Achondroplasia is recognized as the most frequent form of disproportionate short stature in humans, impacting approximately 1 in 15,000 to 1 in 25,000 live births globally. This condition is characterized by a distinctive pattern of growth, primarily affecting the long bones of the limbs, leading to shorter arms and legs, particularly in the upper arm and thigh regions. The head may appear larger than average with a prominent forehead, and the midface can appear flattened.
The Chromosomal Link
Achondroplasia is directly linked to a specific location on human chromosome 4. This chromosome carries the Fibroblast Growth Factor Receptor 3, or FGFR3, gene, which plays a significant role in regulating bone growth and development. The gene is situated on the short arm of chromosome 4, at position 16.3 (4p16.3).
The FGFR3 gene provides instructions for making a protein that functions as a receptor on the surface of cells, particularly those involved in bone formation. This protein is a receptor for fibroblast growth factors, signaling molecules that influence cellular processes. In normal bone development, the FGFR3 protein helps regulate the growth of cartilage, which is later replaced by bone through a process called endochondral ossification. This process is responsible for the formation of most bones in the body, starting before birth and continuing into early adulthood.
The Genetic Mutation
The underlying cause of achondroplasia is a specific change within the FGFR3 gene. Over 97% of achondroplasia cases result from a precise point mutation known as G380R. This mutation involves a single nucleotide substitution, where a guanine (G) nucleotide is replaced by an adenine (A) nucleotide at position 1138 of the gene, or less commonly, a guanine (G) is replaced by a cytosine (C) at the same position.
The G380R mutation leads to a glycine-to-arginine substitution at amino acid position 380 in the protein’s transmembrane domain. This alteration causes the FGFR3 protein to become overactive. Instead of regulating bone growth, the mutated protein constantly inhibits the proliferation and differentiation of chondrocytes (cartilage cells). This premature and excessive inhibition of cartilage growth severely impairs the endochondral ossification process, particularly in the long bones, resulting in the characteristic short stature seen in individuals with achondroplasia.
Inheritance and Genetic Counseling
Achondroplasia follows an autosomal dominant inheritance pattern; only one copy of the altered FGFR3 gene is sufficient to cause the condition. If an individual has achondroplasia, there is a 50% chance they will pass the condition on to each of their children. However, a substantial majority of achondroplasia cases, approximately 80%, arise from a de novo, or new, mutation in individuals whose parents do not have the condition.
These spontaneous mutations often occur during the formation of sperm cells, and there is an observed association with increased paternal age. For families where achondroplasia has occurred due to a de novo mutation, the parents typically have no increased risk of having another child with the condition. Genetic counseling plays a role in helping individuals and families understand the inheritance patterns, assess recurrence risks, and explore reproductive options.