>Importance</h4>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.<h4>Objectives</h4>To characterize audiologic and otologic manifestations in a large cohort of individuals with FD/MAS and to investigate potential mechanisms of hearing loss.<h4>Design, setting, and participants</h ...[more]

PMID: 29192304

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Project description:Normal hearing requires exquisite cooperation between bony and sensorineural structures within the cochlea. For example, the inner ear secretes proteins such as osteoprotegrin (OPG) that can prevent cochlear bone remodeling. Accordingly, diseases that affect bone regulation can also result in hearing loss. Patients with fibrous dysplasia develop trabecular bone overgrowth resulting in hearing loss if the lesions affect the temporal bones. Unfortunately, the mechanisms responsible for this hearing loss, which could be sensorineural and/or conductive, remain unclear. In this study, we used a unique transgenic mouse model of increased Gs G-protein coupled receptor (GPCR) signaling induced by expression of an engineered receptor, Rs1, in osteoblastic cells. These ColI(2.3)+/Rs1+ mice showed dramatic bone lesions that histologically and radiologically resembled fibrous dysplasia. We found that ColI(2.3)+/Rs1+ mice showed progressive and severe conductive hearing loss. Ossicular chain impingement increased with the size and number of dysplastic lesions. While sensorineural structures were unaffected, ColI(2.3)+/Rs1+ cochleae had abnormally high osteoclast activity, together with elevated tartrate resistant acid phosphatase (TRAP) activity and receptor activator of nuclear factor kappa-B ligand (Rankl) mRNA expression. ColI(2.3)+/Rs1+ cochleae also showed decreased expression of Sclerostin (Sost), an antagonist of the Wnt signaling pathway that normally increases bone formation. The osteocyte canalicular networks of ColI(2.3)+/Rs1+ cochleae were disrupted and showed abnormal osteocyte morphology. The osteocytes in the ColI(2.3)+/Rs1+ cochleae showed increased expression of matrix metalloproteinase 13 (MMP-13) and TRAP, both of which can support osteocyte-mediated peri-lacunar remodeling. Thus, while the ossicular chain impingement is sufficient to account for the progressive hearing loss in fibrous dysplasia, the deregulation of bone remodeling extends to the cochlea as well. Our findings suggest that factors regulating bone remodeling, including peri-lacunar remodeling by osteocytes, may be useful targets for treating the bony overgrowths and hearing changes of fibrous dysplasia and other bony pathologies.

Project description:Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cyclic adenosine monophosphate (cAMP)-regulating protein, α-subunit of the Gs stimulatory protein (G(s) α). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. Receptor activator of NF-κB ligand (RANKL) is a cell-surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD-like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal-related events from bone metastases. We present the case of a 9-year-old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pretreatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every 3 months. Over 7 months of treatment he showed marked reduction in pain, bone turnover markers (BTMs), and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium, and calcitriol. BTMs showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTMs with cross-linked C-telopeptide (reflecting osteoclast activity) exceeding pretreatment levels, accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD-related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases.

Project description:ImportanceHearing loss (HL) may be a modifiable risk factor for dementia, and longitudinal studies are needed to examine the association of HL and dementia.ObjectiveTo investigate the association of HL with incident dementia in Taiwanese adults in the general population.Design, setting, and participantsThis population-based cohort study collected data from the National Health Insurance Research Database of Taiwan. Patients newly diagnosed with HL from January 1, 2000, through December 31, 2011 (n = 8135), constituted the exposed (HL) group. The HL group patients were matched by sex, age, residence, and insurance premium to individuals without HL (non-HL group) (n = 8135). Data were analyzed from January 1, 2000, to December 31, 2013.ExposureHearing loss defined according to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.Main outcomes and measuresDementia classified according to ICD-9-CM codes.ResultsOf a total of 16 270 participants (9286 [57.1%] men; mean [SD] age, 65.2 [11.1] years), 1868 developed dementia. The dementia incidence rate in the HL group was higher than that in the non-HL group (19.38 [95% CI, 18.25-20.57] per 1000 person-years vs 13.98 [95% CI, 13.01-15.00] per 1000 person-years) during the follow-up period. In the fully adjusted multivariate Cox proportional hazards regression model applied for risk analysis, patients with HL had a significant risk of dementia (hazard ratio [HR], 1.17; 95% CI, 1.07-1.29; false discovery rate [FDR] P = .003). Subgroup analysis revealed that, among 3 age groups (45-64, 65-74, and ≥75 years), the group aged 45 to 64 years was associated with a risk of dementia (HR, 2.21 [95% CI, 1.57-3.12]; FDR P < .001). In sensitivity analysis, the presence of HL among those aged 45 to 64 years (HR, 1.40; 95% CI, 1.12-1.75; FDR P = .01) was associated with a risk of dementia.Conclusions and relevanceIn this study, hearing loss was positively associated with a risk of dementia, especially in patients aged 45 to 64 years. Hearing protection, screening, and treatment may be used as strategies for mitigating this potential risk factor.

