achondroplasia

Achondroplasia is a genetic disorder whose primary feature is dwarfism. It is the most common cause of dwarfism and affects about 1 in 27,500 people. In those with the condition, the arms and legs are short, while the torso is typically of normal length. Those affected have an average adult height of for males and for females. Other features can include an enlarged head with prominent forehead (frontal bossing) and underdevelopment of the midface (midface hypoplasia). Complications can include sleep apnea or recurrent ear infections. Achondroplasia includes the extremely rare short-limb skeletal dysplasia with severe combined immunodeficiency.

Achondroplasia is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene (located in chromosome 4) that results in its protein being overactive. Achondroplasia results in impaired endochondral bone growth (bone growth within cartilage). The disorder has an autosomal dominant mode of inheritance, meaning only one mutated copy of the gene is required for the condition to occur. About 80% of cases occur in children of parents without the disease, and result from a new (de novo, or sporadic) mutation, which most commonly originates as a spontaneous change during spermatogenesis. The rest are inherited from a parent with the condition. The risk of a new mutation increases with the age of the father. In families with two affected parents, children who inherit both affected genes (for which there is a 25% chance) typically die before birth or in early infancy from breathing difficulties. The condition is generally diagnosed based on the clinical features but may be confirmed by genetic testing. Mutations in FGFR3 also cause achondroplasia-related conditions including hypochondroplasia and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans), a rare disorder of bone growth characterized by skeletal, brain, and skin abnormalities resulting in severe short-limb skeletal dysplasia with severe combined immunodeficiency.