ESPE Abstracts

The ATP-sensitive potassium (KATP) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function variants in either the regulatory (sulfonylurea receptor 1, encoded by ABCC8) or the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.2], encoded by KCNJ11) subunits result in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause neonatal diabetes. Patients with two recessive loss-of-function variants in ABCC8 typically have severe diffuse forms of CHI unresponsive to diazoxide. Patients with hypoglycemia in infancy due to a dominant or mild recessively-inherited variants have been reported to occasionally progress to diabetes later in life. Herein, we report an adolescent boy who was diagnosed with diazoxide-unresponsive CHI in the neonatal period, treated with octreotide until the age of three years and then he developed diabetes at the age of 13 years. His BMI was 28.8 kg/m² (97.5^th percentile), HbA1C 12% and Anti- GAD was negative. A glycemic control was achieved with metformin and diet. His 7-year old younger brother, BMI 20.5 kg/m² (96^th percentile) who also had severe CHI and stopped octreotide therapy at age of three years had HbA1C of 5.8% indicating prediabetes. Both brothers were found to be homozygous for a novel, likely pathogenic ABCC8 missense p.(Cys26Tyr) (c.77G>A) variant. The parents were heterozygous carriers. Multiple missense variants substituting the cysteine at residue 26 have been proven to affect the maturation and hence the function of SUR1 subunit of KATP channel supporting the pathologic nature of this novel variant and the essential role of cysteine at that position in the ABCC8 gene. Functional analyses are being conducted to evaluate the role of the variant in vitro for better understanding of the underlying molecular mechanism and phenotype-genotype relationships. Here we report a novel homozygous ABCC8 variant p.(Cys26Tyr) resulting in a severe CHI phenotype in two brothers. Our data support the increasing evidence that individuals with loss-of-function KATP channel mutations may develop diabetes in late childhood. The severe CHI phenotype is peculiar to this report emphasizing the significance of genetic analyses for CHI patients and the importance of long-term follow up of medically treated patients with ABCC8 -CHI for the risk of developing diabetes in later life.