A 3-month-old boy presents with progressive developmental delay and episodes of central apnoea during sleep. Examination reveals macrocephaly with frontal bossing, midface hypoplasia, and rhizomelic shortening of the limbs. The infant's father is 42 years old and has normal stature. Molecular testing confirms a de novo heterozygous G380R mutation in FGFR3 on chromosome 4p16.3. The condition marked **A** in the diagram is suspected. Which of the following best explains the molecular basis of the growth restriction in this infant?

Question

Accepted Answer

D. FGFR3 gain-of-function mutation causing constitutive activation and suppression of chondrocyte proliferation at the growth plate. ## Why option 1 is correct

The structure marked **A** — achondroplasia caused by FGFR3 gain-of-function mutation — results from constitutive activation of FGFR3, a transmembrane tyrosine-kinase receptor that normally *negatively regulates* chondrocyte proliferation and endochondral ossification. The G380R missense mutation (the recurrent mutation in >99% of achondroplasia cases) in the transmembrane domain causes ligand-independent activation, leading to unopposed MAPK signalling that suppresses cartilage proliferation and causes premature growth-plate closure. This explains the rhizomelic shortening (proximal segments disproportionately short) and growth restriction observed in this infant. The de novo mutation in an unaffected father aged 42 years is consistent with the striking paternal age effect seen in achondroplasia, arising from selective propagation of mutant spermatogonia during spermatogenesis (Horton, Hall & Hecht Lancet 2007).

## Why each distractor is wrong

- **Option 2**: Loss-of-function mutations in FGFR3 would impair growth factor signalling and are not the basis of achondroplasia; achondroplasia is caused by *gain*-of-function, not loss-of-function. This describes a different genetic mechanism entirely.
- **Option 3**: COL2A1 mutations cause spondyloepiphyseal dysplasias and type II collagenopathies, not achondroplasia. While both affect cartilage, the molecular basis is distinct — COL2A1 affects matrix structure, whereas FGFR3 affects growth-plate signalling.
- **Option 4**: Defective FGF23 signalling causes X-linked hypophosphataemic rickets (marked **C** in the diagram), characterized by phosphate wasting and rickets, not the rhizomelic dwarfism and growth-plate suppression seen in achondroplasia.

**High-Yield:** Achondroplasia = FGFR3 *gain*-of-function (constitutive activation) → suppressed chondrocyte proliferation → premature growth-plate closure → rhizomelic dwarfism; >99% cases carry the same G380R mutation; ~80% are de novo with paternal age effect (fathers >35 years).

[cite: Horton, Hall & Hecht Lancet 2007; FDA Vosoritide Label 2021]

Answer

A. Defective collagen type II synthesis due to COL2A1 mutation affecting cartilage matrix formation

Answer

B. Loss-of-function mutation in FGFR3 impairing fibroblast growth factor signalling in osteoblasts

Answer

C. Impaired calcium-phosphate metabolism from defective FGF23 signalling in renal tubules

Explanation

Why option 1 is correct

Why each distractor is wrong

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