Fibrodysplasia Ossificans Progressiva: A Rare Disorder

Fibrodysplasia ossificans progressive (FOP), previously known as myositis ossificans progressiva (MOP) and also referred to as Münchmeyer disease or Stoneman disease, is a rare connective tissue disease characterized by the abnormal formation of bone in soft tissues, a process known as heterotopic ossification. This progressive condition, caused by mutations in the ACVR1 gene, leads to severe disability as muscles, tendons, and ligaments are gradually replaced by bone. The mutation affects the bone morphogenetic protein (BMP) signaling pathway, resulting in inappropriate bone growth. This is a severely debilitating disorder that restricts movement and leads to progressive loss of mobility as bone replaces muscles and tendons. Patients with fibrodysplasia ossificans progressiva have congenital malformations (malformed big toes) at birth.¹Kaplan MD (Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine), F.S. et al. (2008) Fibrodysplasia Ossificans Progressiva, Best Practice & Research Clinical Rheumatology. Retrieved 17 October 2023 from https://www.sciencedirect.com/science/article/abs/pii/S1521694207001313 An injury or disease triggers the formation of bone in areas where the bone is not usually present.
Although rare, fibrodysplasia ossificans progressiva predisposes the patient to fatal complications and early death.²Nucci A, Queiroz LS, Santos AO, Camargo EE, Ribeiro MVLM. Fibrodysplasia ossificans progressiva. Arq. Neuro-Psiquiatr. São Paulo June 2000;58:2A.

Prevalence of Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is an infrequent disorder that affects one individual in every 2 million people.³Baujat, G. et al. (2017) Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: An estimate based on a record linkage of two national databases – orphanet journal of rare diseases, BioMed Central. Retrieved 17 October 2023 from https://ojrd.biomedcentral.com/articles/10.1186/s13023-017-0674-5 The estimated population affected by FOP is 4000, with 900 confirmed cases. The disease occurs in people of all ethnicities and equally in men and women.

Fibrodysplasia Ossificans Progressiva Causes

Fibrodysplasia ossificans progressiva (FOP) is a monogenic disorder caused by a random mutation in the AVCR1 gene.⁴Shore, E.M. et al. (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva, Nature News. Retrieved 18 October 2023 from https://www.nature.com/articles/ng1783 The AVCR1 gene regulates the formation of type I receptors for bone morphogenic protein (BMP), which controls the growth and development of bones and muscles. The mutant ACVR1 gene disrupts the normal mechanism that controls the activity of this receptor, causing the receptor to remain active permanently. Hyperactivity of the receptor causes overgrowth of bones and abnormal replacement of soft connective tissues by bones (ossification).

Fibrodysplasia Ossificans Progressiva Symptoms

Heterotopic ossification in non-osseous soft tissues is the predominant symptom of fibrodysplasia ossificans progressiva. The following signs and symptoms characterize it:

• Impaired movement
• Problems with eating and speaking
• Permanent immobility
• Hearing loss
• Purple or red, hot, painful tumor-like areas
• Hallux valgus (malformed great toe)⁵ Kitterman, J.A. et al. (2012) Neurological symptoms in individuals with fibrodysplasia Ossificans Progressiva – Journal of Neurology, SpringerLink. Retrieved 18 October 2023 from https://link.springer.com/article/10.1007/s00415-012-6562-y

People with FOP present with limited movement due to extraskeletal bone formation. First, signs appear during childhood in the neck and shoulder, and then they proceed to the lower body parts. It appears as a painful tumor-like outgrowth that gradually transforms into a bone. Any trauma, like an illness or surgery, triggers muscle inflammation and worsens the condition.

Fibrodysplasia Ossificans Progressiva Genetic Consultation

FOP appears as a result of random mutations in the ACVR1 gene. The disease passes on from parents to offspring as an autosomal dominant trait. Children of parents with FOP have a 50% chance of developing fibrodysplasia ossificans progressiva.⁶ Pignolo, R.J., Shore, E.M. and Kaplan, F.S. (2011) Fibrodysplasia Ossificans Progressiva: Clinical and genetic aspects – Orphanet Journal of rare diseases, BioMed Central. Retrieved 18 October 2023 from https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-6-80 Mothers with FOP are at risk of developing fatal complications during pregnancy.
Some common risks to pregnant women with FOP are:

• FOP flare-up
• Breathing difficulties in later pregnancy
• Complications during childbirth. For instance, a cesarean section is inevitable due to deformity of the pelvic bone and decreased vaginal flexibility.

