A 2-year-old boy born to unaffected parents presents with short stature. On examination, he has a relatively large head with frontal bossing, a depressed nasal bridge, and notably short upper arms and thighs compared to his forearms and lower legs. The structure marked **A** in the diagram shows disproportionate rhizomelic shortening of the proximal limbs. Which of the following genetic mechanisms best explains this clinical presentation?

Explanation

## Why Gain-of-function FGFR3 mutation is right The clinical presentation—disproportionate rhizomelic shortening (marked **A**), macrocephaly with frontal bossing, midface hypoplasia, and normal intelligence—is pathognomonic for achondroplasia. The most common form of disproportionate short stature (skeletal dysplasia), achondroplasia results from a gain-of-function mutation in the FGFR3 gene on chromosome 4p16.3. This mutation causes the fibroblast growth factor receptor 3 to become constitutively active, which paradoxically *inhibits* endochondral ossification at the growth plate. This selective impairment of long bone growth explains why proximal limbs (humerus and femur) are disproportionately shortened compared to forearms and legs—the hallmark of rhizomelic shortening. The de novo nature of the mutation (80% of cases) and unaffected parents fit this patient perfectly (Nelson 21e Ch 711; Robbins 10e Ch 26). ## Why each distractor is wrong - **Loss-of-function COL2A1 mutation**: This causes achondrogenesis type II and hypochondrogenesis, which present with severe, generalized short stature and are usually lethal in utero or early infancy. The pattern is not rhizomelic and the phenotype is much more severe. COL2A1 mutations do not produce the classic achondroplasia phenotype. - **Autosomal recessive DTDST mutation**: This causes diastrophic dysplasia, characterized by short stature, clubfoot, cleft palate, and joint contractures. While disproportionate, the pattern is not rhizomelic, and the clinical features (especially clubfoot and cleft palate) are absent in this case. DTDST affects sulfate transport, not growth factor signaling. - **X-linked PHEX mutation**: This causes X-linked hypophosphatemic rickets (XLH), which presents with short stature, bowing of legs, and dental problems due to impaired phosphate metabolism. The stature is proportionate or shows lower-limb predominance (not rhizomelic), and rickets is a key feature absent here. **High-Yield:** Achondroplasia = gain-of-function FGFR3 (not loss-of-function) → constitutively active receptor → inhibits growth plate ossification → rhizomelic shortening (proximal > distal). 80% de novo; normal intelligence; screen for foramen magnum stenosis in infancy. [cite: Nelson 21e Ch 711; Robbins 10e Ch 26]