Hypochondroplasia - FGFR3

Clinical Features

Achondroplasia is the most frequent form of skeletal dysplasia and is characterized by disproportionate dwarfism and, more importantly, by rhizomelic shortening of the limbs. The disease is caused by enchondral ossification of the long bones and of the base of the skull. Short extremities, a large head with frontal bossing and midface hypoplasia are often noted at birth or even prenatally.

At early school age, children with hypochondroplasia exhibit a slightly disproportionate short stature with a relatively long narrow trunk and short extremities along with short and broad hands and feet.

Genetic Information

Achondroplasia and hypchondroplasia are inherited in an autosomal dominant manner and are caused by several distinct mutations in the gene encoding FGFR3 (fibroblast growth factor receptor 3) gene on chromosome 4 (4p16.3). Approximately 80 % of the cases are caused by de novo mutations in the FGFR3 gene with the mutation rate being clearly correlated to the father's age.

Approximately 96 % of patients with achondroplasia show a point mutation from G->A or G->C at nucleotide position 1138 of the FGFR3 gene. Both alterations result in the same amino acid substitution G380R (glycine to arginine).

In about 80 % of patients with hypochondroplasia, mutations of the FGFR3 gene can be identified. In about 70% of patients, a mutation affects the amino acid at position 540, mostly resulting in the amino acid exchange N540K. Less frequently, mutations K650N, K650Q, and I538V are found.