Fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva is an extremely rare connective tissue disorder in which fibrous connective tissue such as muscle, tendons and ligaments gradually ossifies into bone, progressively immobilizing the body as new bone replaces musculature and fuses with the skeleton; the condition is nicknamed stone man disease. It results from a mutation in the ACVR1 gene on chromosome 2, substituting arginine for histidine at codon 206 of the ACVR1 protein and causing abnormal activation that turns connective tissue into bone. Children typically experience a first flare up before age ten, often signaled by malformed big toes and painful soft tissue swelling, with bone growth generally progressing downward from the neck and shoulders to the arms, chest and feet. As of 2020 only 834 confirmed cases were known worldwide, an incidence of about 0.88 per million people, though underdiagnosis likely means the true number is higher.