Genetic Analysis of Italian Patients with Congenital Hyperinsulinism of Infancy

TLDR

In children with congenital hyperinsulinism, rapid screening of K(ATP) channel genes (ABCC8 and KCNJ11) is possible for pathogenic mutations. The study aimed to evaluate how rapid genetic testing influences clinical management of CHI. A follow‑up observational study at two referral hospitals assessed 101 CHI children for outcomes such as subtotal pancreatectomy, (18)F‑Dopa PET‑CT scanning, medical stability, and remission. Among the cohort, 32 % carried pathogenic K(ATP) channel mutations (27 ABCC8, 5 KCNJ11, 11 novel); homozygous/compound heterozygous mutations were associated with a 70 % subtotal pancreatectomy rate, paternal heterozygous mutations prompted PET‑CT and led to focal lesionectomy in 54 %, maternal heterozygous mutations achieved 100 % remission, while 65 % of mutation‑negative patients remitted, 33 % remained medically stable, and only one required pancreatectomy.

Abstract

In children with congenital hyperinsulinism (CHI), K(ATP) channel genes (ABCC8 and KCNJ11) can be screened rapidly for potential pathogenic mutations. We aimed to assess the contribution of rapid genetic testing to the clinical management of CHI.Follow-up observational study at two CHI referral hospitals.Clinical outcomes such as subtotal pancreatectomy, (18)F-Dopa positron emission tomography-computed tomography (PET-CT) scanning, stability on medical treatment and remission were assessed in a cohort of 101 children with CHI.In total, 32 (32%) children had pathogenic mutations in K(ATP) channel genes (27 in ABCC8 and five in KCNJ11), of which 11 (34%) were novel. In those negative at initial screening, other mutations (GLUD1, GCK, and HNF4A) were identified in three children. Those with homozygous/compound heterozygous ABCC8/KCNJ11 mutations were more likely to require a subtotal pancreatectomy CHI (7/10, 70%). Those with paternal heterozygous mutations were investigated with (18)F-Dopa PET-CT scanning and 7/13 (54%) had a focal lesionectomy, whereas four (31%) required subtotal pancreatectomy for diffuse CHI. Those with maternal heterozygous mutations were most likely to achieve remission (5/5, 100%). In 66 with no identified mutation, 43 (65%) achieved remission, 22 (33%) were stable on medical treatment and only one child required a subtotal pancreatectomy.Rapid genetic analysis is important in the management pathway of CHI; it provides aetiological confirmation of the diagnosis, indicates the likely need for a subtotal pancreatectomy and identifies those who require (18)F-Dopa PET-CT scanning. In the absence of a mutation, reassurance of a favourable outcome can be given early in the course of CHI.