Clinical and genetic characterization of congenital hyperinsulinism in Spain

Abstract

Context: Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease characterized by severe hypoglycemia caused by inappropriate insulin secretion by pancreatic β-cells. Objective: To characterize clinically and genetically CHI patients in Spain. Design and methods: We included 50 patients with CHI from Spain. Clinical information was provided by the referring clinicians. Mutational analysis was carried out for KCNJ11, ABCC8, and GCK genes. The GLUD1, HNF4A, HNF1A, UCP2, and HADH genes were sequenced depending on the clinical phenotype. Results: We identified the genetic etiology in 28 of the 50 CHI patients tested: 21 had a mutation in K ATP channel genes (42%), three in GLUD1 (6%), and four in GCK (8%). Most mutations were found in ABCC8 (20/50). Half of these patients (10/20) were homozygous or compound heterozygous, with nine being unresponsive to diazoxide treatment. The other half had heterozygous mutations in ABCC8, six of them being unresponsive to diazoxide treatment and four being responsive to diazoxide treatment. We identified 22 different mutations in the K ATP channel genes, of which ten were novel. Notably, patients with ABCC8 mutations were diagnosed earlier, with lower blood glucose levels and required higher doses of diazoxide than those without a genetic diagnosis. Conclusions: Genetic analysis revealed mutations in 56% of the CHI patients. ABCC8 mutations are the most frequent cause of CHI in Spain. We found ten novel mutations in the K ATP channel genes. The genetic diagnosis is more likely to be achieved in patients with onset within the first week of life and in those who fail to respond to diazoxide treatment.

The difficult management of persistent, non‐focal congenital hyperinsulinism: A retrospective review from a single, tertiary center

“…Genetic mutations were found in 53% of our patients, consistent with some, but lower compared to other referral centers, possibly reflecting variations in referral patterns and inclusion/exclusion criteria, and advances in gene analysis methods. The importance of referral patterns was also seen by the fact that our non‐Scandinavian patients more often had highly severe disease compared to Scandinavians.…”

Clinical Management and Gene Mutation Analysis of Children with Congenital Hyperinsulinism in South China

“…The p.Ser498Leu mutation was found in patient 52 and the p.Asn463Asp mutation was found in patient 53. All mutations have been previously reported in patients with HI/HA (26,27,28,29). The serum ammonia concentration of this group of patients was 85-184 μmol/l.…”

Therapies and outcomes of congenital hyperinsulinism‐induced hypoglycaemia

“…In those children who are medically responsive, the severity of the disease decreases over time and remission may be achieved. Genetic forms of CHI are less likely to resolve than forms without identified CHI-causing mutations; however, reduction in severity and resolution is also observed in conservatively treated children with K ATP channel gene mutations [12,23,54,55], not only in those with dominantly acting ABCC8/KCNJ11 mutations, but also in those with homozygous, compound heterozygous and paternally inherited ABCC8/KCNJ11 mutations causing focal CHI [23,54]. Some children with transient CHI can develop ketotic hypoglycaemia [53] at a later stage, which should be differentiated from hypoglycaemia caused by persistent hyperinsulinism.…”