A couple's child is born with thanatophoric dysplasia (lethal skeletal dysplasia). Neither parent has skeletal disease. Which of the following mechanisms best explains the high recurrence risk?
- A De novo gain-of-function mutations in FGFR3; recurrence risk is low but parental mosaicism may rarely increase it ✓
- B Autosomal recessive inheritance; each future pregnancy has 25% risk
- C X-linked inheritance; 50% of male offspring affected
- D Chromosomal translocation in one parent; empiric recurrence risk ~10%
Correct answer: A. De novo gain-of-function mutations in FGFR3; recurrence risk is low but parental mosaicism may rarely increase it
Explanation
Thanatophoric dysplasia is caused by de novo gain-of-function mutations in FGFR3 (most commonly R248C or K650E), constitutively activating FGFR3 signaling and severely inhibiting enchondral bone growth, leading to a lethal skeletal dysplasia. Since these are new mutations (parents are unaffected), the recurrence risk in future pregnancies is very low (<1%) based on new mutations — unless a parent carries a germline mosaic mutation, which slightly increases risk. Achondroplasia (also FGFR3 gain-of-function, Gly380Arg) is non-lethal and autosomal dominant.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.