ESPE Abstracts

Introduction: Congenital hyperinsulinism (CHI) is a disorder of pancreatic beta-cells characterized by inappropriate secretion of insulin leading to hyperinsulinemic hypoglycemia. Insulin secretion is a complex, genetically regulated process. Mutations in several genes known to regulate insulin secretion result in CHI. Recently, non-coding mutations in HK1, which cause the aberrant expression of hexokinase 1 (HK1) in beta cells, have been reported as a novel cause of CHI in 17 individuals. In the initial publication the median birthweight was 0.61SDS [IQR: 0.10-1.84] and 5/17 cases required pancreatic surgery.

Case Report: A 5-month-old girl [FS1] was referred to pediatric endocrinology department with diagnosis of severe hypoglycemia (0.8mmol/l) following an epileptic episode. She underwent an EEG, brain MRI and started with anti-epileptic therapy. Further investigations confirmed that the seizures were due to severe hypoglycemic episodes. A diagnosis of CHI was confirmed based on inappropriately high[FS2] insulin level (7.74mlU/ml) during <2.8mmol/l hypoglycemia (1.1mmol/l), and treatment with diazoxide was initiated. Genetic analysis of the KCNJ11, ABCC8, GLUD1, GCK, HADH, HNF4A, INSR, KDM6A, KMT2D, SLC16A1, CACNA1D, PMM2, TRMT10A and HNF1A genes by targeted next generation sequencing did not identify a disease-causing variant. The patient’s sample was subsequently screened for HK1 mutations and a novel heterozygous variant (g.71,108,654A>C) was identified within the critical regulatory region. The variant was not present in the sample from the unaffected mother, a sample from the unaffected father was not available for testing. This case shows an early onset of severe, symptomatic, diazoxide-sensitive hypoglycemia and seizure episodes in a girl with a novel HK1 mutation.

Conclusion: The present case represents one of the first reports of CHI due to a HK1 mutation and provides new insights into the clinical manifestations associated with this genetic subtype. Further research is needed to investigate the clinical presentation and the natural course of HK1-CHI in comparison with other known molecular-genetic basis of CHI.