Potential complications in children born to parents with FOP are:

• Risk of developing FOP
• Premature birth
• Chance of developing cerebral palsy
• Complications due to general anesthesia

Complications of Fibrodysplasia Ossificans Progressiva

Most people die due to complications associated with FOP. The most common complications are respiratory infections, cardiopulmonary complications, and joint disabilities. FOP flare-ups worsen the symptoms, and ossification occurs in many body systems. The following systems are commonly affected by FOP flare-ups:

Cardiorespiratory System:

Thoracic insufficiency is the most fatal complication of FOP that causes respiratory problems.⁷Kaplan, F.S. and Glaser, D.L. (2005) Thoracic insufficiency syndrome in patients with fibrodysplasia ossificans progressiva – clinical reviews in bone and mineral metabolism, SpringerLink. Retrieved 18 October 2023 from https://link.springer.com/article/10.1385/BMM:3:3-4:213 Thoracic insufficiency syndrome leads to right-sided heart failure and pneumonia.

Renal System:

The risk of acquiring kidney stones increases two-fold in FOP patients. Individuals with FOP are more likely to get kidney stones due to low water and fiber intake and UTIs.

Auditory System:

FOP exacerbation causes ossification of the middle ear, which ultimately causes hearing impairment. Half of the individuals diagnosed with FOP are susceptible to hearing loss.

Immune System:

A compromised immune system makes a person with FOP prone to viral infections. Viral illnesses trigger FOP symptoms that cause inflammation in joints.

Integumentary System:

Bone replaces soft tissues in individuals with FOP. This causes pressure sores due to a reduction in soft tissues.

Fibrodysplasia Ossificans Progressiva Diagnosis

• Early diagnosis is based on a physical examination to detect two predominant symptoms of fibrodysplasia ossificans progressiva. First is the malformed great toe, usually pointed inwards, and second is the development of a tumorous mass at the neck, shoulder, or back that soon turns into a bone.
• Biochemical analysis⁸ Pignolo, R.J., Shore, E.M. and Kaplan, F.S. (2013) Fibrodysplasia Ossificans Progressiva: Diagnosis, management, and Therapeutic Horizons, Pediatric endocrinology reviews : PER. Retrieved 18 October 2023 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995352/ of heterotopic bone is the same as that of normal bone, but the position of heterotopic bone confirms FOP. ESR and serum alkaline phosphatase levels are generally raised during flare-ups.
• Imaging techniques provide a clear view of ectopic skeleton formation. A plain X-ray exhibits atypical bone formation, and a CT Scan also reveals lesions with ectopic ossification. MRI is the most accurate and advanced radiological technique that shows pre-osseous lesions that later form a bone.
• However, confirmed diagnosis is based on gene sequencing through PCR.
• A biopsy may trigger osteogenesis and worsen FOP symptoms, so it is not a good option for diagnosis.

Fibrodysplasia Ossificans Progressiva Treatment

Treatment for FOP is mainly symptomatic, without a single option to cure it completely. Various agents are available for symptomatic management of flare-ups. Following are some of the commonly used agents:

• High-dose corticosteroids provide relief during flare-ups but are not suitable for long-term use.⁹Gabriela, M. (2018) Fibrodysplasia Ossificans Progressiva – diposit.ub.edu, Diposit Digital. Retrieved 18 October 2023 from https://diposit.ub.edu/dspace/bitstream/2445/128152/1/128152.pdf
• NSAIDs, COX-2 inhibitors, amino bisphosphonates, and Mast cell inhibitors are used to reduce inflammation during later flare-ups.
• Muscle relaxants are given in small doses in case of muscle spasms.
• The only FDA-approved drug is palovarotene, which inhibits abnormal bone formation by interfering with proteins, receptors, and growth factors participating in the retinoid signaling pathway.

Multiple novel strategies target the pathways involved in the pathogenesis of FOP. One potential way is to block the activity of the ACVR1/ALK2 gene pathway that inhibits abnormal osteogenesis. Another option is to block the activity of osteoblastic progenitor cells, which obstructs the precise environment for heterotopic ossification. Surgery is not a good choice for such types of patients.

