- Carlos A Bacino, MD, FACMG
Carlos A Bacino, MD, FACMG
- Professor of Molecular and Human Genetics
- Baylor College of Medicine
Achondroplasia is the most common bone dysplasia in humans, with a prevalence of approximately 1 in 20,000 livebirths. It is an autosomal dominant condition caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. The most salient clinical features include disproportionate short stature (adult height is approximately 4 feet), long bone shortening that predominantly affects the proximal aspects of the upper and lower extremities (rhizomelic shortening), and macrocephaly. Patients with achondroplasia may have delayed motor development early on, but cognition is normal. There are a number of medical issues associated with this disorder.
The clinical findings, diagnosis, treatment options, and anticipatory guidance are discussed in this topic review. An overview of the diagnostic approach to skeletal dysplasias is presented in detail separately. (See "Skeletal dysplasias: Approach to evaluation".)
Patients with achondroplasia have gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene . Two specific mutations in the FGFR3 gene account for almost all cases of achondroplasia. These mutations occur at the same nucleotide in the FGFR3 gene, 1138G>A (98 percent) and 1138G>C (1 percent), in both cases resulting in a glycine-to-arginine substitution in amino acid 380 (p.Gly380Arg) in the transmembrane domain of the FGFR3 gene. This mutation permanently activates the FGFR3 receptor, inhibiting chondrocyte proliferation, which ultimately leads to impaired endochondral bone formation, growth restriction, bone shortening, and other skeletal anomalies .
Achondroplasia is inherited in an autosomal dominant manner. Approximately 80 percent of cases are the result of new (de novo) mutations, while the remaining are inherited. When both parents have achondroplasia, the risk to their children of having homozygous achondroplasia (a lethal condition) is 25 percent and of having achondroplasia is 50 percent.
Achondroplasia is characterized by distinctive craniofacial features, disproportionate short stature with rhizomelic shortening of the arms and the legs (picture 1), brachydactyly (shortening of the fingers and toes) (picture 2), kyphoscoliosis (figure 1), and accentuated lumbar lordosis. The craniofacial features and bone shortening are clearly present at birth. The craniofacial features include macrocephaly, frontal bossing, and midface retrusion. The nose is flattened out, often referred to as saddle nose deformity. The kyphoscoliosis can be seen from birth through infancy and typically decreases once the child starts to bear weight and ambulate. The lumbar lordosis is typically seen after ambulation starts at approximately 1.5 years of age.
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