An otherwise healthy couple of average height has a newborn with rhizomelic shortening of the limbs, a large head with a prominent forehead, midface hypoplasia, and trident hand. Radiographs show narrow spinal canal and short long bones with flared metaphyses. The molecular basis involves:
- A Loss-of-function mutation in FGFR3 leading to unregulated cartilage proliferation
- B Gain-of-function mutation in FGFR3 constitutively inhibiting chondrocyte proliferation, usually arising de novo in the paternal allele ✓
- C Defective type II collagen synthesis from a COL2A1 mutation
- D Mutation in COMP causing abnormal cartilage matrix accumulation
Correct answer: B. Gain-of-function mutation in FGFR3 constitutively inhibiting chondrocyte proliferation, usually arising de novo in the paternal allele
Explanation
Achondroplasia results from activating mutations in FGFR3, almost always the same Gly380Arg substitution, which cause ligand-independent receptor signaling that inhibits chondrocyte proliferation in the growth plate. It is autosomal dominant, but most cases represent new mutations, with a strong paternal age effect because the mutations arise during spermatogenesis. Defective COL2A1 gives spondyloepiphyseal dysplasia, and COMP mutations give pseudoachondroplasia.
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.