Endocrine Abstracts

JOINT767

Introduction: Genetic variants in the ABCC8 gene, which encodes the sulfonylurea receptor 1 (SUR1) subunit of the ATP-sensitive potassium channel in pancreatic β-cells, have been associated with various clinical presentations, including hyperinsulinemic hypoglycemia (HH), transient or permanent neonatal diabetes mellitus (NDM), and maturity-onset diabetes of the young (MODY). The present study aims to evaluate the relationship between clinical presentations and the different variants detected in the ABCC8 gene.

Methods: The clinical, biochemical, and molecular data of patients diagnosed with HH, NDM, MODY, or insulin-dependent diabetes and managed at our pediatric endocrinology clinic between 1990 and 2024 were retrospectively reviewed. Only patients with identified ABCC8 gene variants were included in the analysis.

Results: The study analyzed 18 cases, comprising 12 with HH (Cases 1–12), 4 with permanent NDM (Cases 13–16), and 2 with MODY (Cases 17–18). Among the HH cases, 16. 6% (n = 2; Cases 1 and 2) had a histological diagnosis consistent with focal HH. Case 1, harboring a heterozygous c. 4114C>T(p. Gln1372Ter) variant, achieved remission following lesion resection. Case 2, with a heterozygous c. 2041-25G>A variant classified as a variant of uncertain significance (VUS), underwent subtotal pancreatectomy and achieved complete recovery. Autosomal recessive diffuse HH was identified in 33. 3% (n = 4; Cases 3–6), with variants including c. 3512del(p. Leu1171fs), c. 3643C>T(p. Arg1215Trp), c. 96C>A(p. Asn32Lys), and c. 2041-21G>A. Autosomal dominant diffuse HH accounted for 33. 3% (n = 4; Cases 7–10), associated with variants c. 3418G>T(p. Glu1140Ter), c. 4135G>A(p. Gly1379Ser), c. 1792C>T(p. Arg598Ter), and c. 4612-2A>G. Compound heterozygous variants were detected in 16. 6% (n = 2; Cases 11 and 12). Post-pancreatectomy diabetes developed in 25% of HH cases (n = 3; Cases 5, 6, and 7). Among the NDM cases, the identified variants included c. 2476C>T(p. Arg826Trp) (Case 13), c. 1144G>A(p. Glu382Lys) (Cases 14, 15), and compound heterozygous c. 1670T>G(p. Ile557Arg)/c. 3431G>T(p. Arg1145Leu) (Case 16). In the MODY group, Case 17 had a heterozygous c. 1616A>G(p. Tyr539Cys) variant, while Case 18 had a heterozygous c. 946G>A(p. Gly316Arg) variant.

Conclusion: Variants in the ABCC8 gene result in diverse clinical presentations, ranging from severe hypoglycemia to diabetes. In HH cases, modulating genetic and environmental factors may influence disease progression, with the potential for hyperglycemia in the long term due to β-cell dysfunction or surgical interventions. Early identification through molecular analysis is critical for disease progression, preventing complications, and personalized treatment approaches.