FOP is caused by gain-of-function pathogenic variants in the ACVR1 gene on chromosome 2, encoding activin receptor type I (ALK2), a BMP type I receptor involved in bone and muscle development. ACVR1 is classified as a DEFINITIVE cause of FOP by ClinGen. The most prevalent pathogenic variant is p.Arg206His (NM_001105.4:c.617G>A), identified in 12 or more independent ClinVar submissions and representing a well-established hotspot. More than 800 individuals with over 20 distinct ACVR1 pathogenic variants have been reported in the medical literature. Gain-of-function ACVR1 variants cause aberrant BMP receptor signaling, leading to transformation of connective tissues into bone through endochondral ossification. Inheritance is autosomal dominant; de novo variants account for a substantial proportion of cases given the condition's impact on reproductive fitness.

Formal consensus diagnostic criteria for FOP have not been published. The clinical presentation is highly characteristic: congenital bilateral hallux valgus malformations combined with progressive heterotopic ossification are pathognomonic. FOP is suspected in individuals with congenital hallux valgus—often bilateral—together with episodic soft tissue swellings that subsequently ossify. Molecular genetic testing to identify a pathogenic or likely pathogenic variant in ACVR1 confirms the diagnosis. Heterotopic ossification may be triggered or accelerated by trauma, including intramuscular injections, which has important implications for clinical evaluation pathways. Radiographic and MRI evaluation characterize the extent of ossification and associated vertebral abnormalities.

SOHONOS (palovarotene), a retinoic acid receptor gamma agonist, received FDA approval in August 2023 as the first pharmacological therapy for FOP, indicated for individuals with a confirmed ACVR1 pathogenic variant. Prior to this approval, management was entirely supportive. Supportive care addresses progressive complications including respiratory function, mobility, nutrition, and pain. Given the established risk that trauma—including intramuscular injections and surgical procedures—can trigger new ossification episodes, this vulnerability informs clinical care decisions documented in published management guidelines. Physical and occupational therapy contribute to maintaining function, and assistive devices address progressive mobility limitations. Investigational approaches under active clinical evaluation include anti-activin A antibody therapy (garetosmab) and ACVR1-targeted kinase inhibitors (INCB000928).

FOP is a relentlessly progressive condition. Heterotopic ossification accumulates episodically over the lifetime of affected individuals, progressively immobilizing multiple body regions. Respiratory complications arising from thoracic cage restriction represent a significant source of morbidity and a leading contributor to mortality. Most affected individuals experience progressive deterioration in mobility and functional independence over decades. The condition is consistent with survival into adulthood; an international patient registry has documented affected individuals across diverse global populations.

FOP has an active clinical trial portfolio with 7 current studies. A Phase 3 evaluation of garetosmab (Regeneron Pharmaceuticals, NCT05394116) is active, assessing the anti-activin A antibody approach with completion expected in 2029; a separate Phase 3 pediatric study of garetosmab (NCT07559513) is forthcoming. INCB000928, an ACVR1 kinase inhibitor under evaluation by Incyte Corporation, is in a Phase 2 trial recruiting through 2033 (NCT05090891). Andecaliximab is in Phase 2 evaluation (Ashibio Inc., NCT06508021, active through 2029). Ipsen is conducting a long-term post-marketing safety and effectiveness study of palovarotene (NCT06089616, recruiting through 2035). An interleukin-1 inhibition study in FOP is enrolling at the University of California, San Francisco (NCT06724562, through 2027). The International FOP Association maintains an ongoing disease registry (NCT02745158).