The impact of fibrodysplasia ossificans progressiva (FOP) on patients and their family members: results from an international burden of illness survey

Fibrodysplasia ossificans progressiva (FOP; OMIM #135100) is an ultra-rare, severely debilitating genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO), which transforms soft, connective tissues into heterotopic bone [1,2]. Other common signs of FOP are proximal medial tibial osteochondromas, cervical spine malformations, short/broad femoral necks, hearing impairment, and shortened thumbs [3]. The estimated prevalence of FOP is 1.36 per million people (range: 0.036–1.428); the reported prevalence varies by country and region [4–6]. Approximately 97% of all people with FOP carry the same specific mutation in the ALK2/ACVR1R206H gene, which encodes a receptor involved in the  bone morphogenetic protein signaling pathway; this mutation results in a dysregulated pathway and abnormal bone growth [7,8]. People with FOP experience sporadic episodes of often painful soft tissue swelling, or flare- ups [9]. While some flare-ups regress spontaneously, many appear to lead to HO [9]. FOP progression can also occur in the absence of flare-ups [10].