title: Fibrodysplasia ossificans progressiva: middle-age onset of heterotopic ossification from a unique missense mutation (c.974G>C, p.G325A) in ACVR1.
abstract: Fibrodysplasia ossificans progressiva (FOP) is the rare mendelian disease characterized by congenital malformation of the great toes preceding heterotopic ossification (HO) and caused by heterozygous activating mutation of the ACVR1 gene, which encodes the ALK2 receptor for bone morphogenetic proteins. Early adult life is the latest reported presentation for the HO of FOP. The patient of our report first developed HO from FOP at 47 years of age. She had congenital hallux valgus deformity but despite various traumas was previously well. HO began several months after a brief, seemingly viral, illness. Sudden and progressive pain, redness, warmth, and swelling appeared over a scapula. Computed tomography was remarkable for asymmetrical thickening of muscles and fascial planes. At first, the significance of the great toe abnormalities went unrecognized elsewhere, and biopsy for suspected inflammatory fasciitis revealed proliferating fibroblasts with scattered inflammatory cells. Prednisone improved her symptoms but, when tapered, swellings developed on her chest, posterior thorax, and flank, and FOP was diagnosed. Methylprednisolone, methotrexate, and alendronate seemed to help her symptoms, but the lesions worsened and HO appeared and rapidly progressed. Mutation analysis of the ACVR1 gene revealed heterozygosity for a unique missense defect (c.974G>C, p.G325A) that predicted a conservative (mild) amino acid change within the kinase domain of ALK2. Hence, HO in FOP can be delayed until middle-age, and perhaps provoked by a viral illness. Nevertheless, progression of HO can then be rapid despite bisphosphonate and high-dose immunosuppressive therapy. Possibly, our patient's late-onset HO reflects her mild alteration of ALK2 or some protective and therapeutically useful genetic, epigenetic, or nongenetic factor. Recognition of presymptomatic individuals or late-onset HO in FOP should have these patients avoid traumas, treatments, and maybe viral illnesses that can initiate or exacerbate the HO. If the diagnosis of FOP is unclear, ACVR1 mutation analysis is available at certified laboratories.
authors: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO 63131, USA. mwhyte@shrinenet.org
authors: Michael P
authors: MP
authors: Whyte
authors: Deborah
authors: D
authors: Wenkert
authors: Jennifer L
authors: JL
authors: Demertzis
authors: Edward F
authors: EF
authors: DiCarlo
authors: Erica
authors: E
authors: Westenberg
authors: Steven
authors: S
authors: Mumm
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics*; D017668:Age of Onset; D005260:Female; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D009221:Myositis Ossificans / Q000000981:diagnostic imaging / Q000235:genetics*; D009999:Ossification, Heterotopic / Q000235:genetics*; D011859:Radiography
chemical_list: C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I