What is the cause of Fibrodysplasia ossificans progressiva (FOP)?

From the Guidelines

Fibrodysplasia ossificans progressiva (FOP) is caused by a mutation in the ACVR1 gene, specifically a recurrent activating mutation (c.617G>A; p.R206H), which leads to overactive bone morphogenetic protein (BMP) signaling and inappropriate bone formation in soft tissues. The most common mutation is R206H, where the amino acid arginine is replaced by histidine at position 206 in the protein, causing the ACVR1 receptor to become overactive, leading to inappropriate bone formation in soft tissues like muscles, tendons, and ligaments when they experience inflammation or injury 1.

Key Points

• The mutation is typically spontaneous, occurring during early embryonic development, though in some cases it can be inherited from a parent in an autosomal dominant pattern 1.
• The overactive BMP signaling pathway triggered by this mutation results in the characteristic progressive heterotopic ossification seen in FOP patients, where their bodies essentially form a second skeleton of heterotopic bone.
• FOP is characterized by congenital malformations of the great toes and progressive, debilitating heterotopic endochondral ossification in characteristic anatomic patterns 1.
• Currently, there is no FDA-approved treatment specifically for FOP, though clinical trials are investigating potential therapies targeting the abnormal signaling pathway.

Clinical Implications

• The diagnosis of FOP can easily be made by clinical evaluation, and confirmatory genetic testing is available 1.
• Delayed diagnosis still occurs, despite the hallmark changes in great toes, and differential diagnoses are varied but often include progressive osseous heteroplasia (POH), osteosarcoma, lymphoedema, soft tissue sarcoma, desmoid tumours, aggressive juvenile fibromatosis, calcinosis of skin and muscles, infection and non-hereditary (acquired) heterotopic ossification 1.
• Preventative management is based on prophylactic measures against falls, respiratory decline and viral infections, and the median estimated lifespan is 56 years 1.

From the Research

Cause of Fibrodysplasia Ossificans Progressiva (FOP)

The cause of Fibrodysplasia Ossificans Progressiva (FOP) is attributed to genetic mutations, specifically in the ACVR1 gene.

• The ACVR1 gene mutation leads to the substitution of a single amino acid, R206H, in the bone morphogenetic protein (BMP) type I receptor ACVR1, causing mild constitutive activation of the BMP signaling pathway 2.
• This mutation is identified as the primary genetic cause of FOP, with nearly all cases of FOP being caused by the identical mutation in the ACVR1 gene 2.
• The mutation alters the signals that regulate induction of cell differentiation leading to bone formation, resulting in the progressive development of bone in soft tissues 2.
• Additionally, 11 other mutations in the ACVR1 gene have been described as a cause of FOP, although the R206H mutation is the most common 3.
• The overexpression of wild-type ACVR1 has been shown to rescue perinatal lethality and inhibit heterotopic ossification in FOP mice, suggesting a potential therapeutic target for the treatment of FOP 4.
• MicroRNAs, such as miR-148a, have also been found to negatively regulate ACVR1, offering a new potential target for the development of therapeutic agents against FOP 5.