Endocrine Abstracts

Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease. The clinical heterogeneity may range from mild subtle hypoglycaemia to severe life threatening hypoglycaemia. The commonest genetic cause of congenital hyperinsulinism are mutations in the genes ABCC8 and KCNJ11 encoding the two subunits (SUR1 and Kir6.2 respectively) of the pancreatic β-cell K_ATP channel. In the Ashkenazi Jewish population two founder mutations in the ABCC8 gene account for about 88% cases of CHI, with the splicing (c.3992-9G>A) mutation being the most prevalent. We report a family with marked intrafamilial clinical variation in four haploidentical siblings who have the same homozygous c.3992-9G>A mutation in the ABCC8 gene. This clinical heterogeneity ranged from having no symptoms of hypoglycaemia to having macrosomia, transient hyperinsulinism to severe hyperinsulinism and then gradual improvement over time followed by development of diabetes mellitus. It is unclear how the same mutation causes such marked clinical heterogeneity. It is possible that the clinical expression may be modified by background genetic factors and other unknown factors involved in regulating gene expression.