Fibrodysplasia Ossificans Progressiva Prognosis

Fibrodysplasia ossificans is a lifetime disorder with no cure till today. People with this condition usually do not live past 40 years and become utterly immobile by 30 years. However, respiratory infection is the common cause of death in such people. The disease has a poor outlook due to its progressive nature, severity of symptoms, and complications.

Fibrodysplasia Ossificans Progressiva Prevention

Although FOP is a genetic disorder, various preventative measures are helpful to avoid flare-ups that worsen the condition. An occurrence that creates stress in the body, like trauma, surgery, or an illness, leads to an FOP flare-up. Prevention includes avoiding circumstances that cause flare-ups.

• Avoid the risk of injury by limiting physical activity to indoors
• Prefer subcutaneous injection instead of intramuscular injection
• Take precautionary measures to avoid viral illnesses
• Go for diagnostic procedures except tissue biopsy
• Use local anesthetics during a dental procedure

Lifestyle With FOP

When diagnosed with FOP, consult your healthcare provider for an individualized treatment plan. You might consult a genetic counselor to assess the probability of your offspring with FOP. Adopt a lifestyle that limits FOP flare-ups and worsening of symptoms. Consult your healthcare provider to alleviate symptoms during flare-ups to avoid complications.
You should tell your healthcare provider if you face any of the following symptoms:

• Persistent swelling
• Severe pain
• Problems in eating
• Stiffness in joints and restricted mobility
• Breathing difficulty

Final Words

Fibrodysplasia ossificans progressiva is a genetic disease characterized by ectopic bone formation. Living with FOP involves adopting a lifestyle to minimize flare-ups that aggravate symptoms and shorten the lifespan. Once diagnosed with FOP, your healthcare provider will suggest lifestyle modifications and medications to ease symptoms. Genetic counseling also helps understand patterns of FOP inheritance and transmission.

Refrences

• 1
  Kaplan MD (Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine), F.S. et al. (2008) Fibrodysplasia Ossificans Progressiva, Best Practice & Research Clinical Rheumatology. Retrieved 17 October 2023 from https://www.sciencedirect.com/science/article/abs/pii/S1521694207001313
• 2
  Nucci A, Queiroz LS, Santos AO, Camargo EE, Ribeiro MVLM. Fibrodysplasia ossificans progressiva. Arq. Neuro-Psiquiatr. São Paulo June 2000;58:2A.
• 3
  Baujat, G. et al. (2017) Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: An estimate based on a record linkage of two national databases – orphanet journal of rare diseases, BioMed Central. Retrieved 17 October 2023 from https://ojrd.biomedcentral.com/articles/10.1186/s13023-017-0674-5
• 4
  Shore, E.M. et al. (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva, Nature News. Retrieved 18 October 2023 from https://www.nature.com/articles/ng1783
• 5
  Kitterman, J.A. et al. (2012) Neurological symptoms in individuals with fibrodysplasia Ossificans Progressiva – Journal of Neurology, SpringerLink. Retrieved 18 October 2023 from https://link.springer.com/article/10.1007/s00415-012-6562-y
• 6
  Pignolo, R.J., Shore, E.M. and Kaplan, F.S. (2011) Fibrodysplasia Ossificans Progressiva: Clinical and genetic aspects – Orphanet Journal of rare diseases, BioMed Central. Retrieved 18 October 2023 from https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-6-80
• 7
  Kaplan, F.S. and Glaser, D.L. (2005) Thoracic insufficiency syndrome in patients with fibrodysplasia ossificans progressiva – clinical reviews in bone and mineral metabolism, SpringerLink. Retrieved 18 October 2023 from https://link.springer.com/article/10.1385/BMM:3:3-4:213
• 8
  Pignolo, R.J., Shore, E.M. and Kaplan, F.S. (2013) Fibrodysplasia Ossificans Progressiva: Diagnosis, management, and Therapeutic Horizons, Pediatric endocrinology reviews : PER. Retrieved 18 October 2023 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995352/
• 9
  Gabriela, M. (2018) Fibrodysplasia Ossificans Progressiva – diposit.ub.edu, Diposit Digital. Retrieved 18 October 2023 from https://diposit.ub.edu/dspace/bitstream/2445/128152/1/128152.pdf