Endocrine Abstracts

JOINT2638

Background: Osteogenesis imperfecta (OI) type XV, caused by biallelic WNT1 variants, is a rare autosomal recessive skeletal dysplasia linked to impaired osteoblast differentiation. Despite growing recognition of WNT1-related OI, longitudinal clinical data on disease progression and treatment efficacy remain sparse.

Methods: This 14-year cohort study analyzed 44 Chinese patients from 42 unrelated families with OI type XV. The pathogenic mutations were detected by Whole-Exome Sequencing (WES) and verified by Sanger sequencing. Longitudinal assessments included fracture history, spinal radiography, dual-energy X-ray absorptiometry (DXA), and biochemical markers (serum β-CTX, P1NP, calcium, phosphate, ALP).

Results: Two hotspot variants, c. 677C>T(p. S226L) (19. 2%) and c. 301C>T(p. Arg101Cys) (11. 5%), predominated. Key phenotypic features included severe skeletal fragility (mean fracture rate: 19. 3±18. 9; range: 4–100), early-onset fractures (66. 7% within 1 year), universal thin cortical bone (100%) and metaphyseal enlargement (100%), spinal compression fractures (84. 2%), humeral curvature (64. 1%), and extraskeletal manifestations: ptosis (70. 0%), scoliosis (61. 0%), blue sclera (32. 4%), and intellectual abnormalities (28%). Bisphosphonate therapy, initiated at a mean age of 3. 7 years (duration: 7. 7±4. 0 years), improved vertebral height in 80. 9% of patients within 1 year. However, β-CTX and P1NP levels not decreased in 97. 7% of patients, with no long-term reduction in fracture risk or skeletal deformity progression. Two patients died during follow-up.

Conclusions: This study delineates the natural history of OI type XV, marked by profound skeletal fragility and distinct extraskeletal features. While bisphosphonates transiently improved vertebral architecture, their limited long-term efficacy highlights the necessity for WNT pathway-targeted therapies. Our findings expand the genotypic and phenotypic spectrum of OI and provide critical insights for mechanistic studies and genotype-phenotype correlations.