FOP is associated with the gene ACVR1, which has a DEFINITIVE ClinGen validity classification and is located on chromosome 2. The packet records autosomal dominant inheritance. GeneReviews describes the condition as arising through gain-of-function variants in ACVR1, and reports that most affected individuals have a de novo ACVR1 pathogenic variant, while rarely an affected parent is identified; presumed germline mosaicism was reported in one family with recurrence among siblings. The p.Arg206His variant is the most common and is associated with the classic phenotype, including bilateral hallux valgus and early-onset heterotopic ossification, whereas specific variants at residue Gly328 have been associated with limb reduction defects. GeneReviews estimates penetrance of ACVR1 gain-of-function variants as near complete, with no reported nonpenetrant individuals.

GeneReviews states that there are no formal diagnostic criteria for FOP. Suggestive findings include congenital hallux valgus deformity, progressive heterotopic ossification, painful recurrent soft-tissue swellings, and in atypical forms limb reduction defects. Imaging findings described include hallux valgus on prenatal ultrasound as early as 23 weeks of gestation, short malformed first metatarsals on radiographs, and heterotopic ossification on radiographs. According to GeneReviews, the diagnosis is established in a person with hallux valgus malformations, heterotopic ossification, and/or a heterozygous pathogenic or likely pathogenic ACVR1 variant identified by molecular genetic testing, using single-gene testing, multigene panels, or genomic testing. A heterozygous ACVR1 variant of uncertain significance neither establishes nor rules out the diagnosis. GeneReviews adds that single-gene testing targets the common p.Arg206His variant and other missense variants, and that intragenic deletions or duplications and loss-of-function variants have not been described as causes of FOP.

The packet records one FDA-approved treatment with active market status, palovarotene (Sohonos), approved in 2023 under an NDA. GeneReviews describes it as a retinoic acid receptor gamma agonist that reduces BMP signaling and reports FDA approval for FOP in adults and children (females aged 8 years and older and males aged 10 years and older). GeneReviews notes that guidelines for managing FOP have been developed by a multidisciplinary team of experts, and that initial evaluations cover overall clinical staging, hallux malformations, the impact of heterotopic ossification on function, thoracic insufficiency, and soft-tissue swelling. GeneReviews also describes clinical staging of FOP from early or mild through end stage, based on flare-up history, body regions affected, thoracic insufficiency, activities of daily living, and ambulation. Patient assistance programs are not described in the packet.

GeneReviews describes FOP as progressive, with heterotopic ossification typically affecting regions near the axial skeleton in early stages before progressing to the appendicular skeleton, and with restriction of joint movement as ossification accumulates. According to GeneReviews, thoracic insufficiency syndrome, resulting from costovertebral involvement, ossification of chest-wall muscles and progressive spinal deformity, is the predominant cause of mortality. The staging scheme in GeneReviews describes late stages with greater dependence for activities of daily living and wheelchair use or bed confinement.

Packet records list investigational orphan drug designations for FOP, including garetosmab, andecaliximab, and several small-molecule agents, while some designations are recorded as withdrawn; a designation does not indicate approval or availability. GeneReviews describes research focused on inhibition of the ACVR1 receptor, ACVR1 ligands, BMP pathway signaling, and inflammatory triggers of disease activity. ClinicalTrials.gov records in the packet include a long-term palovarotene safety study, studies of garetosmab, INCB000928, andecaliximab, saracatinib, and IL-1 inhibition, and the IFOPA patient registry, at statuses ranging from not yet recruiting to recruiting and active not recruiting. Active clinical trials for this condition are listed on ClinicalTrials.gov.