A couple's first child is born with rhizomelic shortening of the limbs, macrocephaly with a prominent forehead, midface hypoplasia, and trident configuration of the hands. Radiographs show narrow interpedicular distances in the lumbar spine. Both parents are of normal stature. Which statement about the causative defect is correct?

• A Loss-of-function FGFR3 mutation inherited from a parent of advanced age
• B Gain-of-function FGFR3 mutation arising de novo, associated with advanced paternal age ✓
• C Defective type II collagen from COL2A1 mutation with autosomal recessive inheritance
• D Impaired endochondral ossification due to SHH haploinsufficiency

Explanation

Achondroplasia, the most common skeletal dysplasia causing dwarfism, results from activating (gain-of-function) mutations in FGFR3, nearly always the Gly380Arg substitution. Constitutive receptor signaling inhibits chondrocyte proliferation in the growth plates, selectively impairing endochondral ossification while sparing membranous ossification, hence the normal skull vault and face base mismatch. About 80% of cases are sporadic de novo events, and de novo mutation rates rise with advanced paternal age, analogous to Apert syndrome. COL2A1 defects produce spondyloepiphyseal dysplasias, not achondroplasia.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.