Review Question - QID 213914

The affected protein is the activin receptor type 1A (ACVR1). This mutation leads to the fibrodysplasia ossificans progressiva (FOP) aka “Stone Man” syndrome. Congenital bilateral monophalangeal hallux valgus deformities are pathognomonic for this syndrome.

Most cases of FOP are sporadic; however, it can be inherited in an autosomal dominant pattern. The majority of those with FOP have a single nucleotide mutation at position 616 of the cDNA causing a substitution of histidine for arginine (R206H) and causes a downstream gain-of-function mutation in the ACVR1 protein. The mutated ACVR1 protein promotes uninhibited SMAD signaling of Activin A, BMP 2, BMP 4, BMP 6 and BMP 7. FOP is a rare condition that demonstrates recognizable skeletal (bilateral hallux valgus, cervical spine fusions, short/broad femoral necks, and osteochondromas) and extra-skeletal progressive heterotopic ossification, slowly replacing skeletal muscles, tendons, and ligaments in the setting of minor trauma. Treatment of FOP is generally conservative. Surgery is reserved for refractory pain, joint motion limitation, or nerve compression.

Hildebrand et al. compared the signaling responses of ACVR1 R206H to WT form. They found that the mutated R206H lost essential inhibitor interactions which led to ectopic bone formation. See illustration A for a graphic depiction of the normal and abnormal response to different ligands.

Barruet et al. assessed cells from patients with FOP. Their study found that BMP can induce endothelial cell dysfunction and demonstrated that endothelial cells may contribute to the excessive heterotopic ossification in FOP.

Figure A is a radiograph of bilateral feet with symmetric great toe malformations of the metatarsals and phalanges. There is also microdactyly present and fused interphalangeal joints. The pathognomonic bilateral hallux valgus deformity can be seen in this radiograph.

Incorrect answers:
Answer 1: LIM homeobox transcription factor 1-beta is the result of a mutated LMXB1 gene in Nail-Patella Syndrome.
Answer 2: Guanine nucleotide-binding protein G(s) subunit alpha is the result of a mutated GNAS1 gene in Fibrous Dysplasia.
Answer 3: Sulfate transport protein is the result of a mutated DTDST gene in Diastrophic Dysplasia.
Answer 5: Runt-related transcription factor 2 is the result of a mutated RUN-X2 gene in cleidocranial dysplasia.