The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study

Purpose: We report the first prospective, international, natural history study of the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). FOP is characterized by painful, recurrent flare-ups, and disabling, cumulative heterotopic ossification (HO) in soft tissues.

Methods: Individuals aged ≤65 years with classical FOP (ACVR1^R206H variant) were assessed at baseline and over 36 months.

Results: In total, 114 individuals participated; 33 completed the study (mean follow up: 26.8 months). Median age was 15.0 (range: 4-56) years; 54.4% were male. During the study, 82 (71.9%) individuals reported 229 flare-ups (upper back: 17.9%, hip: 14.8%, shoulder: 10.9%). After 84 days, 14 of 52 (26.9%) imaged flare-ups had new HO at the flare-up site (mean new HO volume: 28.8 × 10³ mm³). Mean baseline low-dose whole-body computed tomography (excluding head) HO volume was 314.4 × 10³ mm³; lowest at 2 to <8 years (68.8 × 10³ mm³) and increasing by age (25-65 years: 575.2 × 10³ mm³). The mean annualized volume of new HO was 23.6 × 10³ mm³/year; highest at 8 to <15 and 15 to <25 years (21.9 × 10³ and 41.5 × 10³ mm³/year, respectively) and lowest at 25 to 65 years (4.6 × 10³ mm³/year).

Conclusion: Results from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood.