What Is Fibrodysplasia Ossificans Progressiva?

  • Aumiyo Kumar DasB.D.S., MSc. Oral Medicine – University of Bristol, United Kingdom
  • Philip James ElliottB.Sc. (Hons), B.Ed. (Hons) (Cardiff University), PGCE (University of Strathclyde), CELTA (Cambridge University) , FSB, MMCA

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Introduction

Fibrodysplasia ossificans progressiva (FOP), also referred to as progressive myositis ossificans, is an extremely rare, incurable and progressive genetic disorder that causes the bone to form where it should not – in soft tissues (muscles, tendons, ligaments etc.).

FOP affects approximately 1 in 2 million people worldwide. It is a debilitating, and often fatal disease that starts in early childhood.1,2 Whereas traumatic and non-traumatic myositis ossificans (MO) appear in single muscles, FOP progresses to many different muscles, as well as other soft tissues, including tendons, ligaments and fascia, and can be triggered by minor traumas such as bruises and falls.1

There is currently no cure for FOP, so the mainstays of treatment include: managing symptoms through medication in the early stages of an inflammatory flare-up, maintaining functional mobility (normal movement) in joints, and pain relief.

What are the symptoms of fibrodysplasia ossificans progressiva?

The earliest sign of FOP in children is deformed big toes, whereby the big toes look shorter than other toes, and bend inwards – this is followed by fast-growing soft tissue masses that start developing in infants and young children.1,4 Children also experience acute bouts of inflammation – referred to as ‘flare-ups’ – throughout their early childhood, followed by heterotopic ossification (HO) within their soft tissues.1

Heterotopic ossification is the medical name used to describe the process of bone forming in soft tissues:5

  • Heterotopic means the formation of tissue in a part where its presence is abnormal
  • Ossification describes the process of bone formation6

Typically, flare-ups are caused by small traumas, such as bumps and falls, as well as childhood vaccination injections into muscles.1 However, in some cases, the flare-ups with subsequent HO in soft tissues can happen spontaneously without any known cause.8 

Pignolo et al conducted a global survey on 500 FOP patients which included questions about how patients described their flare-up symptoms.7 Patients described their most common flare-up symptoms as:

  • Swelling
  • Pain
  • Decreased movement
  • Joint stiffness
  • Warmth in the soft tissue
  • Redness in the soft tissue

Because FOP is progressive, a patient may have multiple soft tissue masses at any given time; some in early stages of flare-up and some with mature bone having been formed, and with occurrence in different areas of the body.1,8

Additionally, HO tends to follow a progressive bodily pattern, with the soft tissues around the head and spine affected first.5,8 An example of how this affects infants with FOP is the inability to crawl properly because the cervical vertebrae (first 7 vertebrae nearest the head) are affected, which prevents the infant from being able to extend their head and neck to crawl.8

As the disease progresses, the soft tissues further away from the head and spine also begin to form bone, including in the arms and legs. Some patients are reported to be confined to a wheelchair by the age of 30.8

Which genetic mutation causes fibrodysplasia ossificans progressiva?

FOP is caused by a spontaneous mutation of a specific gene, which changes how specific proteins it codes for function.

In FOP, a spontaneous mutation occurs in a gene called the activin receptor type IA gene (ACVR1), also known as the activin-like kinase 2 (ALK2) gene.1,4,8 

The ACVR1/ALK2 gene has a receptor (think of it like an arm that reaches out) that attaches to another receptor on a protein called a bone morphogenetic protein (BMP).9 BMPs are molecules are well known for instructiing mesenchymal stem cells through signalling to turn into bone.10 

Scientists have discovered a specific type of mutation that occurs in the ACVR1/ALK2 gene known as a R206H mutation.1,4,8,11 It is suggested that this specific mutation of the gene occurs in 90-98% of all FOP cases.4,8,12 However, other mutations have also been identified in recent years, which also affect the ACVR1/ALK2 gene.

In people with FOP, these gene mutations cause hyperactivity in the signalling to BMP for bone formation and thus lead to abnormal bone formation.11,13,14

The mutated ACVR1/ALK2 gene can be passed down from either parent and is known as autosomal dominant, meaning that if one parent carries the gene, it is enough to pass it onto their child.

Although the vast majority of FOP patients have the same genetic mutation on the ACVR1/ALK2 gene, the phenotype (how the disease physically presents itself) varies between patients, depending on their environment and history such as: exposure to viruses, soft tissue injuries and vaccine injections into muscle.4

Physical pathway of fibrodysplasia ossificans progressiva

Following is a detailed stepwise walkthrough of how flare-ups turn into heterotopic ossification (HO) in soft tissues: 

  • Injury or trauma to soft tissue occurs (in most cases)
  • Soft-tissue masses fill with inflammatory cells
  • Healthy soft tissue is damaged
  • Soft tissue develops blood vessels13 and lots of fibroblasts
  • Cartilage and HO result in bone formation in soft tissues
  • Joints become stiff and sometimes fuse together

How is fibrodysplasia ossificans progressiva diagnosed?

