Achondroplasia

Achondroplasia represents the most common genetic cause of dwarfism and the most prevalent skeletal dysplasia, characterized by severe, disproportionate short stature. This condition accounts for more than 90% of cases of disproportionate short stature (ie, dwarfism). The term achondroplasia refers to impaired cartilage formation, resulting from a mutation in the transmembrane portion of fibroblast growth factor receptor-3 (FGFR3) identified between 1994 and 1995. The disorder follows an autosomal dominant inheritance pattern with full penetrance, although over 80% of cases arise from spontaneous mutations. Advanced paternal age serves as a known risk factor for these de novo mutations. Individuals with achondroplasia generally exhibit average intelligence and have a mean lifespan approximately 10 years shorter than the general population. Characteristic physical features include macrocephaly with frontal bossing, midface hypoplasia, rhizomelic shortening of the extremities, brachydactyly with a trident hand configuration, and bowed legs (genu varum). The condition carries increased early childhood mortality from brainstem compression, later otolaryngologic complications, and elevated risks of obesity and cardiovascular disease in adulthood. Affected individuals can also develop joint laxity, thoracolumbar kyphosis (TLK), and spinal stenosis that may progress and contribute to morbidity as an adult. Since 2021, vosoritide has been available as the first pharmacological precision treatment targeting the underlying pathophysiology of achondroplasia, representing a significant advance in disease-modifying therapy.