Endocrine Abstracts

Background: Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in seven genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1 and HNF4A) are known to cause CHI.

Aim: To characterise the clinical and molecular aspects of a large cohort of patients with CHI.

Methodology: 300 patients with biochemically confirmed CHI were recruited. Detailed clinical information was collected prior to genotyping. ABCC8 and KCNJ11 genes were sequenced in all patients with diazoxide unresponsive CHI. Mutations in the GCK, GLUD1 and HADH genes were sought in patients with diazoxide responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyryl-carnitine (HADH) or positive family history with delayed presentation (GCK). If no mutations were identified and in all other patients with diazoxide responsive CHI; ABCC8, KCNJ11 and HNF4A genes were sequenced.

Results: Mutations were identified in 146/300 patients (48.6%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=117, 39%). Among diazoxide unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92(87.6%); of whom 63 patients had recessively inherited mutations while four patients had novel dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide unresponsive patients; of whom 7 had diffuse disease. Among the diazoxide responsive patients (n=183), mutations were identified in 51 patients. These include mutations in the ABCC8 (n=25), KCNJ11 (n=3), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3).

Conclusions: A genetic diagnosis was possible in 48.6% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide responsive CHI (72%) had no mutations identified. Understanding the genetic aetiology of CHI in this large cohort of patients will provide novel insights into pancreatic beta-cell physiology and have implications for hypoglycaemia and diabetes mellitus.