Until recently, FOP was generally diagnosed by the presence of malformed big toes and rapidly growing soft tissue masses.1,2,4,5,8

However, because these symptoms aren’t specific, FOP may be misdiagnosed as cancerous soft tissue tumours, known as soft tissue sarcomas

Historically, such misdiagnoses led to horrific consequences for patients because doctors unknowingly included invasive diagnostic tests and surgeries, which often caused more flare-ups and an explosion of new HO in soft tissues.1,4 

Thankfully, patients can now be tested for ACVR1 mutations, after improvements in genetic testing, which will confirm the diagnosis without the need for invasive investigations and unnecessary surgeries.

How is fibrodysplasia ossificans progressiva monitored?

Blood tests

Doctors may use general blood tests to look for levels of inflammation, however, to date, there are no specific blood tests to measure the progression of FOP, and the current blood tests may only reveal the disease during inflammatory flare-up periods.8

Since FOP is progressive, patients often have soft tissue masses throughout their bodies, in different stages of HO, which may not be picked up in the blood tests.

Imaging

Computerised Tomography (CT) scans are used to monitor FOP progression. However, they may not always be the most useful form of scan in the early inflammatory stages of an FOP soft tissue mass. This is because CT scans are brilliant at viewing bone, however, in the early inflammatory stages of FOP, bone may not be fully formed in the soft tissue mass being scanned, and therefore not visible on the CT scan.8,15

In contrast, Magnetic Resonance Imaging (MRI) has been used to scan FOP and is the favoured imaging method to view soft tissues, and has therefore been shown to good at detecting oedema (swelling) within FOP soft tissue masses. However, it doesn’t have the greatest capability for detecting FOP in its later stages once the inflammatory flare-up has subsided and mature bone cells are formed.16 

Two other unique methods have proven more effective in monitoring the progression of FOP:

1. Cumulative analogue joint involvement scale (CIJAS)

Kaplan et al created the CAJIS scale based on clinical observations of 800 FOP patients over a 25-year period. The study to test the CAJIS scale was conducted on 144 patients with FOP who were seen in hospital clinics around the world, between 2012 and 2015. The scale measures the amount of mobility and restriction patients had in 15 different joints, which corresponds to how much FOP restricted joint mobility and the patients’ daily activities.17

The CAJIS scale is therefore a non-invasive and easily replicable way for doctors to measure how FOP is progressing in patients as part of a patient’s routine hospital appointment.

2. Specialised NaF PET/CT scans

These are a special type of PET-CT scan that involves a radiotracer being injected into the patient’s blood. This radiotracer is called 18F-sodium fluoride (18F-NAF).17 Our bodies naturally absorb this type of tracer into bone, so when FOP patients are in the PET-CT scanner, tissues that are dense with bone light up and are seen clearly.18

F-NAF PET/CT scans have been shown to show the affected soft tissue in early flare-up stages and predict the area of soft tissue that will undergo HO, before a standard CT scan can pick it up.17,15,19 16,20 A case study of a female FOP patient used NAF PET/CT scans to successfully detect an inflammatory flare-up in her jaw muscles within 1 month after jaw surgery.17,20 Later CT scans confirmed that the patient did develop HO in the same jaw muscles predicted.20

How is fibrodysplasia ossificans progressiva treated?

There is currently no cure and very little treatment for FOP, therefore, treatment is mainly focused on managing symptoms of flare-ups, preventing soft-tissue injuries and maintaining patients’ quality of life.

Steroids and NSAIDs

Treatment with short courses of steroids is reportedly quite effective if the steroids are started in the early stages of a flare-up.1,7,8,21 In a large-scale survey conducted by Pignolo et al,7

  • 55% of patients reported that steroids sometimes helped 
  • 30.5% said that steroids always helped their flare-up symptoms 
  • 66.9% of patients said that steroids reduced the soft tissue swelling they had during a flare-up 

However, the effectiveness of steroids for flare-ups is largely anecdotal.8 Non-steroidal anti-inflammatory drugs (NSAIDs) are also used for inflammation and pain relief.8,21 

Off-label medicines

Some medicines – known as off-label medications – may be used at a doctor's discretion. These include:

  • Bisphosphonates, which help with the bone loss that comes as a side effect of steroid use
  • Mast cell inhibitors, are used because mast cells are present in high numbers in the early stages of flare-ups

Medicines currently being clinically trialled for fibrodysplasia ossificans progressiva

According to the International Fibrodysplasia Ossificans Progressiva Association (IFOPA), there are several promising clinical trials in progress for the following medicines:

  • Palovarotene – Suppresses HO
  • Garetosmab – Inhibits the protein ‘Aciving A’ which in turn turns off the mutated receptor on the ACVR1/ALK2 gene
  • Saracatinib – Blocks the ALK2 receptor

How is fibrodysplasia ossificans progressiva managed?

