O Will Towler1, Eileen M Shore2, Frederick S Kaplan3. 1. Departments of Orthopaedic Surgery, The University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Departments of The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States. 2. Departments of Orthopaedic Surgery, The University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Departments of Genetics, The University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Departments of The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States. 3. Departments of Orthopaedic Surgery, The University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Departments of Medicine, The University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States; Departments of The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, 3450 Hamilton Walk, 309A Stemmler Hall, Philadelphia, PA 19104, United States. Electronic address: Frederick.Kaplan@uphs.upenn.edu.
Abstract
RATIONALE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 degenerative joint disease occurring at multiple sites starts in adolescence and progresses throughout life. These phenotypes appear to be uncoupled from heterotopic bone formation, indicating a potential role for ACVR1 in the development and progression of degenerative joint disease. SIGNIFICANCE: FOP is a disease of not only progressive heterotopic ossification, but also widespread and extensive developmental arthropathy and associated degenerative joint disease. These findings have relevance for understanding the natural history of FOP and for designing and evaluating clinical trials with emerging therapeutics.
RATIONALE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 degenerative joint disease occurring at multiple sites starts in adolescence and progresses throughout life. These phenotypes appear to be uncoupled from heterotopic bone formation, indicating a potential role for ACVR1 in the development and progression of degenerative joint disease. SIGNIFICANCE: FOP is a disease of not only progressive heterotopic ossification, but also widespread and extensive developmental arthropathy and associated degenerative joint disease. These findings have relevance for understanding the natural history of FOP and for designing and evaluating clinical trials with emerging therapeutics.