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, HNF4A and HNF1A) 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. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes 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 in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were 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 the ABCC8/KCNJ11 genes 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 in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3).ConclusionsA genetic diagnosis was made for 45.3% 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 (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

“…Mutations in the ABCC8/KCNJ11, which account for the majority of genetically confirmed CHI cases, can either be biallelic or monoallelic (3,4,37). Biallelic ABCC8/KCNJ11 mutations result in diffuse CHI, whereas monoallelic mutations can either be asymptomatic (38).…”

“…Mutations in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, subunits: Kir6.2 encoded by KCNJ11 and SUR1 encoded by ABCC8 gene (2). Both genes are localised in the 11p15.1 region and mutations in these accounts for the majority of CHI patients (3,4,5,6,7,8,9,10,11).…”

“…In diffuse CHI, histologically there is an increase in the b-cell nuclear size throughout the pancreas. Diffuse CHI is genetically heterogeneous and most commonly due to mutations in ABCC8 or KCNJ11 genes (3,12,13,14,15). Diazoxide, an agonist that targets the SUR1 subunit, is usually ineffective in patients with autosomal recessive form of ABCC8 or KCNJ11 mutations.…”

“…Furthermore, diffuse disease can either be diazoxide-responsive or unresponsive depending on the underlying molecular basis of the mutation and other unclear genetic or environmental influences (28). There are isolated case reports of heterozygous paternally inherited ABCC8/ KCNJ11 mutations leading to diffuse CHI in the literature (3,10,29,30). The proportion of patients with paternally inherited heterozygous ABCC8/KCNJ11 mutations who develop focal CHI has not been reported in any study so far.…”

Comprehensive screening shows that mutations in the known syndromic genes are rare in individuals presenting with hyperinsulinaemic hypoglycaemia

“…Routine screening of these genes using a combination of rapid Sanger sequencing and targeted next generation sequencing identifies a mutation in approximately 40-50% of cases with persistent HH [4]. This suggests that further genetic aetiologies remain to be discovered.…”