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Fibrodysplasia ossificans progressiva
FOP causes new bone to form in muscles, tendons, and ligaments, progressively restricting movement. This rare condition typically affects approximately one in a million individuals worldwide and is usually diagnosed in early childhood.
Overview
Fibrodysplasia ossificans progressiva (FOP) is a very rare and severe genetic disorder. It primarily involves the abnormal formation of bone outside the normal skeleton, a process known as heterotopic ossification [PMID:33606775]. This extra bone develops within soft connective tissues, such as muscles, tendons, and ligaments. The progressive nature of FOP means that this new bone formation can occur spontaneously or after minor injuries, leading to irreversible loss of joint mobility and significant disability over time. The condition is usually evident in early childhood, often with characteristic malformations of the big toes as an initial sign.
Symptoms & clinical features
Individuals with FOP typically present with two main types of symptoms. The most distinctive early sign is a congenital malformation of the great (big) toes, where they appear shorter and may have a valgus deformity (bent outwards) [PMID:16120531]. This feature is usually present at birth and can be an important diagnostic clue. The second, more debilitating aspect, is the episodic formation of painful, swollen areas in soft tissues, often in the neck, back, or shoulders. These flare-ups can be triggered by minor trauma, vaccinations, or even viral illnesses, and eventually resolve, leaving behind new, permanent bone. Over time, this progressive heterotopic ossification severely limits movement and can lead to a 'second skeleton'.
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Affected organs
FOP primarily affects the musculoskeletal system. The abnormal bone formation can occur in almost any soft connective tissue, including skeletal muscles, tendons (which connect muscle to bone), ligaments (which connect bones to other bones), and fascia (connective tissue surrounding muscles). While the heart muscle and diaphragm (the muscle involved in breathing) are typically spared, chest wall involvement due to heterotopic ossification can lead to restrictive lung disease, impacting breathing capacity. Around the joints, the new bone can fuse bones together, a process called ankylosis, making movement impossible.
Risks & severity
FOP is a severely debilitating condition. The lifetime risk of developing disabling heterotopic ossification is very high once symptoms begin. The severity of FOP varies between individuals, but it is universally progressive. The average life expectancy is around 40 years, often due to complications such as restrictive lung disease or heart failure, which can be secondary to immobility and chest wall restriction [PMID:33606775]. Children generally begin experiencing flare-ups and new bone formation in early childhood, typically before the age of 10. While trauma can trigger episodes, ossification can also occur spontaneously, making prevention challenging. There is currently no cure, and management focuses on preventing flare-ups and managing symptoms.
Genetic causes
Fibrodysplasia ossificans progressiva is caused by pathogenic variants in the ACVR1 gene. This gene provides instructions for making a protein involved in bone and cartilage development and repair. The ACVR1 protein is a receptor that plays a critical role in the bone morphogenetic protein (BMP) signalling pathway, which is essential for guiding bone formation. In FOP, changes within the ACVR1 gene lead to an overactive ACVR1 protein. This overactivity means the BMP pathway is abnormally switched on or remains active when it should not be, leading to the uncontrolled formation of new bone in soft tissues where it shouldn't be present. This gain-of-function mechanism underlies the progressive nature of the condition.
Inheritance pattern
FOP is inherited in an autosomal dominant pattern. This means that a person only needs one copy of the altered ACVR1 gene in each cell to develop the condition. Most cases of FOP (over 90%) are due to new, spontaneous (de novo) genetic changes that occur early in development and are not inherited from a parent. In these cases, there is no family history of FOP. However, if an affected individual has children, each child would have a 50% chance of inheriting the altered gene and therefore developing FOP, regardless of their sex. Genetic counselling is available to discuss inheritance risks for individuals and families.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of FOP is often based on its characteristic clinical features, particularly the malformation of the great toes and episodic soft tissue swelling that later ossifies [PMID:16120531]. Recognising these signs early is crucial to avoid inappropriate medical interventions, such as biopsies, which can worsen the condition by triggering further bone growth. Genetic testing that identifies a pathogenic variant in the ACVR1 gene is used to confirm the diagnosis. In the UK, genetic testing for FOP is available through the NHS Genomic Medicine Service (GMS), often following a referral from a specialist paediatrician or clinical geneticist. The relevant R-code for FOP genetic testing is currently R145 Fibrodysplasia ossificans progressiva.
