Sclerosteosis is a rare genetic bone dysplasia disorder characterised by generalised craniotubular bone modelling. Alongside many clinical appearances marked in sclerosteosis, the auditory system is considerably compromised on several levels during the disease progression. Extensive otolaryngological research on the history of sclerosteosis, the clinical presentation of sclerosteosis, radiographic studies and the gene causing the condition had been documented. No studies had been found describing the audiological profiles, auditory functioning and abnormalities for subjects with sclerosteosis. Thus the object of this study aimed to describe the auditory profile of subjects with sclerosteosis. A cross-sectional descriptive research design and quantitative research approach was followed to investigate the auditory characteristics of subjects with sclerosteosis. Subjects were selected from a database of patients with confirmed diagnoses of sclerosteosis. Ten subjects responded and provided written informed consent. Test procedures included otoscopy, tympanometry, acoustic reflexes, diagnostic pure-tone airand bone-conduction audiometry, speech audiometry, distortion product otoacoustic emissions (DPOAE), auditory brainstem responses (ABR) and computed tomographic (CT) scans. The subjects were assessed with a comprehensive audiological test-battery within a single test session lasting approximately two hours. A CT scan was conducted on a separate occasion shortly after the audiological data were obtained. Normal type A tympanograms were obtained in 50% (n=10/20) of ears. All subjects presented with mixed hearing losses varying from moderate (5%; n=1), severe (55%; n=11) and profound (40%; n=8) degrees across ears. Hearing loss configurations ranged from rising (15%), sloping (35%) and air-conduction thresholds peaking at 2000 Hz (50%). Air bone gaps (ABG) were larger in older subjects, although not statistically significant (p>.05). The CT scans indicated anatomical abnormalities of the external auditory canal, tympanic membrane, middle ear space, ossicles, oval window, round window and the internal auditory canal. The progressive abnormal bone formation in sclerosteosis involved the middle ear, the round and oval windows of the cochlea and internal auditory canal. The progressive abnormal bony overgrowth, which is the hallmark of sclerosteosis, led to functional impairment at various levels in the auditory system. The current findings provided a comprehensive auditory profile for sclerosteosis. Results might be utilised alongside future research findings to direct criteria and audiological indications for surgical and audiological intervention. / Dissertation (MCommunication Pathology)--University of Pretoria, 2013. / gm2014 / Speech-Language Pathology and Audiology / Unrestricted

Sclerosteosis is a severe autosomal recessive sclerosing skeletal dysplasia with no available treatment. It is characterised by excessive bone formation and is caused by mutations in the SOST gene that lead to loss of expression of sclerostin, a protein that acts as a negative regulator of bone formation by binding to low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) Wnt co-receptors to inhibit the canonical Wnt/β-catenin signalling pathway. This study investigated the effectiveness of sclerostin replacement therapy in a mouse model of sclerosteosis. Recombinant wild type mouse sclerostin (mScl) and two novel mScl fusion proteins containing a C-terminal human immunoglobulin G1 (IgG1) antibody fraction crystallisable (mScl hFc), or C-terminal human Fc with a poly-aspartate motif (mScl hFc PD), to increase serum half-life and promote localisation to bone, respectively, were produced and purified using mammalian expression and standard chromatography techniques. These recombinant mScl proteins bound to LRP6 with high affinity (nM range) and completely inhibited matrix mineralisation in an in vitro bone nodule formation assay. Pharmacokinetic assessment following a single dose administered to wild type (WT) or SOST knock out (SOST-/-) mice indicated that the presence of the hFc increased protein half-life from less than 5 minutes to at least 1.5 days. The effect of a 6-week treatment with these proteins on the skeletal phenotype of young SOST-/- mice revealed that mScl hFc PD treatment resulted in a modest but significant reduction in trabecular bone volume compared with the vehicle control. There was no marked effect on cortical bone indices assessed by μCT, whole body areal bone mineral density by DXA, or terminal levels of the bone formation marker procollagen type 1 N-terminal propeptide (P1NP) in any of the SOST-/- or WT treatment groups, possibly due to insufficient exposure. Administration of recombinant mScl hFc PD protein partially corrected the high bone mass phenotype of the SOST-/- mouse, suggesting that bone-targeting of sclerostin engineered to improve half-life was able to negatively regulate bone formation in the SOST-/- mouse model of sclerosteosis. However, the modest efficacy indicates that sclerostin replacement may not be an optimal strategy to mitigate excessive bone formation in sclerosteosis, hence alternative approaches should be explored. / Thesis (PhD)--University of Pretoria, 2020. / UCB Pharma (Slough, UK) / National Research Foundation (NRF) / University of Pretoria (Pretoria, South Africa) / Paraclinical Sciences / PhD / Unrestricted