Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva

•Fibrodysplasia ossificans progressiva (FOP) causes characteristic joint and skeletal dysmorphology throughout the body.•Individuals with FOP frequently develop early onset degenerative arthropathy of the spine and lower limbs.•Hip dysplasia, ankylosed vertebral and costovertebral joints, and fused proximal tibio-fibular joints are common in FOP. Fibrodysplasia ossificans progressiva (FOP) is primarily a disease of progressive heterotopic ossification (HO) leading to impaired mobility throughout life. An additional diagnostic feature is a characteristic malformation of the great toes. The culpable gene for FOP,ACVR1 (activin A receptor type 1) has a clear effect on the induction of extra-skeletal bone formation. However, this bone morphogenetic protein (BMP) pathway receptor is expressed widely throughout skeletal development and has a seminal role in axial and appendicular chondrogenesis, prompting suspicion of widespread bone and joint defects in those with ACVR1 mutations. We analyzed baseline whole body (minus skull) computed tomographic (CT) scans of 113 individuals with classic clinical features of FOP and the ACVR1 (R206H) mutation who were enrolled in a non-interventional natural history study ((NCT02322255)) for skeletal malformations, atypical morphology, intra-articular synovial osteochondromatosis, developmental arthropathy, and associated degenerative joint phenotypes. Individuals were evaluated in three age groups: 4–13; 14–25; and 25–56 years old, based on historical models of FOP disease progression. We found widespread evidence of developmental arthropathy throughout the axial and appendicular skeleton in all age groups (61M, 52F; ages: 4–56 years). Asymmetric narrowing and subchondral sclerosis were present throughout the joints of the normotopic skeleton and osteophytes were common in the hips and knees of individuals who have FOP in all age groups. The costovertebral joints, intervertebral facet joints, and proximal tibio-fibular joints frequently showed partial or total intra-articular ankylosis, particularly after age 13. The hips of FOP subjects are frequently malformed and dysplastic. We also found evidence of degenerative joint phenotypes after age 13, particularly in the spine, sacro-iliac joints, and lower limbs. The effects of ACVR1 mutation on the normotopic skeletons of individuals who have FOP extend beyond malformation of the great toes and include both morphological defects and developmental arthropathy. Associated degenera