Management & lifestyle
Currently, there is no cure for FOP, and management focuses on supportive care, preventing flare-ups, and managing symptoms. Avoiding injuries, intramuscular injections, and certain dental procedures that could trigger new bone growth is important. Corticosteroids may be used for short durations during acute flare-ups to reduce inflammation, though their effect on preventing new bone formation is limited. Physiotherapy can be helpful to maintain existing mobility, but aggressive movements or surgery are generally avoided due to the high risk of stimulating further ossification. Research into disease-modifying therapies that target the overactive ACVR1 pathway is ongoing, offering future hope for treatment. Individuals with FOP receive care through specialist centres, often coordinated by clinical geneticists and other multidisciplinary teams within the NHS.
UK care pathway
In the UK, suspected cases of FOP are typically referred to a clinical geneticist or a specialist paediatrician. These specialists can then refer for genetic testing through the NHS Genomic Medicine Service, using the appropriate R-code, such as R145 for Fibrodysplasia ossificans progressiva. A confirmed genetic diagnosis enables access to specialist care pathways, including genetic counselling, to understand the condition, its inheritance, and implications for the wider family. Genetic counsellors offer support and information throughout the diagnostic and management process.
Frequently asked questions
What causes FOP?
FOP is caused by a genetic change (pathogenic variant) in the ACVR1 gene. This change makes a protein involved in bone development overactive, leading to new bone forming in soft tissues where it shouldn't.
Is FOP inherited from my parents?
Most cases of FOP are due to new genetic changes that happen spontaneously and are not inherited from a parent. However, once a person has FOP, there is a 50% chance of passing the condition on to each child they have.
What are the first signs of FOP?
The earliest and most distinctive sign of FOP is usually a malformation of the big (great) toes, which are often shorter and may be bent outwards. Swelling in soft tissues that later turns into bone often appears in early childhood.
Can FOP be cured?
Currently, there is no cure for FOP. Treatment focuses on preventing flare-ups that cause new bone growth, managing pain, and maintaining as much mobility as possible. Research is ongoing to find effective therapies.
Can vaccinations trigger FOP flare-ups?
Yes, intramuscular injections, such as vaccinations, have been reported to trigger FOP flare-ups in some individuals due to the associated tissue trauma. It is important to discuss vaccination strategies with your specialist healthcare team if you have FOP.
References
- Kaplan FS, Al Mukaddam M, Baujat G. Medical guidelines for fibrodysplasia ossificans progressiva. JBMR plus. 2025. PMID: 41143155
- Smit C, Uys A. Fibrodysplasia ossificans progressiva. Clinical case reports. 2023. PMID: 37942184
- Acosta CES, Fernández ER. Fibrodysplasia Ossificans Progressiva. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2021. PMID: 35073643
- Diolintzi A, Pervin MS, Hsiao EC. Immunologic Aspects in Fibrodysplasia Ossificans Progressiva. Biomolecules. 2024. PMID: 38540775
- Juan C, Bancroft AC, Choi JH. Intersections of Fibrodysplasia Ossificans Progressiva and Traumatic Heterotopic Ossification. Biomolecules. 2024. PMID: 38540768
- Khan F, Yu X, Hsiao EC. Cardiopulmonary and Neurologic Dysfunctions in Fibrodysplasia Ossificans Progressiva. Biomedicines. 2021. PMID: 33562570
- Haga N, Nakashima Y, Kitoh H. Fibrodysplasia ossificans progressiva: Review and research activities in Japan. Pediatrics international : official journal of the Japan Pediatric Society. 2020. PMID: 31774601
- Smilde BJ, Botman E, de Ruiter RD. Monitoring and Management of Fibrodysplasia Ossificans Progressiva: Current Perspectives. Orthopedic research and reviews. 2022. PMID: 35480068