Fibrodysplasia Ossificans Progressiva (Stoneman Disease, or Münchmeyer Disease)
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder where soft tissues of the body transform into bone. Muscles, tendons, and ligaments gradually become bony, which eventually makes them too rigid to move. People with FOP experience stiffness and limited movement that begins during childhood and worsens over time.[1] The condition is disabling with a median life expectancy of 56 years.[2]
Other names for FOP include Stoneman disease or Münchmeyer disease.[3]
Prevalence
FOP is a very rare condition. It is estimated that FOP affects roughly 1 in 1 million people worldwide.[3] A study of FOP prevalence in the United States estimated that 0.88 in 1 million Americans have FOP.[4]
Clinical Features
Features that are present at birth (congenital):
- Malformations of the big toes, usually on both feet. This can include shortened big toes and/or bunions (hallux valgus).[5][6]
- Skeletal malformations. This can include thumb malformations, curved spine (scoliosis), and others.[5][7]
- “Flare-ups”: episodic swelling of soft tissues. Tissues include muscle, tendons, ligaments, and other soft tissues. This can happen unpredictably or after an injury. Areas affected by a flare-up may begin transforming to bone. Flare-ups are painful and begin in early childhood.
- Osteochondromas: overgrowth of bones near the growth plates. Most often occurs in the tibia (shinbone, the larger of the two bones in the lower leg).
- Heterotropic ossification: bone formation in soft tissues outside of the normal skeleton. This usually begins before age ten, but can start later in some people. This can happen anywhere in the body and cannot be reversed. It usually starts in the core bones of the body such as the head, neck, spine, and ribcage (axial skeleton). Over time, it can spread to the limbs and other parts of the body (appendicular skeleton).
- Thoracic insufficiency syndrome: difficulty breathing because the airways and muscles around the ribcage are becoming too rigid. This is the most common cause of mortality in FOP.
Diagnosis
There are no formal diagnostic criteria for FOP. The gold standard diagnostic test for FOP is a genetic test that finds a disease-causing mutation in the ACVR1 gene. A clinical diagnosis is given for individuals with big toe malformations at birth (congenital hallux valgus malformation) and heterotropic ossification.[5]
People with FOP are usually misdiagnosed. For example, osteochondromas are often misdiagnosed as cancers, especially if big toe malformation and other signs of FOP were initially overlooked. Big toe malformations and heterotropic ossification are what make FOP different from other disorders of bone formation.[5]
Misdiagnosis can lead to unnecessary surgical intervention, causing trauma to soft tissues during surgery that triggers tissue transformation into bone. This can cause permanent loss of mobility. A survey published in 2005 showed that 87% of people with FOP were misdiagnosed, and 67% of FOP patients had unnecessary surgery.[8] Almost half of the people who had unnecessary surgery developed permanently mobility problems as a result.[8]
Inheritance
FOP is a genetic disorder, which means it is caused by a change in DNA that happens by chance. Changes in the ACVR1 gene lead to FOP.[5]
Most of the time, a person with FOP is the first member of the family with the disorder. The change in the ACVR1 gene happened in that person for the first time, and none of their family members have this gene change. This called a de novo change. In other cases, a person with FOP inherited the gene change from one of their parents who also has FOP.[5]
The inheritance pattern for FOP is autosomal dominant. This means that one copy of the altered ACVR1 gene is enough to cause FOP. Everybody carries two copies of the ACVR1 gene. People without FOP have two normal copies of ACVR1. People who have FOP have one normal copy and one altered copy that causes the disease. If a person with FOP has a child, they will randomly pass on either the normal copy or the altered copy of ACVR1. The chance that a person with FOP will pass on the altered copy to their child is 50%. FOP is fully penetrant, which means that all people who carry the altered ACVR1 gene change will have the disease.[5]
Genetic Testing
If a diagnosis of FOP is suspected, genetic testing can be performed by single-gene testing of the ACVR1 gene or a skeletal dysplasia panel that includes ACVR1.[5] Because FOP is rare, it is common that FOP is not considered as a possible diagnosis due to unawareness of the condition. In this case, genetic testing may be performed by whole exome or genome sequencing to sequence all genes.[5]
Treatment and Management
There is no definitive treatment for FOP and no cure. Symptoms are managed on a case-by-case basis to help people with FOP adapt their daily routines. This can include:
- avoiding falls, injuries, and unnecessary surgery or dental work. Damage to soft tissues can trigger tissue transformation into bone [2]
- getting vaccinations in the skin (subcutaneous) instead of in the muscle (intramuscular) [9]
- anti-inflammatory medications to reduce flare-ups [9]
- occupational therapy to adapt daily routines around restricted mobility [9]
- using mobility equipment like braces and wheelchairs [9]
- training to improve lung capacity such as swimming and singing. Especially important for those with thoracic insufficiency syndrome [2]
- dietician if reduced jaw mobility causes difficulty eating [2]
- mental health support for anyone who finds it hard to adapt to life with FOP [2]
- genetic counselling. A genetic counsellor can help you understand your diagnosis, explain how FOP runs in the family and identify at-risk family members, and provide emotional support [9]
Clinical Trials
To find new treatments that are currently in clinical trials, please visit:
- International FOP Association (IFOPA): https://www.ifopa.org/ongoing_clinical_trials_in_fop
- ClinicalTrials.gov from the NIH: https://clinicaltrials.gov/search?cond=fibrodysplasia%20ossificans%20progressiva&aggFilters=status:rec
Psychosocial Implications
People who live with FOP are resilient and adaptable, and many can build fulfilling lives. FOP comes with a unique set of challenges beyond the medical aspects, including:
- spending lots of time in doctor’s offices and at medical appointments
- the diagnostic odyssey: the long process of getting a diagnosis
- being misdiagnosed
- adapting to a new diagnosis of FOP
- difficulty finding other people with FOP to connect with, because it is so rare
- having to explain FOP to family, friends, doctors, and new people you meet
- navigating family dynamics and relationships with caregivers
There are supports for anyone facing these challenges. See “Patient Resources” below.
