Fibrodysplasia ossificans progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition of congenital skeletal malformations and progressive heterotopic ossification (HO), is the most catastrophic disorder of HO in humans. Episodic disease flare-ups are precipitated by soft tissue injury, and immobility is cumulative. Recently, a recurrent mutation in activin receptor IA/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, was reported in all sporadic and familial cases of classic FOP, making this one of the most highly specific disease-causing mutations in the human genome. The discovery of the FOP gene establishes a critical milestone in understanding FOP, reveals a highly conserved target for drug development in the transforming growth factor (TGF)-beta/BMP signalling pathway, and compels therapeutic approaches for the development of small molecule signal transduction inhibitors for ACVR1/ALK2. Present management involves early diagnosis, assiduous avoidance of iatrogenic harm, and symptomatic amelioration of painful flare-ups. Effective therapies for FOP, and possibly for other common conditions of HO, may potentially be based on future interventions that block ACVR1/ALK2 signalling.

Fibrodisplasia ossificante progressiva: diagnóstico em atenção primária

“…Individuals with FOP appear normal at birth except for the characteristic malformation of the great toes (3,4,10,11) , which was noticed by the parents of the girl reported in the present study, but they did not pay much attention to this, since it did not cause functional changes. As for treatment, there are anecdotal reports on the efficacy of corticoids in limiting inflammation and progression of heterotopic ossification during flare-ups, which means that if prednisone is administered at a 2mg/Kg/d dose during 4 days, starting within the first 24 hours after the flare-up, the intense inflammation and tissular edema observed in the first stages of ossification will be reduced.…”

“…This mutation causes a deregulation of the bone morphogenetic protein signaling pathway (7,8) . Previous studies have demonstrated that there was no ethnic, racial, gender or geographic predisposition for the development of the disease (3,4) . It is known that both genetic and environmental factors determine FOP phenotype, the first during prenatal development and the latter in the progression of heterotopic ossifications (5,7,8) .…”

“…Because FOP diagnosis is made clinically, it is possible to establish it in the primary health care setting, based on the clinical features that define the disease: malformation of the great toes and progressive heterotopic ossification (3,4,6,(9)(10)(11) . Individuals with FOP appear normal at birth except for the characteristic malformation of the great toes (3,4,10,11) , which was noticed by the parents of the girl reported in the present study, but they did not pay much attention to this, since it did not cause functional changes.…”

“…In 1969, Munchmever changed the designation to FOP, which encompasses the involvement of more soft tissues besides that of muscles (2,3) . FOP is a rare condition of skeletal malformations such as bilateral hallux valgus and progressive heterotopic ossification of soft tissues; in other words, a new non-neoplastic bone is produced in places where it should not be, leading to permanent immobility throughout the years (3,4) . This disease is produced by a mutation in one of the copies of the gene that encodes the Receptor I of the bone morphogenetic protein, called Activin type 1 receptor or ACVR1 (5) .…”

“…This disease is produced by a mutation in one of the copies of the gene that encodes the Receptor I of the bone morphogenetic protein, called Activin type 1 receptor or ACVR1 (5) . It affects men and women equally, with a current worldwide prevalence of approximately 1 case in 2 million individuals (4,6) .…”