The congenital great toe malformation of fibrodysplasia ossificans progressiva? - A close call

Abstract Background Congenital bilateral hallux valgus with associated absence or fusion of the interphalangeal joint is a classic diagnostic feature of fibrodysplasia ossificans progressiva (FOP), a human genetic disease of extra-skeletal bone formation caused in nearly all cases by a gain-of-function mutation in Activin A Receptor I/Activin-like Kinase 2 (ACVR1/ALK2), which encodes a bone morphogenetic protein (BMP) Type 1 receptor. This toe malformation prompts the suspicion of FOP even before the appearance of extra-skeletal bone. Here we report the case of a four-month-old child who was suspected of having FOP on the basis of a great toe malformation identical to that seen in children with the disease. Methods The patient's genomic DNA of the coding region of ACVR1 was sequenced and analyzed for mutations known to cause FOP and novel mutations. Subsequent comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) analyses were performed to detect mutations elsewhere in the genome. Results Genetic testing exonerated ACVR1 as culpable for the patient's toe malformation. CGH and SNP analyses identified a large intragenic deletion in a different BMP Type 1 receptor gene, BMP Receptor 1B/Activin-like kinase 6 (BMPR1B/ALK6), a gene associated with a variable spectrum of autosomal dominant brachydactyly phenotypes. Conclusions This report illustrates that while toe morphology remains the earliest indicator of FOP, toe morphology alone is not an unequivocal clinical diagnostic feature of FOP, and supports that embryonic development of the great toe is highly sensitive to dysregulated signaling from at least two BMP type I receptors.