A 14-year-old lean boy has fasting glucose of 132 mg/dL and HbA1c of 7.6%. His father and paternal grandmother developed diabetes before age 25 without obesity. Anti-GAD and anti-islet cell antibodies are negative, C-peptide is preserved, and ketosis has never occurred despite 3 years of mild hyperglycaemia. Which genetic defect is most likely?
- A WFS1 mutation causing Wolfram syndrome
- B KCNJ11 mutation causing permanent neonatal diabetes
- C HNF1A mutation (MODY 3) ✓
- D INS gene mutation
Correct answer: C. HNF1A mutation (MODY 3)
Explanation
Autosomal dominant transmission across three generations, onset in adolescence, absence of autoantibodies, preserved A-peptide, and non-ketotic mild hyperglycaemia define maturity-onset diabetes of the young. HNF1C (MODY 3) is the commonest form and is highly sensitive to sulfonylureas. KCNJ11 mutations present in the first six months of life, not adolescence. Wolfram syndrome includes optic atrophy and deafness, and INS mutations typically cause earlier, more severe diabetes.
Reference: ISPAD Clinical Practice Consensus Guidelines, 2022 ed.
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Written and medically reviewed by the StethoPrep medical team.