The International Clinical Council on FOP (ICC) 2022 guidelines recommend the following management protocols for patients with FOP as outlined below.21

Exercise and physical therapy

FOP patients can develop problems with their lungs, which can lead to severe complications and death. This often presents as thoracic insufficiency syndrome (TIS), which is a deformity in the chest wall and rib cage that causes breathing problems and is associated with pneumonia in FOP patients.1,8 Therefore, physical activity – such as swimming – and physiotherapy are encouraged to maintain mobility in joints, strengthen muscles and improve cardiovascular health.

Singing is also advised to maintain good lung function. Lung function tests, chest-x-rays and echocardiograms are routinely repeated for FOP patients to monitor heart and lung health.21 

Dental care and anaesthesia

Dentists should take special care with FOP patients because overstretching the jaw can cause flare-ups and HO in jaw muscles. Similarly, routine intubation (a tube inserted down the throat for breathing during surgery) may not be possible for FOP patients with deformities and restricted movement in their neck and jaw. These patients may have to have a different type of anaesthesia through a tube in the nose.21

Falls, injuries and daily activities

FOP patients are advised to reduce the risk of injuries and trauma by avoiding contact sports and dangerous activities.21 Other measures to maintain quality of life as mobility declines include:

  • installing mobility devices
  • handrails
  • stairlifts
  • customised wheelchairs
  • adapted toilets and showers8

Surgery

If at all possible, surgery should be avoided and only used in patients who require life-saving interventions or to avoid life-threatening complications of FOP, because surgery is reported to cause an eruption of new HO in the soft tissue affected by the surgery.2,5

What support is available for FOP patients?

Because this disease is incurable, progressive and debilitating, providing support, information and guidance for patients and their caregivers is essential and should start at the time of diagnosis and continue throughout the patient’s life.

The International Fibrodysplasia Ossificans Progressiva Association (IFOPA) is a global organisation that provides information and support to patients and their families. It also funds research into FOP treatments and educates patients about the ongoing research into the disease.

Summary

FOP is a rare and progressive genetic disorder which causes soft tissue to gradually turn into bone. The disease starts in early childhood and small injuries can cause inflammatory flare-ups that result in new atypical bone formation within soft tissues. There is currently no cure and treatments are focused on maintaining a patient’s quality of life and reducing pain. However, experimental treatments are in clinical trial stages, and advocacy groups are available to provide support and information to patients and their families.

