Background Neonatal diabetes (NDM) is a rare condition and presents within the first 6 months of life (1 in 90,000-160,000 births). Traditionally treated with lifelong insulin, recent genetic findings point to oral sulfonylurea responsive mutations in KCNJ11 and ABCC8 genes, offering improved glycemic control and quality of life.

Case Report(s) This case series presents five infants from The Aga Khan University Hospital Karachi with NDM of varying clinical manifestations. Four of them experienced severe DKA within their first month, while one showed failure to thrive at six months. All infants had negative family histories of early neonatal/infant death or genetic diabetes, with four born to consanguineous parents. Most were full-term with uneventful pregnancies, except for one born late preterm with low birth weight due to Gestational Diabetes. Elevated HbA1c levels (6.7–16%) and below-normal C-peptide levels were observed at the presentation. Following DKA management with subcutaneous insulin (1.3–2.3 units/kg/day), genetic testing at the University of Exeter identified KCNJ11 mutations in four patients and a novel ABCC8 mutation in one. All successfully transitioned to oral Glibenclamide upon molecular diagnosis. Initial discharge doses ranged from 0.8 to 1.0 mg/kg/day and were later adjusted due to hypoglycemia. Neurodevelopmental assessments using the Bayley III scale showed normal progress, except for the Small for Gestational Age (SGA) infant, who displayed delays in motor skills and cognition. Overall, all patients achieved excellent glycemic control (HbA1c < 6.7%).

Conclusion(s) Genetic testing should be sought in all patients with neonatal diabetes as oral Sulfonylurea is a safe and effective treatment option in patients with KCNJ11 and ABCC8 mutations. The identification of a novel mutation in ABCC8 underscores the potential genetic diversity in NDM, particularly within the Pakistani population.