High Bone Mass Phenotype in a Cohort of Patients with Osteogenesis Imperfecta Caused Due to and C-propeptide Cleavage Variants in

Objectives: Osteogenesis Imperfecta (OI) is a heterogeneous condition mainly characterised by bone fragility; extra-skeletal features in OI include blue sclerae, dentinogenesis imperfecta, skin laxity and joint hyper-extensibility. Most patients with OI are thought to have a low bone mass but contrary to expectations there are certain forms of OI with high bone mass which this study explores in further detail.

Method: A cohort of n = 6 individuals with pathogenic variants in and the C-propeptide cleavage variants in were included in this study. Detailed clinical and radiological phenotyping was done and correlated with genotype to identify patterns of clinical presentation and fracture history in this cohort of patients. This data was compared to previously reported literature in this group.

Results: 2 patients with and 4 patients with pathogenic variants in C-propeptide region in were deep-phenotyped as part of this study and 1 patient with C-propeptide variant in , showed low bone mineral density. In those with an elevated bone mineral density, this became even more apparent on bisphosphonate therapy. Patients in this cohort had variable clinical presentation ranging from antenatal presentation to more of an insidious course resulting in later confirmation of genetic diagnosis up to 19 years of age.

Conclusions: Patients with pathogenic variants in the C-propeptide region of and appear to have a high bone mass phenotype with increased sensitivity to bisphosphonate therapy. It is important to closely monitor patients with these genotypes to assess their response to therapy and tailor their treatment regime accordingly.