Name: Atebrioz (zilurgisertib) in Fibrodysplasia ossificans progressiva: Definition and etiology
Published: 2026-09-27T12:28:00-04:00

Definition of fibrodysplasia ossificans progressiva

“Fibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare, disabling, fully penetrant, autosomal dominant, genetic condition characterized by congenital malformations of the great toes and progressive, heterotopic ossification (HO) in specific anatomic patterns.” (opens the source at this quote in a new tab)
“Flare-ups that often lead to HO are episodic and may be misdiagnosed as tumors; immobility is cumulative.” (opens the source at this quote in a new tab)

Genetic cause: gain-of-function variants in ACVR1, with R206H in about 97% of cases

“A common gain-of-function, missense pathogenic variant in activin receptor IA (ACVR1, also known as ALK2), encoding a bone morphogenetic protein (BMP) type I receptor, occurs in all sporadic and familial cases with a classic presentation of FOP.” (opens the source at this quote in a new tab)
“Approximately 3% of affected individuals have different pathogenic variants in ACVR1” (opens the source at this quote in a new tab)
“However, all known individuals with FOP have gain-of-function, heterozygous, pathogenic variants in the gene encoding ACVR1.” (opens the source at this quote in a new tab)

“We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G-A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined.” (opens the source at this quote in a new tab)

Classic and variant genotypes

“All patients with classic clinical features of FOP (great toe malformations and progressive HO) have the same heterozygous mutation (c.617G>A; p.R206H) in the glycine-serine activation domain of ACVR1 (~97% of all FOP patients worldwide). Approximately 3% of FOP patients have been identified with clinical features unusual compared to classical FOP, most notably greater or lesser severity of the great toe malformations. These patients with “variant” clinical presentation of FOP have novel non-R206H activating mutations in the ACVR1 gene.” (opens the source at this quote in a new tab)

“Genotype–phenotype correlations are indicated between some ACVR1 pathogenic variants and the age of onset of HO” (opens the source at this quote in a new tab)

Inheritance, de novo occurrence, and paternal age

“All races are affected with FOP. There is no ethnic, racial, gender, or geographic predisposition. Autosomal dominant transmission with complete penetrance but variable expression is established. Inheritance can be from either mothers or fathers” (opens the source at this quote in a new tab)
“Most cases arise as a result of a spontaneous new mutation” (opens the source at this quote in a new tab)
“Fewer than ten small families with multigenerational members with FOP are known worldwide. Phenotypic heterogeneity is observed” (opens the source at this quote in a new tab)

“The vast majority of cases are due to the same alteration, R206H, and results from a spontaneous de novo mutation” (opens the source at this quote in a new tab)
“A paternal age effect has been reported” (opens the source at this quote in a new tab)

“We found this mutation in all affected members of seven families, including all five families used for linkage analysis (Fig. 1c).” (opens the source at this quote in a new tab)
“Investigation of sporadic cases of FOP with unambiguous clinical features showed the presence of the identical de novo mutation in 32 of 32 cases.” (opens the source at this quote in a new tab)
“The 617G-A nucleotide mutation was not found in any of 159 unaffected individuals (112 unrelated controls and 47 clinically unaffected family members).” (opens the source at this quote in a new tab)

Genetic and environmental determinants of phenotype

“A study of three pairs of monozygotic twins with FOP found that within each pair, congenital toe malformations were identical. However, postnatal HO varied greatly depending on life history and environmental exposure to viral illnesses and to soft tissue trauma.” (opens the source at this quote in a new tab)