Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism

Abstract

BackgroundCongenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8,KCNJ11,GLUD1,GCK,HADH,SLC16A1,HNF4AandHNF1A) are known to cause CHI.AimTo characterise the clinical and molecular aspects of a large cohort of patients with CHI.MethodologyThree hundred patients were recruited and clinical information was collected before genotyping.ABCC8andKCNJ11genes were analysed in all patients. Mutations inGLUD1,HADH,GCKandHNF4Agenes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A).ResultsMutations were identified in 136/300 patients (45.3%). Mutations inABCC8/KCNJ11were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations inABCC8/KCNJ11were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in theABCC8/KCNJ11genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations inABCC8/KCNJ11(n=15),HNF4A(n=7),GLUD1(n=16) andHADH(n=3).ConclusionsA genetic diagnosis was made for 45.3% of patients in this large series. Mutations in theABCC8gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.