Clinical features and molecular characterization of Chinese patients with FKBP10 variants.

BACKGROUND: Osteogenesis imperfecta (OI) is a group of rare skeletal dysplasia. Long bone deformity and scoliosis are often associated with progressively deforming types of OI. FKBP65 (encoded by FKBP10, OMIM *607063) plays a crucial role in the processing of type I procollagen. Autosomal recessive variants in FKBP10 result in type XI osteogenesis imperfecta. METHODS: Patients diagnosed with OI were recruited for a genetic test. RT-PCR and Sanger sequencing were applied to confirm the splicing defect in FKBP10 mRNA with the splice-site variant. The bone structure was characterized by Goldner's trichrome staining. Bioinformatic analyses of bulk RNA sequencing data were performed to examine the effect of the FKBP10 variant on gene expression. RESULTS: Here we reported three children from a consanguineous family harboured a homozygous splice-site variant (c.918-3C > G) in FKBP10 intron and developed long bone deformity and early onset of scoliosis. We also observed frequent long bone fractures and spinal deformity in another 3 OI patients with different FKBP10 variants. The homozygous splicing variant identified in the fifth intron of FKBP10 (c.918-3C > G) led to abnormal RNA processing and loss of FKBP65 protein and consequently resulted in aberrant collagen alignment and porous bone morphology. Analysis of transcriptomic data indicated that genes involved in protein processing and osteoblast differentiation were significantly affected in the patient-derived osteoblasts. CONCLUSION: Our study characterized the clinical features of OI patients with FKBP10 variants and revealed the pathogenesis of the c.918-3C > G variant. The molecular analyses helped to gain insight into the deleterious effects of FKBP10 variants on collagen processing and osteoblast differentiation.

Retrospective analyses of clinical features in 28 Chinese patients with type V osteogenesis imperfecta: new perspectives in an old issue.

Type V osteogenesis imperfecta (OI) is a form of OI characterized by radial head dislocation (RHD), calcification of interosseous membrane (CIM), and hyperplastic callus (HPC). In this study, we characterized the clinical features of 28 type V OI patients. We presented that dysfunctions of elbow, hip joint, and abnormal epiphyseal growth plate were associated with ectopic calcification and summarized the history of HPC progression and treatment. INTRODUCTION: The current study aims to systematically characterize the skeletal phenotypes of patients with type V OI and suggested possible surgical solutions. METHODS: A total of 28 patients were admitted for inpatient care at The Hong Kong University-Shenzhen Hospital diagnosed with type V OI (either clinically diagnosed or genetically confirmed with the IFITM5 c.-14C > T mutation). RESULTS: Prevalence of type V radiological features was comparable to previous literatures (RHD, 100%; CIM, 100%; HPC, 44%; and scoliosis, 50%). Novel skeletal phenotypes were presented including extension of coronoid process, acetabular labrum, acetabular protrusion, spontaneous autofusion of the hip, bulbous epiphysis, and popcorn calcification. Significant increase in BMD was observed in patients with bisphosphonate treatment. Twenty-five percent (3/12) of patients with preoperative use of indomethacin developed HPC postoperatively, and HPCs were absorbed in 2 young patients 2 years later. CONCLUSION: This retrospective study summarized the clinical features and highlighted the abnormalities in elbow, hip joint, and growth plate in type V OI patients. Our study contributed to a more comprehensive clinical spectrum of type V OI. We also characterized the natural progression of HPC formation and resorption in patients in different ages. The use of bisphosphonate treatment is effective in improving bone mineral density in type V OI patients, and whether indomethacin can reduce incidence of HPC formation deserves further investigation.

Patient-reported outcomes in a Chinese cohort of osteogenesis imperfecta unveil psycho-physical stratifications associated with clinical manifestations.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare congenital disorder of the skeletal system, inflicting debilitating physical and psychological distress on patients and caregivers. Over the decades, much effort has been channeled towards understanding molecular mechanisms and developing new treatments. It has recently become more apparent that patient-reported outcome measurements (PROM) during treatment, healing and rehabilitation are helpful in facilitating smoother communication, refining intervention strategies and achieving higher quality of life. To date, systematic analyses of PROM in OI patients remain scarce. RESULTS: Here, utilizing a PROM Information System, we report a cross-sectional and longitudinal study in a southern Chinese cohort of 90 OI patients, covering both the child and adult age-groups. In the child group where both self and parental surveys were obtained, we identified two clusters of comparable sizes showing different outlooks in physical mobility and emotional experiences. One cluster (Cluster 1) is more negative about themselves than the other (Cluster 2). A concordance of 84.7% between self and parental assessments was recorded, suggesting the stability and validity of PROM-based stratification. Clinical subtyping, deformity, leg length discrepancy, and limited joint mobility were significantly associated with this stratification, with Cluster 1 showing higher percentages of severe phenotypes than Cluster 2. Since OI is a genetic disorder, we performed genetic testing on 72 of the 90 patients, but found no obvious association between genotypes and the PROM stratification. Analyses of longitudinal data suggested that patients tended to stay in the same psychological state, in both clusters. Adult patients also showed a continuous spectrum of self-evaluation that matches their clinical manifestations. CONCLUSION: By systematically analyzing patient-reported outcomes, our study demonstrated the link between the sociopsychological wellbeing of OI patients, and their clinical manifestations, which may serve as the basis for evaluating clinical interventions and help achieve better patient-centric medical practices. The lack of genotype-PROM association may be due to the diverse mutational spectrum in OI, which warrants further investigation when a larger sample size is available.

Phenotypic Spectrum and Molecular Basis in a Chinese Cohort of Osteogenesis Imperfecta With Mutations in Type I Collagen.

Osteogenesis imperfecta (OI) is a rare inherited connective tissue dysplasia characterized with skeletal fragility, recurrent fractures and bone deformity, predominantly caused by mutations in the genes COL1A1 or COL1A2 that encode the chains of type I collagen. In the present study, clinical manifestations and genetic variants were analysed from 187 Chinese OI patients, majority of whom are of southern Chinese origin. By targeted sequencing, 63 and 58 OI patients were found carrying mutations in COL1A1 and COL1A2 respectively, including 8 novel COL1A1 and 7 novel COL1A2 variants. We validated a novel splicing mutation in COL1A1. A diverse mutational and phenotypic spectrum was observed, coupling with the heterogeneity observed in the transcriptomic data derived from osteoblasts of six patients from our cohort. Missense mutations were significantly associated (χ2 p = 0.0096) with a cluster of patients with more severe clinical phenotypes. Additionally, the severity of OI was more correlated with the quality of bones, rather than the bone mineral density. Bone density is most responsive to bisphosphonate treatment during the juvenile stage (10-15 years old). In contrast, height is not responsive to bisphosphonate treatment. Our findings expand the mutational spectrum of type I collagen genes and the genotype-phenotype correlation in Chinese OI patients. The observation of effective bisphosphonate treatment in an age-specific manner may help to improve OI patient management.