Fibrodysplasia ossificans progressiva.
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.
Kaplan
Frederick S
FS
Departments of Orthopedic Surgery & Medicine, The University of Pennsylvania School of Medicine, c/o Hospital of The University of Pennsylvania, Philadelphia, PA, USA. frederick.kaplan@uphs.upenn.edu
Le Merrer
Martine
M
Glaser
David L
DL
Pignolo
Robert J
RJ
Goldsby
Robert E
RE
Kitterman
Joseph A
JA
Groppe
Jay
J
Shore
Eileen M
EM
D030201:Activin Receptors, Type I / Q000235:genetics; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D009154:Mutation; D009221:Myositis Ossificans / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D009999:Ossification, Heterotopic; D011859:Radiography; D051785:Smad Proteins / Q000235:genetics
D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D052005:Bone Morphogenetic Protein Receptors, Type I