Fibrodysplasia ossificans progressiva (FOP) occurs in ~1 per 2 million population. It is characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) leading to immobility (1). In 2006, the disorder was associated with mutation in activin receptor 1A (ACVR1, also known as ALK2), a type 1 bone morphogenetic protein receptor; a heterozygous c.617G>A, (p.Arg206His) mutation de novo is found in most FOP subjects, and a variant ACVR1 mutation occurs in the remainder (2). Individuals with FOP will appear normal at birth except for the great toe malformation. During the first decade of life, most will develop episodic, painful soft tissue swellings which mature into heterotopic bone through an endochondral process. Skeletal muscles (excepting the diaphragm, extra-ocular muscles and tongue), tendons, ligaments, fascia and aponeuroses may be affected. Progressive disability occurs as HO progresses to encasement. Most patients with FOP will be wheelchair-bound by their third decade. Death commonly results from complications of chest wall restriction.
Current management is focused on early diagnosis, avoiding injury, prompt treatment of flare-ups and functional support. A short course of prednisone is often used at the start of a flare; selective COX-2 inhibitors are also used for pain relief. Strategies for inhibiting BMP signalling include retinoic acid receptor γ agonists, small molecule inhibitors or monoclonal antibodies against ALK2, and inhibition of HIF1α/mTOR signalling.
Lessons learnt from FOP will likely be relevant to understanding non-genetic forms of HO, although the latter form through both endochondral and intramembranous ossification pathways. Therapies developed for FOP may be relevant for HO in other situations