An infant has rhizomelic shortening of the limbs, a large head with a prominent forehead and depressed nasal bridge, and trident hand. Radiographs show short tubular bones with flared metaphyses and a narrow thorax. Both parents are of normal stature. The molecular basis of this skeletal dysplasia is:

• A Loss-of-function mutation in FGFR3 reducing receptor signaling
• B Defect in sulfate transporter leading to defective proteoglycan synthesis
• C Mutation in COL2A1 impairing type II collagen fibril formation
• D Gain-of-function mutation in FGFR3 causing constitutive activation of the receptor ✓

Explanation

Achondroplasia is an autosomal dominant dwarfism caused almost universally by a gain-of-function missense mutation in FGFR3 (glycine to arginine at position 380). Constitutive FGFR3 signaling inhibits chondrocyte proliferation in the growth plate, suppressing endochondral ossification while membranous ossification proceeds normally, giving the large calvarium with small skull base. Most cases are sporadic new mutations, consistent with unaffected parents. Diastrophic dysplasia involves the sulfate transporter SLC26A2.

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.