Project description:ImportanceSudden sensorineural hearing loss (SSHL) accompanied by vertigo may portend a negative prognosis in the hearing outcome.ObjectiveTo investigate the association of vertigo with prognosis of hearing variables in SSHL.Data sourcesA literature search of eligible studies was performed in PubMed, Web of Science, and Embase from September 26, 1973, through September 26, 2017. Studies published in English were retrieved with no restrictions on the date of publication. References were identified by screening the proceedings of relevant reviews, and annual meeting and other correlative papers were scanned manually for enrollment.Study selectionAll original research studies and retrospective or prospective studies focusing on the role of vertigo in the prognosis for the hearing outcome of SSHL were systematically retrieved. Studies that did not include data regarding the association between the rate of hearing recovery and vertigo were excluded, as were reviews, comments, case reports, editorials, letters, and practice guidelines.Data extraction and synthesisData were extracted and evaluated by 2 researchers. Data extracted included research type, number of participants with or without vertigo, treatment regime, definition of pure-tone average, criteria for hearing improvement, and length of follow-up. The quality of included studies was evaluated using the Newcastle-Ottawa Scale (scores range from 0-9, with a score of ≥6 indicating a high-quality study). The data were synthesized in Mantel-Haenszel models; the aggregate results were estimated in forest plots.Main outcomes and measuresAssociation of vertigo with the prognosis for the hearing outcome of SSHL.ResultsOf the 4814 unique patients identified in 10 studies, 1709 were included in the SSHL group with vertigo and 3105 were included in SSHL group without vertigo. The Newcastle-Ottawa Scale score of each study selected was greater than 7. The recovery rate of hearing was 42.13% in the group with vertigo, compared with 60.29% in the group without vertigo. Vertigo was significantly associated with a worse hearing recovery (odds ratio, 2.22; 95% CI, 1.54-3.20; I2 = 74%). Similar results were obtained in subgroup analyses of the grading system using the Siegel criteria and systemic corticosteroid therapy. However, no association of vertigo with the prognosis of SSHL was observed within the subgroup receiving intratympanic corticosteroids (odds ratio, 1.78; 95% CI, 0.64-4.94; I2 = 70%).Conclusions and relevanceCurrent evidence revealed that vertigo may be negatively associated with hearing recovery in patients with SSHL, except in a subgroup that received intratympanic corticosteroids. Corticosteroid injection may be more effective for treatment of SSHL accompanied by vertigo; future studies are needed to determine whether treatment of vertigo might contribute to the recovery of SSHL.

Project description:Fibroblast growth factor-23 (FGF23) is a phosphate- and vitamin D-regulating hormone derived from osteoblasts/osteocytes that circulates in both active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms. O-glycosylation by O-glycosyl transferase N-acetylgalactosaminyltransferase 3 (ppGalNAcT3) and differential cleavage by furin have been shown to be involved in regulating the ratio of active to inactive FGF23. Elevated iFGF23 levels are observed in a number of hypophosphatemic disorders, such as X-linked, autosomal recessive, and autosomal dominant hypophosphatemic rickets, whereas low iFGF23 levels are found in the hyperphosphatemic disorder familial tumoral calcinosis/hyperphosphatemic hyperostosis syndrome. Fibrous dysplasia of bone (FD) is associated with increased total FGF23 levels (cFGF23 + iFGF23); however, classic hypophosphatemic rickets is uncommon. Our results suggest that it can be explained by increased FGF23 cleavage leading to an increase in inactive cFGF23 relative to active iFGF23. Given the fact that FD is caused by activating mutations in the small G-protein G(s) α that results in increased cyclic adenosine monophosphate (cAMP) levels, we postulated that there may be altered FGF23 cleavage in FD and that the mechanism may involve alterations in cAMP levels and ppGalNacT3 and furin activities. Analysis of blood specimens from patients with FD confirmed that the elevated total FGF23 levels are the result of proportionally increased cFGF23 levels, consistent with less glycosylation and enhanced cleavage by furin. Analysis of primary cell lines of normal and mutation-harboring bone marrow stromal cells (BMSCs) from patients with FD demonstrated that BMSCs harboring the causative G(s) α mutation had higher cAMP levels, lower ppGalNAcT3, and higher furin activity. These data support the model wherein glycosylation by ppGalNAcT3 inhibits FGF23 cleavage by furin and suggest that FGF23 processing is a regulated process that controls overall FGF23 activity in FD patients.

Dataset Information

Association of Hearing Loss and Otologic Outcomes With Fibrous Dysplasia.

Publications

Association of Hearing Loss and Otologic Outcomes With Fibrous Dysplasia.

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