References

  1. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. Pediatr Endocrinol Rev [Internet]. 2013 Jun [cited 2023 Aug 1];10(0 2):437–48. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995352/
  2. Morales-Piga A, Kaplan FS. Osteochondral diseases and fibrodysplasia ossificans progressiva. Adv Exp Med Biol [Internet]. 2010 [cited 2023 Aug 3];686:335–48. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913786/
  3. Botman E, Netelenbos JC, Rustemeyer T, Schoonmade LJ, Nieuwenhuijzen JA, Teunissen BP, et al. Radiotherapy in fibrodysplasia ossificans progressiva: a case report and systematic review of the literature. Frontiers in Endocrinology [Internet]. 2020 [cited 2023 Aug 5];11. Available from: https://www.frontiersin.org/articles/10.3389/fendo.2020.00006  
  4. Kitoh H. Clinical aspects and current therapeutic approaches for fop. Biomedicines [Internet]. 2020 Sep 2 [cited 2023 Aug 5];8(9):325. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555688/   
  5. Meyers C, Lisiecki J, Miller S, Levin A, Fayad L, Ding C, et al. Heterotopic ossification: a comprehensive review. JBMR Plus [Internet]. 2019 Feb 27 [cited 2023 Aug 2];3(4):e10172. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478587/   
  6. Breeland G, Sinkler MA, Menezes RG. Embryology, bone ossification. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Aug 2]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK539718/
  7. Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, et al. The natural history of flare-ups in fibrodysplasia ossificans progressiva (Fop): a comprehensive global assessment: natural history of flare-ups in fop. J Bone Miner Res [Internet]. 2016 Mar [cited 2023 Aug 9];31(3):650–6. Available from: https://onlinelibrary.wiley.com/doi/10.1002/jbmr.2728
  8. Smilde B, Botman E, De Ruiter R, Smit JM, Teunissen B, Lubbers W, et al. Monitoring and management of fibrodysplasia ossificans progressiva: current perspectives. ORR [Internet]. 2022 Apr [cited 2023 Aug 5];Volume 14:113–20. Available from: https://www.dovepress.com/monitoring-and-management-of-fibrodysplasia-ossificans-progressiva-cur-peer-reviewed-fulltext-article-ORR
  9. Song GA, Kim HJ, Woo KM, Baek JH, Kim GS, Choi JY, et al. Molecular consequences of the acvr1r206h mutation of fibrodysplasia ossificans progressiva. Journal of Biological Chemistry [Internet]. 2010 Jul [cited 2023 Aug 8];285(29):22542–53. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0021925820602897   
  10. Wang RN, Green J, Wang Z, Deng Y, Qiao M, Peabody M, et al. Bone Morphogenetic Protein (Bmp) signaling in development and human diseases. Genes & Diseases [Internet]. 2014 Sep 1 [cited 2023 Aug 10];1(1):87–105. Available from: https://www.sciencedirect.com/science/article/pii/S2352304214000105
  11. Hatsell SJ, Idone V, Wolken DMA, Huang L, Kim HJ, Wang L, et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med [Internet]. 2015 Sep 2 [cited 2023 Aug 10];7(303):303ra137. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164166/
  12. Rauner M, Seefried L, Shore E. Genetics and future therapy prospects of fibrodysplasia ossificans progressiva. medgen [Internet]. 2019 Dec 1 [cited 2023 Aug 8];31(4):391–6. Available from: https://doi.org/10.1007/s11825-019-00279-y  
  13. Shore EM. Fibrodysplasia ossificans progressiva (Fop): A human genetic disorder of extra-skeletal bone formation, or - How does one tissue become another? Wiley Interdiscip Rev Dev Biol [Internet]. 2012 [cited 2023 Aug 9];1(1):153–65. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297114/
  14. Towler OW, Shore EM. bmp signaling and skeletal development in fibrodysplasia ossificans progressiva(fop). Developmental Dynamics [Internet]. 2022 Jan [cited 2023 Aug 8];251(1):144–57. Available from: https://onlinelibrary.wiley.com/doi/10.1002/dvdy.387
  15. Park PSU, Raynor WY, Sun Y, Werner TJ, Rajapakse CS, Alavi A. 18f-sodium fluoride pet as a diagnostic modality for metabolic, autoimmune, and osteogenic bone disorders: cellular mechanisms and clinical applications. International Journal of Molecular Sciences [Internet]. 2021 Jan [cited 2023 Aug 6];22(12):6504. Available from: https://www.mdpi.com/1422-0067/22/12/6504
  16. Botman E, Teunissen BP, Raijmakers P, Graaf P, Yaqub M, Treurniet S, et al. Diagnostic value of magnetic resonance imaging in fibrodysplasia ossificans progressiva. JBMR Plus [Internet]. 2020 Jun [cited 2023 Aug 6];4(6). Available from: https://onlinelibrary.wiley.com/doi/10.1002/jbm4.10363
  17. Kaplan FS, Mukaddam MA, Pignolo RJ. A cumulative analogue joint involvement scale (CAJIS) for fibrodysplasia ossificans progressiva (FOP). BONE [Internet]. 2017 [cited 2023 August 6]. Available from: http://www.iccfop.org/dvlp/wp-content/uploads/2019/05/A-cumulative-analogue-joint-involvement-scale-CAJIS-for-fibrodysplasia.pdf  
  18. Jadvar H, Desai B, Conti PS. Sodium 18f-fluoride pet/ct of bone, joint and other disorders. Semin Nucl Med [Internet]. 2015 Jan [cited 2023 Aug 6];45(1):58–65. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258001/
  19. de Ruiter RD, Smilde BJ, Pals G, Bravenboer N, Knaus P, Schoenmaker T, et al. Fibrodysplasia ossificans progressiva: what have we achieved and where are we now? Follow-up to the 2015 lorentz workshop. Frontiers in Endocrinology [Internet]. 2021 [cited 2023 Aug 8];12. Available from: https://www.frontiersin.org/articles/10.3389/fendo.2021.732728
  20. Eekhoff EMW, Netelenbos JC, De Graaf P, Hoebink M, Bravenboer N, Micha D, et al. Flare-up after maxillofacial surgery in a patient with fibrodysplasia ossificans progressiva: an [ 18 f]-naf pet/ct study and a systematic review: flare-up after maxillofacial surgery in a patient with fop. JBMR Plus [Internet]. 2018 Jan [cited 2023 Aug 6];2(1):55–8. Available from: https://onlinelibrary.wiley.com/doi/10.1002/jbm4.10008   
  21. Guidelines | international clinical council (Icc) on fibrodysplasia ossificans progressiva(Fop) [Internet]. [cited 2023 Aug 9]. Available from: https://www.iccfop.org/guidelines/

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