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

Robert J. Pignolo, Geneviève Baujat, Matthew A. Brown, Carmen De Cunto, Edward C. Hsiao, Richard Keen, Mona Al Mukaddam, Kim Hanh Le Quan Sang, Amy Wilson, Rose Marino, Andrew Strahs, Frederick S. Kaplan

Research output: Contribution to journalArticlepeer-review


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 (ACVR1R206H 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.

Original languageEnglish (US)
Pages (from-to)2422-2433
Number of pages12
JournalGenetics in Medicine
Issue number12
StatePublished - Dec 2022


  • Fibrodysplasia ossificans progressiva
  • Natural history study

ASJC Scopus subject areas

  • Genetics(clinical)


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