Identification of an ABCC8 variant in a kindred with transient diazoxide responsive hyperinsulinism.

Summary: Congenital hyperinsulinism is a rare disorder characterized by hypoglycemia and inappropriately elevated insulin levels. The genetics of congenital hyperinsulinism is complex, with the most common cause being pathogenic variants in the ATP-sensitive potassium channel. Depending on the parent of origin, patients may present with focal or diffuse hyperinsulinism. Typically, patients with focal hyperinsulinism are non-responsive to diazoxide and likely progress to surgical therapy. However, there can be exceptions to these rules. We evaluated two siblings with congenital hyperinsulinism. Genetic testing identified a paternally inherited variant in ABCC8. One sibling had significant neonatal hypoglycemia requiring diazoxide for several years before weaning off daily diazoxide, whereas the second sibling experienced transitional hypoglycemia in the neonatal period but only requires diazoxide therapy during periods of intercurrent illness. This case highlights the importance of genetic testing for congenital hyperinsulinism. Learning points: The most common genetic cause of hyperinsulinism is gain-of-function variants in ABCC8 and KCNJ11, which make up the ATP-sensitive potassium channel (KATP). First-degree relatives of affected individuals should be considered for genetic testing. Parent-of-origin testing should be done to determine if the patient is likely to have focal or diffuse hyperinsulinism. Diazoxide is helpful for many patients with diffuse hyperinsulinism, and some patients with focal hyperinsulinism.