From soft-tissue to bone: Clinical presentation of fibrodysplasia ossificans progressiva (FOP)

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DSFOP-UK-000013 Date of preparation October 2021

FOP recognition in the pediatric and adult population and importance of increasing disease awareness

Can you imagine living with a condition that turns your muscles and soft-tissues progressively and irreversibly into hard bone? This is what patients with fibrodysplasia ossificans progressiva (FOP) experience^1,2.

FOP is an ultra-rare genetic disorder affecting 1.4 in a million people that presents at birth and ultimately leads to shortened lifespan^1–3. The genetic cause of the disease has been identified, with almost all patients carrying the same gain-of-function ALK2/ACVR1 gene mutation²

Clinical presentation of FOP

The earliest phenotypic evidence of FOP are bilateral malformations of the great toes at birth and the development of soft-tissue swellings known as ‘flare-ups’, which initially occur along the scalp, upper back and neck^1,2. This is followed by the transformation of soft- and connective tissues into ribbons, sheets, and plates of bone via a progressive, cumulative, and irreversible process known as heterotopic ossification (HO)^1,2. Typically in FOP, HO begins in the dorsal, axial, cranial, and proximal regions of the body prior to development in the ventral, appendicular, and distal regions².

In FOP, HO can occur spontaneously or precipitated by injury, falls, fatigue, viral infection, surgical procedures, or biopsies¹. This clinical presentation, compounded by lack of awareness of disease characteristics, results in the misdiagnosis of FOP in approximately 53% of patients⁴. Common misdiagnoses such as cancer, juvenile fibromatosis, and myositis ossificans (Figure 1), can often lead to unnecessary medical intervention, which can precipitate further HO and ultimately lead to progressive disability and immobilization of joints over time⁴.

Figure 1. Lack of fibrodysplasia ossificans progressiva disease awareness causes delays to accurate diagnosis⁴. FOP, fibrodysplasia ossificans progressiva.

Together, the current lack of FOP disease awareness and frequent misdiagnosis have the potential to negatively impact the quality of life of patients and their caregivers, highlighting the clear need for increased disease education.

Would you be able to recognize FOP?

Focusing on the bilateral great toe malformations (the earliest phenotypic evidence) and soft-tissue swellings (to learn more, please read the second article of this series) (Figure 2), will support early diagnosis of FOP and help to avoid unnecessary interventions, thus limiting disability accumulation. Subsequently, genetic testing to identify ALK2/ACVR1 gene mutations can be used to confirm the clinical diagnosis.

Figure 2. Identifying the signs and symptoms of fibrodysplasia ossificans progressiva^2,5. FOP, fibrodysplasia ossificans progressiva.

To learn more, stay tuned for next month’s article of the series, which will focus on flare-ups.

FOP knowledge check

Abbreviations

FOP, fibrodysplasia ossificans progressiva; HO, heterotopic ossification.

References

1. Baujat G, Choquet R, Bouée S, Jeanbat V, Courouve L, Ruel A, et al. Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet J Rare Dis. 2017;12:123.
2. 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. 2012;1:153–65.
3. IFOPA. Available at: https://www.ifopa.org/fop_on_inside_edition (accessed October 2021).
4. Sherman LA, Cheung K, De Cunto C, Kile S, Pignolo RJ, Kaplan FS. The diagnostic journey in fibrodysplasia ossificans progressiva: insights from the FOP registry. Presented at ASBMR 2020, 11–15 September 2020. Virtual Meeting. P-841.
5. Kaplan FS, Al Mukaddam M, Baujat G, Brown M, Cali A, Cho T-J, et al. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP. 2019;1:1–111.