Congenital hyperinsulinism due to NEUROD1 gene mutation

To the editor, Congenital hyperinsulinism (CHI) is a rare disease, but most frequent of persistent hypoglycemia in infants and children.CHI is caused by unregulated insulin secretion by the pancreatic cells.In these patients, recurrent episodes of hyperinsulinemic hypoglycemia lead to significant risk of permanent brain damage [1].Usually, CHI is clinically diagnosed when plasma insulin levels exceeded 2 U/ mL, despite a blood glucose concentration of <50 mg/dL, free fatty acids (FFA) <1.7 mmol/L, -hydroxybutyrate <1.8 mmol/L, and a glycemic response to glucagon >30 mg/dL [2].Transient hyperinsulinemic hypoglycemia usually resolves on its own within a few days or months [3,4].A prompt diagnosis of CHI and immediate management of glucose levels is critical to prevent complications such as epilepsy, cerebral palsy and neurodevelopmental deficits [1,3,4].Disease-causing variants in 16 different genes have been reported to cause isolated CHI.Recently, advances in genetic analysis technology have made improved accessibility to genetic diagnosis, as a result, more new genes causing CHI are continuously being identified.According to recent studies, FOXA2, CACNA1D and EIF2S3 gene mutations have been considered as a cause of CHI [4].These can be classified into defects in genes encoding the pancreatic ATP sensitive potassium channels (ABCC8 and KCNJ11) and other channels/transporter proteins (KCNQ1, CACNA1D and SLC16A1), enzymatic gene defects (GLUD1, GCK, HADH, UCP2, HK1, PMM2 and PGM1) and defects in genes encoding the transcription factors (HNF1A, HNF4A, FOXA2 and EIF2S3) [4].Herein, we report a case of CHI with a novel heterozygous variant in NEUROD1 detected by next-generation sequencing (NGS) panels associated with CHI.A 3-day-old girl presented with hypoglycemia for 4 days.She was delivered via cesarean section at a gestational age of 39 +2 weeks and had a birth weight of 3.0 kg (30.2 percentile).Her mother had no gestational diabetes.She was diagnosed with transient tachypnea of the newborn immediately after birth and received high-flow nasal cannula therapy.On the third day post-birth, hypoglycemia developed, and intravenous fluids were administered with a glucose infusion rate of 13.3 mg/kg/ min.Laboratory findings during the hypoglycemic episode (44 mg/dL) revealed plasma insulin of 3.5 U/mL, FFA levels of 0.198 mmol/L, and negative ketones, fulfilling the diagnostic criteria for CHI.Diazoxide therapy was initiated at a dose of 10 mg/kg/day for 2 days, followed by a reduction to 6.75 mg/kg/day, which resulted in effective blood glucose control.The medication was discontinued after 70 days without any side effects except for mild hirsutism, with sustained euglycemia observed postdiscontinuation.NGS panel test was conducted in the patient at the diagnosis of CHI, resulting in the NEUROD1 gene variant,c.79C>T,p.Leu27Phe (NM_002500.4).This variant was initially classified into variant of uncertain significance.Minor allele frequency of the variant is estimated to be 0.0008% (gnomAD).In silico analysis predicted the p.Leu27Phe is disease-causing variant