Fibrodysplasia ossificans progressiva: from clinical complexity to therapeutic opportunity

Abstract Fibrodysplasia Ossificans Progressiva (FOP) is an ultra-rare and severely disabling genetic disorder affecting approximately one in two million individuals worldwide. It is characterised by progressive endochondral heterotopic ossification (HO), in which ectopic cartilage formation precedes and directs subsequent bone formation within muscles, tendons, and ligaments. Activating mutations in the ACVR1 gene—most commonly the R206H variant—cause dysregulated bone morphogenetic protein (BMP) signaling through both SMAD-dependent and SMAD-independent pathways, leading to inappropriate osteogenic differentiation. Clinically, FOP presents with congenital great toe malformations and recurrent, painful flare-ups that progressively restrict mobility and cause complications such as thoracic insufficiency, ankylosis, and hearing loss. Early genetic diagnosis is critical to avoid iatrogenic harm. Current treatments rely on corticosteroids and NSAIDs, while Palovarotene—a selective retinoic acid receptor gamma agonist approved by the FDA in 2023—marks a major therapeutic advance despite safety limitations. Our review integrates recent breakthroughs, including Phase 3 Garetosmab results and ongoing trials of STOPFOP, INCB000928, and IPN60130, alongside emerging insights into fibro-adipogenic progenitors and molecular mechanisms of HO. Incorporation of regional case analyses from India, together with global data, strengthens the clinical relevance for low- and middle-income regions where FOP remains underreported. This comprehensive review provides the most current translational perspective on FOP, highlighting the alarming need for continued innovation to improve patient outcomes.