Patient Resources
1. International FOP Association (IFOPA): https://www.ifopa.org/
This non-profit organization provides:
- information about FOP
- information about research studies on FOP
- patient stories from people living with FOP and their families
- support groups for anyone impacted by FOP
- other patient resources
2. Canadian FOP Network: http://www.cfopn.org/
A non-profit Canadian charity that raises funds for research into new FOP treatments.
3. FOP Australia: https://fopaustralia.org/
Advocacy organization based in Australia and New Zealand that aims to promote education about FOP, provide a support network for affected families, and raise funds for research.
Glossary of Terms:
The following are terms you might see if you decide to do your own research about FOP.
- bilateral: both sides of the body
- congenital: present at birth
- hallux valgus: bunion
- heterotopic ossification: development of bony tissue in places where bone is not usually present. Non-bony tissues transforming into bone.
- ossification: process of forming bone
- progressive disease: gets worse over time
For a more extensive list of searchable terms related to FOP, visit the IFOPA glossary: https://www.ifopa.org/glossary
References
- ↑ Agrawal U, Tiwari V. Fibrodysplasia Ossificans Progressiva. [Updated 2023 Aug 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK576373/
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Smilde, B. J., Botman, E., Ruiter, R. D. de, Smit, J. M., Teunissen, B. P., Lubbers, W. D., Schwarte, L. A., Schober, P., & Eekhoff, E. M. W. (2022). Monitoring and Management of Fibrodysplasia Ossificans Progressiva: Current Perspectives. Orthopedic Research and Reviews, 14, 113–120. https://doi.org/10.2147/ORR.S337491
- ↑ 3.0 3.1 "Fibrodysplasia ossificans progressiva". Medline. Jul 15, 2022. Retrieved Jan 13, 2024.
- ↑ Pignolo, R. J., Hsiao, E. C., Baujat, G., Lapidus, D., Sherman, A., & Kaplan, F. S. (2021). Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: Estimate from three treatment centers and a patient organization. Orphanet Journal of Rare Diseases, 16(1), 350. https://doi.org/10.1186/s13023-021-01983-2
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 Akesson, Lauren; Savarirayan, Ravi (May 11, 2023) [June 11, 2020]. "Fibrodysplasia Ossificans Progressiva". GeneReviews. Retrieved Jan 13, 2024.
- ↑ Towler, O. W., Kaplan, F. S., & Shore, E. M. (2020). The Developmental Phenotype of the Great Toe in Fibrodysplasia Ossificans Progressiva. Frontiers in Cell and Developmental Biology, 8, 612853. https://doi.org/10.3389/fcell.2020.612853
- ↑ Anwar, S., & Yokota, T. (2023). Navigating the Complex Landscape of Fibrodysplasia Ossificans Progressiva: From Current Paradigms to Therapeutic Frontiers. Genes, 14(12), Article 12. https://doi.org/10.3390/genes14122162
- ↑ 8.0 8.1 Kitterman, J. A., Kantanie, S., Rocke, D. M., & Kaplan, F. S. (2005). Iatrogenic Harm Caused by Diagnostic Errors in Fibrodysplasia Ossificans Progressiva. Pediatrics, 116(5), e654–e661. https://doi.org/10.1542/peds.2005-0469
- ↑ 9.0 9.1 9.2 9.3 9.4 "Fibrodysplasia Ossificans Progressiva". Cleveland Clinic. Nov 29, 2022. Retrieved Jan 13, 2024.