Different clinical courses of monogenic diabetes in childhood

Abstract

Introduction: Neonatal diabetes mellitus (NDM) is a rare monogenic form of diabetes defined by its onset within the first 6 months of life. Variants in KCNJ11 or ABCC8 genes are major causes of NDM, and can also result in milder, late-onset forms of diabetes. These genes encode the adenosine triphosphate-sensitive potassium (K-ATP) channels, which are essential for the glucose-stimulated insulin secretion pathway. This case study highlights how clinical presentation varies with the specific genetic variants. Matherials and methods: A 5-month-old patient with a KCNJ11 variant presented with severe diabetic ketoacidosis requiring intensive care management. Laboratory tests revealed hyperglycaemia and severe metabolic acidosis (glucose: 777 mg/dL (43.1 mmol/L), hemoglobin A1c (HbA1c): 15% (140.4 mmol/mol), pH 6.9­–6.8, C-Reactive Protein (CRP): 163 mg/L (1552.4 mmol/L)). Initially, the patient was treated with intensive insulin therapy, fluids and antibiotics. Whole-exome sequencing (Centogene-Rostock, Germany) confirmed a heterozygous pathogenic variant in the KCNJ11 gene in both the patient and the mother. At 10 months, treatment was switched to sulfonylureas, resulting in normoglycemia. By comparison, a 15-year-old patient with an ABCC8 gene variant presented with weight gain, fatigue, ankle edema, and fasting glucose levels (126 mg/dL (7 mmol/L) and 129 mg/dL (7.2 mmol/L)) allowing to set the diagnosis of diabetes based on the diagnosis and classification of diabetes mellitus according Standards of Care in Diabetes, the position of Diabetes Poland 2025. At the endocrinology ward, laboratory tests showed HbA1c: 5.96% (42.0 mmol/mol), pH 7.39. Initially, the patient was started on metformin and recommended dietary changes. Due to improper blood glucose levels and a positive family history, genetic testing was performed at age 16, detecting a variant in the gene ABCC8. The patient had no typical clinical signs of hyperglycaemia. These contrasting cases highlight the broad spectrum of monogenic diabetes in children. Conclusions: While KCNJ11 variants are mostly associated with permanent neonatal diabetes, ABCC8 variants present as transient or permanent forms, possibly suggesting a less severe course of the disease. The significant phenotypic variety of the K-ATP channel demonstrates the wide range of clinical courses within NDM. Understanding the variability of clinical expression is essential for accurate diagnosis and targeted therapy.