Early diagnosis is essential for a child with FOP, but this has rarely been easy. The symptoms can easily be mistaken for those of other diseases; FOP is ultra-rare, affecting only one in 1.4 million people1, so many health-care professionals (HCPs) are unaware of it.
But it is important to raise awareness: FOP causes cumulative disability and pain, and shortens lifespan. An accurate diagnosis is critical to maximize a patient’s long-term health by managing their exposure to risk and potentially harmful interventions.
The diagnostic journey
Medical attention is often first sought when a young child starts to develop painful swellings; commonly, these initially occur in the neck, shoulders or back2. Based on these symptoms, early misdiagnoses of FOP include cancer and disorders of connective tissue or bone.
But there is a second telltale sign of FOP that will have been present since birth: bilateral malformation of the big toes. Together, these relatively minor signs should suggest the correct diagnosis, which can be confirmed with a routine genetic test3.
Delay in diagnosis raises the risk of irreversible harm. Any inflammatory damage to soft tissue, whether by injury, biopsy, muscle fatigue or intramuscular injection, will cause or accelerate FOP’s characteristic heterotopic ossification — that is, the conversion of soft tissue to bone. Only once FOP is identified can efforts be made to avoid these events.
That diagnosis will hopefully be improved thanks to a new milestone: the publication of the first natural history study, providing an invaluable resource for any HCP caring for someone living with FOP4.
Underlying cause and manifestations
Although there are descriptions of FOP dating back to 1740, for centuries the disease remained an enigmatic medical curiosity. FOP’s origins were eventually revealed in 2006. A team of scientists at the University of Pennsylvania School of Medicine, led by Fred Kaplan and Eileen Shore, found that it is caused by mutations in the gene that codes for ALK2/ACVR1, a receptor involved in regulating bone development. Approximately 97% of people with FOP have the same mutation5.
These genetic insights improved understanding and management of FOP, but knowledge gaps remained. There is variability in FOP manifestation; flare-ups can occur in different parts of the body, leading to referrals to various medical specialties. To improve medical education, and to raise awareness generally, Kaplan and a team including Robert Pignolo, a physician-scientist at the Mayo Clinic, and researchers at Clementia Pharmaceuticals (acquired by Ipsen in 2019), launched a wide-ranging, prospective natural history study4 in 2014.
The ambitious study tracked roughly 15% of all known patients with FOP at the time of the study initiation. The 114 participants recorded the frequency and nature of their flare-ups; had repeated whole-body computed tomography scans to measure increases in heterotopic ossification; and tracked their changing mobility in a customized questionnaire.
The granular data allowed rigorous quantification of the link between flare-ups and the formation of new bone. The study also accurately mapped the relationship between the number of joints affected by ossification, mobility, and the ability to conduct activities of daily living.
FOP and different medical specialities
Once a person has been diagnosed, they and their physician can connect with FOP specialists as well as patient support organizations such as IFOPA, the International FOP Association. Current guidelines highlight the benefits of a multidisciplinary clinical and social support team, preferably coordinated by a physician in contact with a FOP expert6.
These networks can help people with FOP navigate the challenges of everyday life, including routine medical procedures. Some special considerations are listed below.
● Pediatricians should administer childhood vaccines subcutaneously rather than intramuscularly.
● Extra care must be taken during dental procedures to avoid unnecessary injections and soft tissue trauma.
● Anesthetists should be aware of complications associated with FOP and should consult expert guidelines; for instance, regarding intubation and airway management.
● Dermatologists may become involved for pressure ulcers, for instance, and should be aware of risks.
● Approximately half of patients experience some degree of hearing loss.
● Specialist physiotherapy can help people living with FOP, but must be administered according to recommended protocols.
● Optimizing pain management is a vital element of supporting people with FOP.
● Psychological support can also become essential. Up to 74% of people with FOP report anxiety, depression and irritability during flare-ups, and nearly half report similar emotional issues during pain-free periods.
With this more-complete picture of the natural history of FOP4, HCPs will have the tools to recognize the condition and hone strategies to manage it, with the aim to improve the care for people living with this ultra-rare disease. And the study’s rich dataset will be a tool for years to come, powering systematic clinical trials of potential therapies to show meaningful change.
DRSC-ALL-000033. Approved September 2022.