A novel COL1A2 C-propeptide cleavage site mutation causing high bone mass osteogenesis imperfecta with a regional distribution pattern

Osteogenesis imperfecta (OI) is typically characterized by low bone mass and increased bone fragility caused by heterozygous mutations in the type I procollagen genes (COL1A1/COL1A2). We report two cases of a 56-year-old woman and her 80-year-old mother who suffered from multiple vertebral and non-vertebral fractures with onset in early childhood. A full osteologic assessment including dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and serum analyses pointed to a high bone mineral density (BMD) in the hip (DXA Z-score + 3.7 and + 3.9) but low to normal bone mass in the spine and preserved bone microstructure in the distal tibia. Serum markers of bone formation and bone resorption were elevated. Using whole exome sequencing, we identified a novel mutation in the COL1A2 gene causing a p. (Asp1120Gly) substitution at the protein level and affecting the type I procollagen C-propeptide cleavage site. In line with previously reported cases, our data independently prove the existence of an unusual phenotype of high bone mass OI caused by a mutation in the procollagen C-propeptide cleavage with a clinically persistent phenotype through adulthood.